Ketanov MD, 10 mg 20 pcs.

Pharmacotherapeutic group: Non-steroidal anti-inflammatory drug.

Code ATX: M01AB15

Pharmacological properties.

Pharmacodynamics

Non-steroidal anti-inflammatory drug (NSAID), has a pronounced analgesic effect, also has anti-inflammatory and moderate antipyretic effects.

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

The drug does not affect the opioid receptors, does not depress respiration, does not cause addiction and has no sedative and anxiolytic action. Its analgesic effect is comparable with that of morphine; it is considerably superior to other non-steroidal anti-inflammatory drugs.

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

Pharmacokinetics

After oral administration, ketorolac is well absorbed in the gastrointestinal tract – maximum concentration (C_mah) in plasma (0.7-1.1 µg/mL) is reached 0.4 h after an empty stomach dose of 10 mg of ketorolac in the oral dispersible tablet form. Fat-rich food reduces the maximum blood concentration of the drug and delays its achievement by 1 hour. 99% of the drug is bound to blood plasma proteins; in case of hypoalbuminemia the amount of free substance in blood increases. Bioavailability is 80-100 %. Time to reach equilibrium concentration – C_ss (0.39-0.79 mcg/ml), when administered orally 10 mg ketorolac 4 times daily (dose above subtherapeutic), is 24 hours.

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

Prevalence in breast milk: after maternal administration of 10 mg of ketorolac C_mah 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.

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. It is excreted by the kidneys (91%) and through the intestine (6%).

The elimination half-life (T_1/2) in patients with normal renal function is 2.4-9 h after an oral dose of 10 mg. T_1/2 is longer in elderly patients and shorter in younger patients. Impaired liver function has no effect on T_1/2. In patients with impaired renal function at a plasma creatinine concentration of 19-50 mg/L (168-442 μmol/L), T_1/2 is 10.3-10.8 h; in more severe renal impairment it is more than 13.6 h.

In an oral dose of 10 mg, the total clearance is 0.025 l/h/kg; in renal failure (plasma creatinine concentration 19-50 mg/l), 0.016 l/h/kg.

It is not excreted by hemodialysis.

Indications

Pain syndrome of moderate and severe intensity of various origins. 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

Pharmacotherapeutic group: non-steroidal anti-inflammatory drug.

ATX code: M01AB15

Pharmacological properties

Pharmacodynamics

A non-steroidal anti-inflammatory drug (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 the enzyme cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-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 of [-]S and [+]R enantiomers, and the analgesic effect is due to the [-]S form.

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

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

Pharmacokinetics

After oral administration, ketorolac is well absorbed from the gastrointestinal tract – the maximum concentration (Cmax) in the blood plasma (0.7-1.1 μg/ml) is achieved 0.4 hours after taking 10 mg of ketorolac on an empty stomach in the dosage form of tablets dispersible in the oral cavity. Food rich in fat reduces the maximum concentration of the drug in the blood and delays its achievement by 1 hour. 99% of the drug is bound to plasma proteins; with hypoalbuminemia, the amount of free substance in the blood increases. Bioavailability – 80-100%. The time to reach equilibrium concentration – Css (0.39-0.79 µg/ml), with oral administration of 10 mg of ketorolac 4 times a day (dose higher than subtherapeutic), is 24 hours.

The volume of distribution is 0.15-0.33 l/kg. In patients with renal failure, the volume of distribution of the drug may increase by 2 times, and the volume of distribution of its R-enantiomer by 20%.

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.

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. Excreted by the kidneys (91%) and through the intestines (6%).

The half-life (T1/2) in patients with normal renal function is 2.4-9 hours after oral administration of a 10 mg dose. T1/2 lengthens in elderly patients and shortens in young ones. Impaired liver function 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 taking a dose of 10 mg orally, the total clearance is 0.025 l/h/kg; for renal failure (plasma creatinine concentration 19-50 mg/l) – 0.016 l/h/kg.

Not excreted during hemodialysis.

Special instructions

Before using the drug, it is necessary to clarify the question of a possible history of allergies when using drugs containing ketorolac or other NSAIDs. Due to the possible 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 monitoring of hemostasis is required.

Hypovolemia increases the risk of developing adverse reactions from the kidneys.

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

The drug should not be used in obstetric practice.

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

The risk of developing adverse reactions increases with lengthening the course of treatment and increasing the dose of ketorolac to more than 40 mg/day.

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

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 may 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, existing 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 H-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, side effects from the central nervous system (drowsiness, dizziness, headache) may develop, which reduces the speed of mental and motor reactions, and therefore it is necessary to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Ketorolac

Composition

One tablet contains:

Active ingredient:

Ketorolac trometamol 10.00 mg

Excipients:

Mannitol* 115.56 mg

Microcrystalline cellulose (Avicel PH112) 18.00 mg

Corn starch 18.00 mg

Aspartame 3.60 mg

Crospovidone 9.00 mg

Propyl gallate 0.50 mg

Indigo carmine dye 3.00 mg

Peppermint flavor 0.54 mg

Magnesium stearate 1.80 mg

* The amount is adjusted taking into account the actual content of ketorolac trometamol to maintain a constant “tablet weight”

Pregnancy

Pregnancy

The use of the drug during pregnancy is contraindicated. The safety of this drug during pregnancy has not been established. The use of drugs that interfere with the synthesis of prostaglandins during the third trimester of pregnancy can cause premature closure of the ductus arteriosus in the fetus, weakening of uterine contractility with a slowdown in labor. Both mother and baby have an increased risk of bleeding.

Breastfeeding period

The use of the drug during breastfeeding is contraindicated. Ketorolac passes into breast milk.

The use of ketorolac during breastfeeding is contraindicated.

Contraindications

Hypersensitivity (including 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 non-steroidal anti-inflammatory drugs (including a history);
Erosive and ulcerative lesions of the gastrointestinal tract, active gastrointestinal bleeding, inflammatory bowel diseases (including ulcerative colitis, Crohn’s disease);
Severe renal failure (creatinine clearance below 30 ml/min).
Severe liver failure;
Acute diseases or conditions accompanied by impaired liver function or exacerbation of chronic liver diseases;
Thyroid diseases;
Confirmed hyperkalemia;
Acute myocardial infarction;
The period after coronary artery bypass surgery;
Acute cerebrovascular accidents (ischemic, hemorrhagic stroke);
Diseases of the bone marrow and blood (leukopenia, including a history of it, thrombocytopenia, conditions accompanied by hypocoagulation, including hemophilia), myelosuppression;
Severe myopathy, myasthenia gravis;
Pregnancy, breastfeeding period;
Children’s age (up to 16 years);
Concomitant use with probenecid;
Simultaneous use with pentoxifylline;
Concomitant use with acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (including cyclooxygenase-2 inhibitors);
Simultaneous use with lithium salts;
Concomitant use with anticoagulants (including warfarin and heparin).

The drug is not used:

– for preventive pain relief before and during major surgical interventions due to the high risk of bleeding.

– for the treatment of chronic pain.

With caution

Peptic ulcer of the stomach and duodenum, ulcerative colitis, Crohn’s disease, history of liver disease, hepatic porphyria, chronic renal failure (creatinine clearance 30-60 ml/min), chronic heart failure, arterial hypertension, significant decrease in circulating blood volume (including after surgery), elderly patients over 65 years of age (including those receiving diuretics, debilitated patients and low body weight), bronchial asthma, concomitant use of glucocorticosteroids (including prednisolone), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline), coronary heart disease, cerebrovascular diseases, dyslipidemia/hyperlipidemia, diabetes mellitus, peripheral arterial disease, smoking, Helicobacter infection pylori, long-term use of non-steroidal anti-inflammatory drugs, tuberculosis, severe osteoporosis, alcoholism, severe somatic diseases, hypotension, hypertension.

Side Effects

By frequency, side effects are divided according to WHO criteria into the following categories: very often (≥ 1: 10); often (≥ 1: 100 and < 1: 10); infrequently

(≥ 1: 1000 and < 1: 100); rare (≥ 1: 10000 and < 1: 1000); very rare (< 1: 10,000), frequency unknown (frequency cannot be estimated from available data).

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 [severe abdominal pain] and bleeding [vomiting like “coffee grounds”, melena]), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.

From the urinary system

Rarely – acute renal failure, lower back pain with or without hematuria and/or azotemia, hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia purpura), frequent urination, increased or decreased daily diuresis, nephritis, edema of renal origin.

From the senses

Rarely – hearing loss, ringing in the ears, visual impairment (including blurred vision); frequency unknown – taste disturbance.

From the respiratory system

Rarely – bronchospasm, dyspnea, shortness of breath, rhinitis, laryngeal edema

From 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

Uncommon: increased blood pressure; rarely – pulmonary edema, syncope.

From the hematopoietic organs

Rarely – anemia, eosinophilia, leukopenia.

From the hemostasis system

Rarely – bleeding from a postoperative wound, nosebleeds, rectal bleeding.

From the skin

Uncommon: skin rash (including maculopapular rash), purpura; rarely – exfoliative dermatitis (fever with or without chills, redness, thickening or flaking of the skin, swelling and/or tenderness of the tonsils), urticaria, Stevens-Johnson syndrome, Lyell’s syndrome.

Allergic reactions

Rarely – anaphylaxis, anaphylactoid reactions (skin hyperemia, rash, urticaria, itching, shortness of breath, difficulty breathing, angioedema).

Other violations

Often – swelling (face, legs, ankles, fingers, feet, weight gain); uncommon – increased sweating; rarely – fever; frequency unknown – hyperkalemia, hyponatremia.

Interaction

Concomitant use of ketorolac with acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including cyclooxygenase-2 inhibitors), 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. Concomitant use with non-steroidal anti-inflammatory drugs is contraindicated.

Simultaneous use with paracetamol increases nephrotoxicity, and with methotrexate – hepato- and nephrotoxicity. The simultaneous use of ketorolac and methotrexate is possible only when using low doses of the latter (monitor the concentration of methotrexate in the blood plasma).

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

Concomitant use with indirect anticoagulants, heparin, thrombolytics, antiplatelet agents, cefoperazone, cefotetan and pentoxifylline increases the risk of bleeding. Concomitant use with anticoagulants (including warfarin and heparin) and pentoxifylline is contraindicated. Reduces the effect of antihypertensive and diuretic drugs (the synthesis of prostaglandins in the kidneys decreases).

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

Antacids do not affect the absorption of the drug.

Ketorolac enhances the hypoglycemic effect of insulin and oral hypoglycemic drugs (dose recalculation is necessary).

Concomitant use with sodium valproate causes disruption of platelet aggregation.

Increases the plasma concentration of verapamil and nifedipine.

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

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

Concomitant use with probenecid leads to an increase in the plasma concentration and half-life of ketorolac. Concomitant use with probenecid is contraindicated. The simultaneous use of lithium salts and certain drugs that suppress the synthesis of prostaglandins leads to impaired excretion and an increase in the plasma concentration of lithium salts. Simultaneous use with lithium salts is contraindicated.

When using cyclosporine, tacrolimus with ketorolac (as with other NSAIDs), caution is recommended due to the increased risk of nephrotoxicity. Cases of hematoma formation have been reported in HIV-infected patients with hemophilia receiving concomitant zidovudine and ibuprofen. Therefore, caution should be exercised when using NSAIDs and zidovudine simultaneously. Ketorolac does not affect the binding of digoxin to blood proteins.

According to animal studies, the concomitant use of NSAIDs with quinolone antibiotics increases the risk of seizures.

It is not recommended to use NSAIDs for 8-12 days after using mifepristone, as the effect of mifepristone may be reduced.

Overdose

Symptoms: abdominal pain, nausea, vomiting, erosive and ulcerative lesions of the gastrointestinal tract (including the development of peptic ulcers of the stomach; erosive gastritis), 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

At a temperature not higher than 25°C.
Keep out of the reach of children.

Shelf life

4 years.
Do not use after expiration date.

Manufacturer

Sun Pharmaceutical Industries Ltd, India