Ketorol (ketorolac) tablets, ampoules

The composition and form of issue: 

Tablets, film-coated. 1 tablet contains:

tromethamine Ketorolac (Ketorolac trometamol) 10 mg

other ingredients: microcrystalline cellulose lactose starch maize silica colloidal anhydrous magnesium stearate carboximetilkrahmal sodium (type A) 

the composition of the shell: hypromellose propylene glycol titanium dioxide olive green (quinoline yellow dye, the dye brilliant blue) 

blistere in 10 PCs in the paper cartons 2 blister.

Solution for intramuscular injection. 1 ml contains:

Ketorolac 30 mg trometamina

auxiliary substances: sodium chloride, alcohol, disodium edetate octoxynol propylene glycol sodium hydroxide water for injection 

in 1 ml ampoules in blister packs of 10 PCs.

Description pharmaceutical form:

Tablets: round, biconvex, film-coated green in color, on one side embossed with the letter “S”. View of the transversal cut: the shell is green and the kernel white, or almost white.

The solution for the/m introduction: clear, colorless or pale yellow solution.

Characteristic:

NPVS.

Pharmacokinetics:

The ingestion well absorbed from the gastrointestinal tract. Cmax after oral administration of 10 mg — (0, 82-1, 46 µg/ml), Tmax — min. 10-78 fat-Rich food reduces Cmax and detains her achievement on 1 hours Linking plasma protein — 99%.

Bioavailability of 80-100%. Absorption in the/m introduction — full and quick. After the/m injection in a dose of 30 mg Cmax (1, 74-3, 1 µg/ml) achieved through 15-73 min, 60 mg Cmax (3, 23-5, 77 µg/ml) is achieved after 30-60 min. Time to reach CSS for parenteral and oral administration — 24 hours at the destination 4 times a day (subtherapeutic above) is when the/m introduction 15 mg — 0, 65-1, 13 µg/ml, 30 mg — 1, 29-2, 47 mcg/ml after ingestion of 10 mg — 0, 39-0, 79 µg/ml. Vd is 0, 15-0, 33 l/kg. In patients with renal insufficiency Vd may increase in 2 times, and Vd R-enantiomer — on 20%.

Passes into breast milk when taken by the mother 10 mg of Ketorolac Cmax in milk is achieved after 2 hours after the first dose and is 7, 3 ng/ml, 2 h after the second dose (when using the drug 4 times a day) of 7, 9 ng/L.

More than 50% of the administered dose is metabolized in the liver to form pharmacologically inactive metabolites. The main metabolites are the glucuronide, which is excreted by the kidneys and p-hydroxyketones, which is excreted by the kidneys (91%) and through the intestine (6%).

T1/2 in patients with normal renal function is an average of 5, 3 h (3, 5-9, 2 h after the/m introduction 30 mg, and 2, 4-9 h after ingestion of 10 mg). T1/2 longer in elderly patients and shortened young. Liver function does not affect T1/2. In patients with impaired renal function at the concentration of creatinine 19-50 mg/l (168-442 µmol/l) T1/2 is 10, 3-10, 8 h, with more pronounced renal failure — more 13, 6 PM

Total clearance when the/m introduction 30 mg — 0, 023 l/kg/h (0, 019 l/kg/HR in older patients), when administered 10 mg — 0, 025 l/kg/h in patients with renal insufficiency with creatinine concentration in the blood plasma 19-50 mg/l in the/m introduction 30 mg — 0, 015 l/kg/h, the ingestion of 10 mg — 0, 016 l/kg/h.

Not displayed during hemodialysis.

Description of the pharmacological action:

Ketorolac has a marked analgesic effect, as well as anti-inflammatory and antipyretic.

The mechanism of action is nonselective inhibition of the activity of the enzyme COX-1 and COX-2, mainly in peripheral tissues, resulting in the inhibition of the biosynthesis of PG — modulators of pain sensitivity, thermoregulation and inflammation. Ketorolac is a racemic mixture of (?)S and (+)R enantiomers, with the analgesic effect due to (?)S form.

The drug does not affect opioid receptors, not oppressing breathing, does not cause drug dependence, does not possess sedative and anxiolytic effect.

After the/m introduction and admission into the beginning of the anesthetic observed after 0, 5 and 1 h, respectively, the maximum effect is achieved in 1-2 hours

Indications:

Tablets

Pain syndrome strong and moderate symptoms (intended for symptomatic therapy, reducing intensity of pain and inflammation at the time of use on disease progression is not affected):

• injuries
• toothache
• pain in the postpartum and postoperative period
• oncological disease
• myalgia, arthralgia, neuralgia, radiculitis
• sprains, strains
• rheumatic disease.

The solution for the on/m introduction

• Pain syndrome moderate and strong intensity of different Genesis (including pain in the postoperative period, in Oncology).

Contraindications:

Tablets

• hypersensitivity to Ketorolac
• full or partial combination of bronchial asthma, recurrent polyposis of the nose or paranasal sinuses and intolerance of acetylsalicylic acid and other NSAIDs (including history)
• erosive-ulcerative changes of the gastric mucosa and duodenal ulcers, active gastrointestinal bleeding cerebrovascular bleeding or other
• inflammatory bowel disease (Crohn’s disease, ulcerative colitis) in the acute phase
• hemophilia and other blood clotting disorder
• decompensated heart failure
• hepatic insufficiency or active liver disease
• expressed kidney failure (Cl creatinine <30 ml/min), progressive kidney diseases, confirmed hyperkalemia
• since the coronary artery bypass surgery
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption
• pregnancy, childbirth
• lactation
• children up to age 16 years.

With caution:

• hypersensitivity to other NSAIDs
• bronchial asthma
• CHD
• congestive heart failure
• edema syndrome
• arterial hypertension
• cerebrovascular disease
• pathological dyslipidemia/hyperlipidemia
• violation of kidney function (Cl creatinine 30-60 ml/min)
• diabetes
• cholestasis, active hepatitis
• sepsis
• systemic lupus erythematosus
• peripheral arterial disease
• smoking
• concomitant use with other NSAIDs
• elderly age (over 65 years)
• anamnestic data about the development of ulcerative lesions of the gastrointestinal tract
• alcohol abuse
• serious somatic diseases
• concomitant therapy the following medications: anticoagulants (e.g. warfarin), antiplatelet agents (e.g. acetylsalicylic acid, clopidogrel), oral corticosteroids (e.g. prednisolone), selective inhibitors of reverse takeover serotonin (e.g. citalopram, fluoxetine, paroxetine, sertraline).

The solution for the on/m introduction

• hypersensitivity to Ketorolac or other NSAIDs
• aspirin asthma, bronchospasm, angioedema
• hypovolemia (whatever the causes that caused it), dehydration
• erosivno-azwenne shock syndrome in acute phase, peptic ulcer
• hypocoagulation (including hemophilia)
• hepatic and/or renal failure (plasma creatinine above 50 mg/l)
• haemorrhagic stroke (confirmed or suspected), hemorrhagic diathesis
• high risk of bleeding or recurrence (i.e. after operations)
• violation of hematopoiesis
• concomitant use with other NSAIDs
• pregnancy, childbirth
• lactation
• children up to age 16 years
• anesthesia before and during surgical operations because of the high risk of bleeding
• chronic pain.

With caution:

• bronchial asthma
• cholecystitis, cholestasis, active hepatitis
• chronic heart failure
• arterial hypertension
• the impairment of renal function (plasma creatinine below 50 mg/l)
• sepsis
• systemic lupus erythematosus
• elderly age (over 65 years)
• polyps of the nasal mucosa and nasopharynx.

Application of pregnancy and breastfeeding:

Contraindicated in pregnancy. At the time of treatment should stop breastfeeding.

Side effect:

Often more than 3%, less often — 1-3%, rarely less than 1%.

From the digestive system: often (especially in elderly patients older than 65 years with a history of erosive-ulcerative lesions of the gastrointestinal tract) — gastralgia, diarrhea, less often — stomatitis, flatulence, constipation, vomiting, feeling of fullness of the stomach rarely, nausea, erosive-ulcerative lesions of the gastrointestinal tract (including with perforation and/or bleeding — abdominal pain, spasm or burning sensation in the epigastrium, melena, vomiting type “coffee grounds”, nausea, heartburn, etc.), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.

From the urinary system: rarely — acute renal failure, back pain with or without hematuria and/or azotemii, hemolytic uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), frequent urination, increase or decrease the volume of urine, nephritis, edema of renal origin.

From the sensory organs: rarely — hearing loss, ringing in the ears, visual disturbances (including blurring of visual perception).

The respiratory system: rarely bronchospasm or dyspnoea, rhinitis, laryngeal edema (shortness of breath, difficulty breathing).

CNS: frequently — headache, dizziness, drowsiness, rarely — aseptic meningitis (fever, severe headache, convulsions, rigidity of the muscles of the neck and/or back), hyperactivity (change in mood, anxiety), hallucinations, depression, psychosis.

From the side of cardiovascular system: less often — increased blood pressure rare — pulmonary edema, syncope.

Organs of hematopoiesis: rarely — anemia, eosinophilia, leukopenia.

From the hemostatic system: rarely — bleeding from the postoperative wound, nasal bleeding, rectal bleeding.

With the skin: less often — skin rash (including maculopapular rash), purpura rare — exfoliative dermatitis (fever with or without chills, redness, induration, or skin peeling, swelling and/or soreness of the tonsils), urticaria, Stevens-Johnson syndrome, Lyell’s syndrome.

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

Allergic reactions: rare — anaphylaxis or anaphylactoid reaction (discoloration of the skin, skin rash, hives, itching of the skin, tachypnea or dyspnea, swelling of the eyelids, periorbital swelling, wheezing, shortness of breath, heaviness in chest, wheezing).

Other: often — swelling (face, legs, ankles, fingers, feet, weight gain) less often, excessive sweating is rarely tongue swelling, fever.

Drug interaction:

The simultaneous use of Ketorolac with acetylsalicylic acid or other NSAIDs, calcium supplements, corticosteroids, ethanol, corticotropin may lead to ulceration of the gastrointestinal tract and the development of gastrointestinal bleeding.

Joint appointment with paracetamol increases nefrotoksicnosti, with methotrexate — gepato – and nefrotoksicnosti. Co-administration of Ketorolac and methotrexate is only possible when using low doses of the latter (it is necessary to control the concentration of methotrexate in plasma).

Probenecid decreases plasma clearance and Vd of Ketorolac, increases its concentration in blood plasma and increases T1/2. On the background of the use of Ketorolac may decrease clearance of methotrexate and lithium and increased toxicity of these substances. Joint appointment with indirect antikoagulyantami, heparin with thrombolytic drugs, antiplatelet agents, cefoperazone, and cefotetan with pentoxifylline increases the risk of bleeding. Reduces the effect of antihypertensive and diuretic drugs (decreases synthesis of GHGs in the kidneys). When combined with opioid analgesics dose of the latter can be significantly reduced.

Antacids means do not affect the completeness of absorption of medicine.

Increases hypoglycemic effect of insulin and oral hypoglycemic drugs (requires the recalculation of doses). Joint appointment with valproate sodium causes a disturbance of platelet aggregation. Increases concentration in plasma of verapamil and nifedipine.

In the appointment with other nefrotoksicnami drugs (including drugs with gold) increased risk of nephrotoxicity. Drugs that block tubular secretion, reduce the clearance of Ketorolac and increase its concentration in the blood plasma.

The solution for injection should not be mixed in the same syringe with morphine sulfate, prometazinom and hidroxizina due to sedimentation. Farmatsevticeski incompatible with the solution of tramadol, drugs lithium.

The solution for injection is compatible with normal saline, 5% dextrose solution, ringer solution and ringer-lactate solution “Plasmalite”, as well as with infusion solutions, containing aminophylline, lidocaine hydrochloride, dopamine hydrochloride, human insulin short-acting and heparin sodium salt.

Method of application and doses:

Inside, at a dose of 10 mg.

When expressed pain syndrome the drug is taken repeatedly on 10 mg to 4 times a day, depending on the severity of the pain. The maximum daily dose should not exceed 40 mg. you Should use the minimum effective dose.

In/m deep, in minimally effective doses, selected in accordance with the intensity of pain and response of the patient. If necessary, at the same time you can optionally assign opioid analgesics in small doses.

Single doses with a single on/m introduction: patients up to 65 years — 10-30 mg, depending on severity of pain, patients over 65 years or with impaired renal function — 10-15 mg.

The dose repeated when the/m introduction: patients up to 65 years administered 10-30 mg, then — on 10-30 mg every 4-6 h, patients over 65 years or with impaired renal function — on 10-15 mg every 4-6 h

The maximum daily dose for patients to 65 years should not exceed 90 mg, and for patients older than 65 years or with impaired renal function — 60 mg when I/m route of administration.

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

When switching from parenteral administration of the drug on its intake the total daily dose of both medicinal forms in day of transfer should not exceed 90 mg for patients till 65 years and 60 mg for patients older than 65 years or with impaired renal function. The dose of the drug in tablets on the day of transfer should not exceed 30 mg.

Overdose:

Symptoms: abdominal pain, nausea, vomiting, the appearance of peptic gastric ulcers or erosive gastritis, violation of function of kidneys, metabolic acidosis.

Treatment: gastric lavage, introduction of adsorbents (activated carbon), symptomatic therapy (maintaining vital body functions). Not excreted sufficiently by dialysis.

Special instruction:

Ketorol it has two dosage forms (tablets, coated tablets and solution for injection). The choice of method of drug administration depends on the severity of pain and the patient’s condition.

Influence on platelet aggregation is terminated 24-48 hours.

Hypovolemia increases the risk of adverse reactions in the kidneys. If necessary, you can assign in combination with narcotic analgesics.

Ketorol is not recommended as a means for sedation support anesthesia and analgesia in obstetric practice.

Do not use simultaneously with paracetamol more than 5 days. Patients with impaired blood clotting the drug is prescribed only under constant control the number of platelets (especially important in the postoperative period requires careful monitoring of hemostasis).

The risk of medicinal complications increases when extending the duration of treatment longer than 5 days, and increasing oral doses more than 40 mg/day. You should not use this medication simultaneously with other NSAIDs.

When co-administered with other NSAIDs may experience fluid retention, decompensation of cardiac activity, increased blood pressure. Influence on platelet aggregation is terminated 24-48 hours.

The drug can change the properties of platelets, but does not replace the preventive effect of acetylsalicylic acid in cardiovascular diseases. To reduce the risk of NSAID-gastropathy are appointed by antacid medicines, misoprostol, omeprazole.

Because a significant portion of patients in the appointment of Ketorol develop side effects from the CNS (drowsiness, dizziness, headache), it is recommended to avoid jobs that require attention and fast reactions (driving vehicles, work with mechanisms, etc.).