Ketorolac solution for intravenous and intramuscular administration 30 mg/ml

Ketorolac solution for intravenous and intramuscular administration 30 mg/ml

International nonproprietary name

Ketorolac

Pharmacological group

Нестероидные противовоспалительные препараты

Composition

Active ingredient:
Ketorolac trometamol (Ketorolac trometamin) - 30 mg
Excipients:
odium chloride - 4.35 mg
Ethyl alcohol 95 % - 100 mg
1 М sodium hydroxide solution -up to рН 7.0-8.0
Water for injection - up to 1 ml

Pharmacological action

Ketorolac has a pronounced analgesic effect, it also has an anti-inflammatory and moderate antipyretic effect.
The mechanism of action is associated with non-selective inhibition of the 1 and 2 cyclooxygenase enzyme activity, mainly in peripheral tissues, resulting in inhibition of the prostaglandin biosynthesis - modulators of pain sensitivity, thermoregulation and inflammation.
Ketorolac is a racemic mixture of [-]S and [+]R enantiomers with analgesic effect is ensured by [-]S form.
The drug does not affect opioid receptors, does not depress respiration, does not cause drug dependence, does not have sedative and anxiolytic effects.
The analgesic effect is similar to morphine, it is significantly superior the other non-steroidal anti-inflammatory drugs (NSAIDs).
After intramuscular administration the analgesic effect onset is observed after 0.5 h, the maximum effect is achieved in 1-2 hours.

Pharmacokinetics

Absorption after intramuscular administration is complete and rapid. After intramuscular administration of 30 mg of the drug, the maximum plasma concentration (Cmax) is 1.74-3.1 μg/ml; 60 mg - 3.23-5.77 mg/ml, time to maximum concentration, respectively - 15-73 min and 30-60 min; the maximum concentration after intravenous administration of 15 mg is - 1.96-2.98 mg/ml, 30 mg - 3.69-5.61 mg/ml. Time to steady state concentration (Css) after parenteral administration is 24 hours when administered 4 times per day (more than the subtherapeutic dose) and is 0.65-1.13 mg/ml after intramuscular administration of 15 mg , 30 mg - 1,29- 2.47 mg/ml, after intravenous administration of 15 mg - 0.79-1.39 mg/ml, 30 mg - 1.68-2.76 mg/ml.
99.2% of the drug binds to blood plasma proteins and free substance amount in the blood increases in case of hypoalbuminemia.
Volume of distribution is 0.15 - 0.33 l/kg. In patients with renal failure, the volume of distribution of the drug can be doubled, and the volume of distribution of its R-enantiomer can increase by 20%. The drug crosses poorly the blood-brain barrier, crosses the placenta (10%). The drug is identified in small quantities in breast milk.
More than 50% of the administered dose is metabolized in the liver with generation of pharmacologically inactive metabolites. The main metabolites are glucuronides, which are excreted by the kidneys, and p-hydroxycetorolac, 91% of which is excreted by the kidneys, 6% by the intestine.
The half-life (T 1/2) in patients with normal renal function averaged 5.3 hours (3.5-9.2 hours after intramuscular administration of 30 mg and 4-7.9 hours after intravenous administration of 30 mg). Half-life is prolonged in elderly patients and is shortened in young patients.
The liver function has no effect on the half-life. In patients with renal dysfunction with creatinine plasma concentration 19-50 mg/l (168-442 μmol/L), the half-life is 10.3-10.8 hours, with more severe renal failure - more than 13.6 hours.
The total clearance after intramuscular administration of 30 mg is 0.023 l/kg/h (0.019 l/kg/h in elderly patients), after intravenous administration of 30 mg - 0.03 l/kg/h; in patients with renal failure a creatinine plasma concentration 19-50 mg/l after intramuscular injection of 30 mg - 0.015 l/kg/h. The drug is not excreted during hemodialysis.
Data about the drug efficacy in bilious blind headache attacks are not available.

Indications for Use

Moderate or severe pain syndrome of various genesis (including postsurgical pain, with cancer). The drug is intended for expectant therapy, pain or inflammation reduction at the administration moment, has no effect on progression of the disease.

Contraindications

- increased sensation to ketorolac;
- complete or partial composition of bronchial asthma, recurrent nasal and air cell polyposis or intolerance of acetylsalicylic acid or other NSAIDs (including in the past medical history);
- cerosive-ulcerative changes of gastric and duodenum mucosa, active gastrointestinal bleeding, cerebrovascular or other hemorrhage;
- inflammatory bowel diseases (Crohn's disease, ulcerative colitis) in the acute phase;
- hemophilia and other blood-clotting disorders;
- decompensated heart failure;
- hepatic failure or active hepatic disease;
- severe renal failure (creatine clearance less than 30 ml/min), advanced renal diseases, confirmed hyperkalemia;
- postsurgical period after coronary artery bypass graft surgery;
- simultaneous administration with probenecid, pentoxifylline, acetylsalicylic acid and other NSAID (including cyclooxygenase-2 selective inhibitors), lithium salts, anticoagulating agents (including warfarin and heparine);
- the drug is not used for preventive analgesia before and during extensive surgery due to the high risk of bleeding;
- pregnancy, delivery period, lactation cycle;
- pediatric use at the age less than 16 years old (safety and efficacy are not determined).
With care
Bronchial asthma, coronary heart disease, congestive cardiac failure, edema syndrome, arterial hypertension, cerebrovascular diseases, pathological dyslipidemia or hyperlipidemia, renal failure (creatine clearance 30-60 ml/l), diabetes mellitus, cholestasis, sepsis, systemic lupus erythematosus, peripheral arterial diseases, smoking, elderly age (older than 65 years old), medical history data about ulcer of gastrointestinal tract, frequent alcohol drinking, severe somatic diseases, concomitant therapy with the following drugs: antiaggregants (for example Clopidogrel), oral glucocorticosteroids (for example, prednisolone), selective serotonin reuptake inhibitors (for example, citalopram, fluoxetine, paroxetine, sertraline).
Administration during pregnancy and lactation period
Administration during pregnancy is contraindicated: adequate and strictly controlled studies in pregnant women were not conducted. Administration of the drug during childbirth and delivery is contraindicated as inhibiting the synthesis of prostaglandins, it can adversely affect the blood circulation of the fetus and weaken the uterus labor increasing the risk of uterine bleeding.
Breastfeeding shall be discontinued for the period of treatment because the drug inhibiting prostaglandin synthesis may cause adverse effects in infants.

Cautions

The previous allergic reaction to the drug or NSAIDs shall be considered before administration of the drug. Due to the risk of allergic reactions the first dose shall be administered under close supervision of the doctor.
Hypovolemia increases the risk of nephrotoxic adverse reactions. If required the drug can be used in combination with narcotic analgesics.
Administration of the drug as an agent for preventive analgesia, before and during extensive surgical interventions is not recommended due to high risk of bleeding.
Do not use the drug together with NSAIDs (including cyclooxygenase-2 inhibitors), because simultaneous administration with other NSAIDs mau cause fluid retention, cardiac decompensation and blood pressure increase. The effect on platelet aggregation stops after 24-48 hours.
The drug can change the platelet properties.
Patients with blood clotting disorder shall receive the drug only under constant platelet count control, it is especially important for postoperative patients requiring careful control of hemostasis.
The risk of drug complications increases with prolonged treatment (in patients with chronic pain) and the drug dose escalation up to more than 90 mg/day. To reduce the risk of adverse event development, the minimum effective dose shall be administered during the minimum possible short course.
Effects of the drug on ability to drive and use machines
As adverse the central nervous system effects may develop in significant part of patients after administration of ketorolac (somnolency, dizziness, headache), avoid performing the work requiring increased attention and quick response (driving and operation of mechanisms, etc.).

 

Dosing and Administration

The drug shall be administered intravenously during not less than 15 seconds (for dosage form containing ethanol).

The drug shall be injected deeply intramuscularly at slow rate at minimum effective doses titrated based on pain severity and patients reaction. If required, opioid analgesics may additionally be administered in reduced doses.
Single doses for single intramuscular or intravenous administration:
                - in patients at 16-64 years old with body weight more than 50 kg - 10-30 mg, based on the severity of the pain syndrome,
                - in patients at 16-64 years with body weight less than 50 kg, in patients older than 65 years old or with renal dysfunction - 10-15 mg.
Doses for repeated parenteral administration:
Intramuscular administration:
- in patients at 16-64 years old with body weight more than 50 kg receive 10-30 mg with the first administration, then - 10-30 mg every 4-6 hours;
- in patients with body weight less than 50 kg, in patients older than 65 years old or with renal dysfunction - 10-15 mg every 4-6hours,
Intravenous administration:
-patients at 16-64 years old with body weight more than 50 kg shall receive stream infusion of 10-30 mg, then 10-30 mg every 6 hours with continuous infusion using an infusomator, the initial dose is 30 mg, and then the infusion rate is 5 mg/hour;
- in patients at 16-64 years with body weight less than 50 kg, in patients older than 65 years old or with renal dysfunction - stream infusion of 10-15 mg every 6 hours.
The maximum daily dose for patients at 16-64 years old with body weight more than 50 kg shall not exceed 90 mg, and for patients at 16-64 years old with body weight less than 50 kg, patients older than 65 years old or with renal dysfunction - 60 mg both for intramuscular and intravenous routes of administration.
Duration of the continuous intravenous infusion shall not exceed 24 hours.
Duration of treatment with parenteral administration shall not exceed 2 days.
When changing from parenteral administration of the drug to its oral administration, the total daily dose of both dosage forms on the day of transfer shall not exceed 90 mg for patients at 16-64 years old with body weight more than 50 kg and 60 mg for patients at 16-64 years old with body weight less than 50 kg, patients older than 65 years old or with renal dysfunction. In this case, the dose of the drug in tablets on the day of transition shall not exceed 30 mg.

Side effect

common (frequent) - 1-10 %; uncommon (infrequent) - 0.1-1%; rare - 0.01-0.1 %; very rare - less than 0.001%, including individual cases.

Adverse digestive system effects: common (frequent) (especially in elderly patients from 65 years old, with erosive and ulcerative lesions of the gastrointestinal tract in the past medical history) - gastralgia, diarrhea; uncommon (infrequent) - stomatitis, flatulence, constipation, vomiting, stomach overflow sense; rare - nausea, erosive and ulcerative lesions of the gastrointestinal tract (including with perforation and / or bleeding - abdominal pain, spasm or burning in the epigastric region, blood in the feces or melena, vomiting with blood or coffee thick type vomiting , nausea, heartburn, etc.), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.
Adverse urinary system effects: rare - acute renal failure, back pain with or without hematuria and / or azotemia, hemolytic uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura) frequent urination, increased or decreased urine volume, nephritis, edema of the kidney genesis.
Adverse sense organ effects: rare - diminished hearing, ringing in the ears, visual impairment (including blurred vision).
Adverse respiratory system effects: rare - bronchospasm or dyspnoea, rhinitis, pulmonary edema, laryngeal edema (dyspnea, difficulty breathing).
Adverse the central nervous system effects:  common (frequent) - headache, dizziness, somnolency; rare - aseptic meningitis (fever, severe headache, convulsions, neck and / or back muscle stiffness), hyperactivity (mood changes, anxiety), hallucinations, depression, psychosis.
Adverse cardiovascular effects: uncommon (infrequent) - blood pressure increase, rare - pulmonary edema, fainting.
Adverse hematopoietic organ effects:  rare - anaemia, eosinophilia, leukopenia.
Adverse hemostasis system effects: rare - bleeding from a postsurgical wound, epistaxis, rectal bleeding.
Adverse skin effects: uncommon (infrequent) - exanthema (including maculopapular rash), purpura, rare - exfoliative dermatitis (fever with or without chills, hyperemia, redness, densification or flaking of the skin, swelling and / or tenderness of tonsils), urticaria fever, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).
Local reactions: uncommon (infrequent) - burning or pain at the injection site.
Allergic reactions: rare - anaphylaxis or anaphylactoid reactions (faceskin discoloration, exanthema, urticaria fever, skin itch, tachypnea or dyspnea, edema of eyelids, periorbital edema, dyspnea, difficult breathing, chest pain, wheezing).
Other: common (frequent) - edema (face, legs, ankles, fingers, feet), weight gain, uncommon (infrequent) - excessive sweating, rare - tongue swelling, fever.
Overdose
Symptoms: abdominal pain, nausea, vomiting, peptic ulcers of the stomach or erosive gastritis, renal disorders, metabolic acidosis.
Treatment: expectant therapy (maintenance of vital functions in the body). It is not excreted sufficiently by dialysis.

Interaction with other medicines

Simultaneous administration of ketorolac with acetylsalicylic acid or other NSAIDs, including cyclooxygenase-2 inhibitors, calcium drugs, glucocorticosteroids, ethanol, corticotropin may cause gastrointestinal ulceration and gastrointestinal bleeding.
Do not use the drug concurrently with other NSAIDs (including cyclooxygenase-2 inhibitors), as well as with probenecid, pentoxifylline, acetylsalicylic acid, lithium salts, anticoagulating agents (including warfarinand heparine).
Do not use with paracetamol during more than 2 days. Simultaneous administration with paracetamol increases nephrotoxicity, with methotrexate-hepato- and nephrotoxicity. Simultaneous administration of ketorolac and methotrexate is possible only at low doses of ketorolac (control the plasma concentration of methotrexate).
Probenecid reduces plasma clearance and the volume of ketorolac distribution, increases its plasma concentration and increases its half-life. Administration of ketorolac may decrease in the clearance of methotrexate and lithium and increase toxicity of these substances.
Simultaneous administration with indirect coagulants (for example, warfarin), heparine, thrombolytic agents, antiaggregants, cefoperazone, cefotetan and pentoxifylline increases the risk of bleeding.
The drug reduces the effect of antihypertensive and diuretic drugs (decreases the synthesis of prostaglandins in the kidneys). Combined administration with narcotic analgesics, the doses of the latter can be significantly reduced.
Antacids do not affect the full absorption of the drug.
The drug increase the hypoglycemic effect of insulin and oral hypoklikemic drugs (dose recalculation is required).
Simultaneous administration with valproic acid causes disruption of platelet aggregation. The drug increases the plasma concentration of verapamil and nifedipine.
Simultaneous administration with other nephrotoxic drugs (including with gold preparations) increases the risk of nephrotoxic reactions.
The drugs blocking tubular secretion, reduce the clearance of ketorolac and increase its plasma concentration.
Possible interactions shall be considered for simultaneous administration of ketorolac with cyclosporine, zidovudine, digoxin, tacrolimus, quinoline drugs, selective serotonin reuptake inhibitors, mifepristone.
 

Form release

Storage conditions

In a dark place at temperature maximum 25 °С.  Do not freeze.

Expiration date

2 years