Ketorol^® Express (Tablets) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

Contact Information

DR. REDDY’S LABORATORIES LTD. (India)

ATC Code

M01AB15 (Ketorolac)

Active Substance

Ketorolac (Rec.INN registered by WHO)

Dosage Form

Ketorol® Express

Orally disintegrating tablets, 10 mg: 10 or 20 pcs.

Dosage Form, Packaging, and Composition

Orally disintegrating tablets, light yellow in color, round, flat, with a bevel, engraved with “I” on one side.

Excipients: microcrystalline cellulose (Avicel PH101), silicon dioxide, butylated hydroxyanisole, mannitol, crospovidone (type A), sucralose, peppermint flavor, quinoline yellow dye (E104), magnesium stearate.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

NSAIDs with pronounced analgesic action

Pharmacotherapeutic Group

Anti-inflammatory and antirheumatic agents; non-steroidal anti-inflammatory and antirheumatic agents; acetic acid derivatives and related substances

Pharmacological Action

NSAID, has a pronounced analgesic effect, possesses anti-inflammatory and moderate antipyretic action. The mechanism of action is associated with non-selective inhibition of the activity of COX – COX-1 and COX-2, which catalyze 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, with the analgesic effect due to the [-]S-form.

In terms of analgesic potency, Ketorolac is comparable to morphine, significantly exceeding other NSAIDs. The drug does not affect opioid receptors, does not depress respiration, does not cause drug dependence, and does not have sedative or anxiolytic effects.

After oral administration, the onset of analgesic action is noted after 1 hour, the maximum effect is achieved in 1-2 hours.

Pharmacokinetics

Absorption

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

Distribution

Plasma protein binding is 99%, in hypoalbuminemia the amount of free substance in the blood increases. The time to reach C_ss (0.39-0.79 µg/ml) with oral administration of 10 mg ketorolac 4 times/day (dose above subtherapeutic) is 24 hours. V_d is 0.15-0.33 l/kg.

Penetrates into breast milk: after the mother takes 10 mg of ketorolac, C_max 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 intestines (6%).

T_1/2 in patients with normal renal function is 2.4-9 hours after oral administration of a 10 mg dose.

With oral administration of a 10 mg dose, the total clearance is 0.025 l/h/kg.

Pharmacokinetics in special clinical cases

In patients with renal failure, the V_d of ketorolac may double, and the V_d of its R-enantiomer may increase by 20%.

T_1/2 increases in elderly patients and decreases in young patients. Impaired liver function does not affect T_1/2. In patients with impaired renal function, with 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.

With oral administration of a 10 mg dose, the total clearance in patients with renal failure (with plasma creatinine concentration of 19-50 mg/l) is 0.016 l/h/kg.

Not removed by hemodialysis.

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 the intensity of pain and inflammation at the time of use, does not affect the progression of the disease.

ICD codes

Dosage Regimen

Place the tablet on the tongue, where it will immediately begin to dissolve. Hold in the mouth for a few seconds until completely dissolved; if desired, it can be washed down with liquid.

Taking orally disintegrating tablets does not require mandatory drinking with water, does not affect increased saliva production, and allows the drug to be taken by patients with swallowing difficulties due to behavioral and neurological disorders.

Ketorol^® Express is used orally as a single dose or repeatedly depending on the severity of the pain syndrome.

A single dose is 10 mg; with repeated administration, it is recommended to take 10 mg up to 4 times a day, depending on the intensity 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.

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

When switching from parenteral administration of the drug to oral administration, the total daily dose of both dosage forms on the day of transition should not exceed 90 mg for patients aged 16 to 65 years and 60 mg for patients over 65 years 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.

Adverse Reactions

Definition of frequency of side effects: common (1-10%), uncommon (0.1-1%), rare (0.01-0.1%), very rare (< 0.01%) and frequency unknown, including individual reports.

From the digestive system: common (especially in elderly patients over 65 years of age with a history of erosive and ulcerative lesions of the gastrointestinal tract) – epigastric pain, diarrhea; uncommon – stomatitis, flatulence, constipation, vomiting, feeling of stomach fullness; rare – nausea, erosive and ulcerative lesions of the gastrointestinal tract (including with perforation and/or bleeding – abdominal pain, cramping or burning in the epigastric region, melena, vomiting resembling “coffee grounds”, nausea, heartburn), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.

From the urinary system rare – acute renal failure, 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 sensory organs rare – hearing loss, tinnitus, visual impairment (including blurred vision); frequency unknown – taste disturbance.

From the respiratory system rare – bronchospasm or dyspnea, rhinitis, laryngeal edema (shortness of breath, difficulty breathing).

From the CNS common – headache, dizziness, drowsiness; rare – 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 uncommon – increased blood pressure; rare – pulmonary edema, fainting.

From the hematopoietic system rare – anemia, eosinophilia, leukopenia.

From the hemostasis system: rare – bleeding from the postoperative wound, nosebleed, rectal bleeding.

From the skin uncommon – skin rash (including maculopapular rash), purpura; rare – exfoliative dermatitis (fever with or 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: rare – anaphylaxis or anaphylactoid reactions (facial skin discoloration, skin rash, urticaria, skin itching, tachypnea or dyspnea, eyelid edema, tongue edema, periorbital edema, shortness of breath, difficulty breathing, chest tightness, wheezing).

Other common – edema (face, legs, ankles, fingers, feet, weight gain); uncommon – increased sweating; rare – fever; frequency unknown – hyperkalemia, hyponatremia.

Contraindications

• Hypersensitivity (including to other NSAIDs);
• Complete or incomplete combination of bronchial asthma, recurrent nasal and sinus polyposis and intolerance to acetylsalicylic acid or other NSAIDs (including in 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 in history; thrombocytopenia; hypocoagulation, including hemophilia),
• Myelosuppression;
• Bleeding or high risk of their development;
• Severe renal failure (creatinine clearance less than 30 ml/min);
• Confirmed hyperkalemia;
• Severe hepatic failure or active liver disease;
• Condition after coronary artery bypass surgery;
• Prophylactic analgesia before and during extensive surgical interventions due to the high risk of bleeding;
• Active cerebrovascular diseases (including intracranial hemorrhage or suspicion of it);
• Pregnancy;
• Labor;
• Breastfeeding period;
• Children under 16 years of age (safety and efficacy of use have not been established);
• Simultaneous use with probenecid;
• Simultaneous use with pentoxifylline;
• Simultaneous use with acetylsalicylic acid and other NSAIDs (including selective COX-2 inhibitors);
• Simultaneous use with lithium salts;
• Simultaneous use with anticoagulants (including warfarin and heparin).

With caution

Bronchial asthma; presence of factors that increase toxicity to the gastrointestinal tract: alcoholism, tobacco smoking and cholecystitis; postoperative period; chronic heart failure; edematous syndrome; arterial hypertension; moderate renal failure (creatinine clearance 30-60 ml/min); cholestasis; active hepatitis; sepsis; systemic lupus erythematosus; coronary artery disease; cerebrovascular diseases; dyslipidemia/hyperlipidemia; diabetes mellitus; peripheral arterial diseases; 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 glucocorticosteroids (including prednisone), antiplatelet agents (including clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline); elderly age (over 65 years).

Use in Pregnancy and Lactation

Pregnancy

The use of the drug during pregnancy is contraindicated (adverse effect on the fetal cardiovascular system – premature closure of the ductus arteriosus), during labor and in the early postpartum period (by inhibiting the synthesis of prostaglandins, Ketorolac can negatively affect fetal circulation and weaken uterine contractility, which increases the risk of uterine bleeding).

Breastfeeding period

The use of ketorolac during breastfeeding is contraindicated. Ketorolac is excreted in breast milk.

Use in Hepatic Impairment

Contraindication: severe hepatic failure or active liver disease.

Use in Renal Impairment

Contraindication: severe renal failure (creatinine clearance less than 30 ml/min).

Special Precautions

The choice of the drug’s dosage form 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; orally disintegrating tablets; solution for intravenous and intramuscular administration.

Before using the drug, it is necessary to clarify the issue of previous allergy to the drug or other NSAIDs. Due to the risk of developing 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 monitoring of hemostasis is required.

Hypovolemia increases the risk of nephrotoxic adverse reactions.

If necessary, it 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 the extension of the treatment course and an increase in the oral dose of ketorolac above 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 analgesia before and during extensive surgical interventions is contraindicated due to the high risk of bleeding.

Ketorolac is not recommended for use as a premedication and maintenance anesthesia agent.

Cases of fluid retention, increased blood pressure, and edema have been reported with the use of ketorolac.

Caution should be exercised when prescribing to patients with heart failure, arterial hypertension.

Concomitant use of ketorolac with other NSAIDs may lead to disorders such as decompensation of heart failure and increased blood pressure.

According to clinical studies, the use of some NSAIDs in high doses may lead to an increased risk of arterial thrombotic complications (e.g., myocardial infarction, stroke). Although such complications have not been reported with the use of ketorolac, the available data are insufficient to exclude the risk of such complications.

To reduce the risk of NSAID-induced gastropathy, the use of antacids, 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 course.

Effect on ability to drive vehicles and operate machinery

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

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 charcoal) and symptomatic therapy (maintenance of vital body functions). Hemodialysis is not very effective.

Drug Interactions

Concomitant use of ketorolac with acetylsalicylic acid or other NSAIDs, calcium preparations, glucocorticosteroids, ethanol, corticotropin may 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 concomitantly with other NSAIDs (including COX-2 inhibitors), fluid retention, decompensation of cardiac activity, and increased blood pressure may be observed.

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 plasma and increases its T_1/2.

Concomitant use of ketorolac with valproate causes impaired platelet aggregation.

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

Concomitant use with paracetamol increases the nephrotoxicity of ketorolac.

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

Concomitant use of ketorolac with methotrexate increases the hepatotoxicity and nephrotoxicity of methotrexate. Concomitant use of ketorolac and methotrexate is only possible when using low doses of the latter. A decrease in methotrexate clearance is possible (it is necessary to monitor the plasma concentration of methotrexate).

During treatment with ketorolac, a decrease in lithium clearance, an increase in its plasma concentration, and an enhancement of the toxic effect of lithium are possible. Concomitant use with lithium salts is contraindicated.

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

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, which requires a dose adjustment of these drugs.

Ketorolac increases the plasma concentration 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 taking mifepristone.

Concomitant use of NSAIDs and cyclosporine increases the risk of nephrotoxicity.

Concomitant 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 hematologic toxicity.

When used concomitantly with digoxin, Ketorolac does not impair 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 enhance the manifestations of hematotoxicity of ketorolac.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

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.