INSTRUCTIONS FOR MEDICAL USE
DROLAKET
Trade name of the drug: Drolaket
Active ingredients (INN): ketorolaca tromethamine, dimedrol (diphenhydramide hydrochloride)
Dosage form: solution for injection.
Contents:
2 ml of the solution contains:
Active ingredients: ketorolac tromethamine – 30.0 mg; dimedrol (diphenhydramide hydrochloride) – 1 mg
Excipients: ethyl alcohol, sodium chloride, sodium hydroxide, water for injection.
Description: pale yellow transparent solution.
Pharmacotherapeutic group: Nonsteroidal anti-inflammatory agent.
ATX code: M01AB15
Pharmacological properties
Pharmacodynamics
It is a combined preparation, the action of which is related to the constituent components of the drug.
Ketorolac is 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 COX1 and COX2 activity, which catalyzes the formation of prostaglandins from arachidonic acid, which play an important role in the pathogenesis of pain, inflammation and fever. It is comparable with morphine in strength of analgesic effect and is significantly superior to other NSAIDs.
Dimedrol. A 1st generation blocker of H1-histamine receptors eliminates the effects of histamine mediated through this type of receptors. Its action on the CNS is due to blockade of H3-histamine receptors in the brain and inhibition of central cholinergic structures. It has pronounced antihistamine activity, reduces or prevents histamine-induced smooth muscle spasms, increased capillary permeability, tissue edema, itching and hyperemia. It has the effect of local anesthesia (when ingested, there is a short-term numbness of the oral mucous membranes), blocks the cholinoreceptors of the ganglia (reduces BP) and the CNS, has sedative, hypnotic, anti-Parkinsonian and antiemetic effects. Antagonism with histamine is more in relation to local vascular reactions in inflammation and allergy than systemic reactions, i.e. BP reduction. However, when parenterally administered to patients with circulating blood volume deficiency, a decrease in BP and an increase in existing hypotension due to ganglioblocating action are possible.
Pharmacokinetics
Ketorolac after injection/injection causes the onset of analgesic effect in 0.5 hours, maximum effect is achieved after 1 – 2 hours. Bioavailability is 80-100%, absorption by intramuscular injection is complete and rapid. After intramuscular administration of 30 mg, maximum blood plasma concentration (Cmax) is 1.74-3.1 µg/ml, 60 mg – 3.23-5.77 µg/ml, time to reach maximum concentration is 15-73 minutes and 30-60 minutes, respectively; Cmax after intravenous infusion of 15 mg is 1.96-2.98 µg/ml, 30 mg – 3.69-5.61 µg/ml. Time to reach equilibrium concentrations (Css) when parenterally administered – 24 h when administered 4 times a day (above subtherapeutic) and is 0.65-1.13 mcg/ml, 1.29-2.47 mcg/ml for intramuscular administration of 15 mg, 1.29-2.47 mcg/ml for 30 mg, 0.79-1.39 mcg/ml for intravenous infusion of 15 mg, 1.68-2.76 mcg/ml for 30 mg.
99% of the drug is bound to plasma proteins, and in case of hypoalbuminemia the amount of free substance in blood increases.
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%. It passes poorly through the blood-brain barrier, penetrates through the placenta (10%). Small amounts are detected in breast milk.
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 91% by the kidneys (40% as metabolites), 6% – through the intestine.
The elimination half-life (T1/2) in patients with normal renal function is on average 5.3 hours (3.5-9.2 hours after 30 mg IM, 4-7.9 hours after 30 mg IM). The T1/2 is longer in elderly patients and shorter in younger patients. Liver function has no effect on T1/2. In patients with impaired renal function in creatinine concentration in plasma 19-50 mg/l (168-442 µmol/l) the T1/2 is 10.3-10.8 hours, in more severe renal failure – more than 13.6 hours.
Total clearance is 0.023 l/kg/h (0.019 l/kg/h in elderly patients), intravenous infusion of 30 mg – 0.03 l/kg/h; in patients with renal insufficiency with creatinine concentration in blood plasma of 19-50 mg/l, intravenous infusion of 30 mg – 0.015 l/kg/h.
Not excreted by hemodialysis.
Dimedrol. Binding to plasma proteins is 98-99%. Most of it is metabolized in the liver, a smaller part is excreted unchanged in the urine within 24 hours. The elimination half-life (T1/2) is 1-4 hours. It is well distributed in the body, penetrates through the blood-brain barrier.
It is metabolized mainly in the liver by hydroxylation and conjugation to glucuronides; the products of biotransformation are eliminated in the urine. It is excreted with mother’s milk and may cause sedation in infants. Maximum activity occurs after 1 hour, duration of action – from 4 to 6 hours.
Indications for use
- Pain relief during postoperative period (including dental treatment)
- Pain management in muscles and joints
- post-traumatic pain syndrome
- renal colic.
Administration and dosages.
It is administered deep into the muscle, slowly at least 15 seconds in minimum effective doses selected according to the pain intensity and patient’s reaction. If necessary, opioid analgesics in reduced doses may be administered simultaneously.
Single dose when administered intramuscularly:
- Adults under 65 years of age and children over 16 years of age – 10-30 mg, depending on the severity of the pain syndrome;
- Adults over 65 years of age or with impaired renal function: 10-15 mg.
Doses for multiple parenteral intramuscular administration:
- Adults under 65 years of age and children over 16 years of age are given 10-60 mg on the first administration, followed by 10-30 mg every 6 hours (usually 30 mg every 6 hours);
- Adults over 65 years of age or with impaired renal function: 10-15 mg every 4-6 hours.
The maximum daily dose for adults under 65 years of age and children over 16 years of age should not exceed 90 mg, and for adults over 65 years of age or with impaired renal function, 60 mg when administered intramuscularly.
When parenteral administration the duration of treatment should not exceed 5 days.
Side effects
Often – more than 3%, less often – 1-3%, rarely – less than 1%.
Side effects associated with the use of ketorolac.
The digestive system: frequently – gastralgia, diarrhea; less frequently – stomatitis, flatulence, constipation, vomiting, feeling of stomach fullness; rarely – decreased appetite, nausea, gastrointestinal erosive and ulcerative lesions (including with perforation and/or bleeding – abdominal pain, epigastric spasm or burning, blood in stool or melena, vomiting with blood or “coffee grounds” type, nausea, heartburn, etc.), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.
Urinary system disorders: rare – acute renal failure, lower back pain, hematuria, azotemia, hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), increased frequency of urination, increased or decreased volume of urine, nephritis, edema of renal genesis.
Sensory system: rare: decreased hearing, tinnitus, visual impairment (including blurred vision).
Respiratory system: rarely – bronchospasm or dyspnea, rhinitis, pulmonary edema, laryngeal edema (shortness of breath, difficulty in breathing).
The central nervous system: often – headache, dizziness, somnolence, rarely – aseptic meningitis (fever, severe headache, cramps, neck and/or back stiffness), hyperactivity (mood changes, anxiety), hallucinations, depression, psychosis, fainting states.
Cardiovascular system: less frequently – increase in blood pressure.
Blood organs: rarely – anemia, eosinophilia, leukopenia.
Hemostasis: rarely – bleeding from the postoperative wound, nasal bleeding, rectal bleeding.
Skin: less common – skin rash (including maculopapular rash), purpura, rarely – exfoliative dermatitis (fever with or without chills, hyperemia, thickening or peeling of the skin, enlargement and/or pain of the palatine tonsils), urticaria, erythema malignant exudative (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome).
Local reactions: less frequent – burning or pain at the injection site.
Allergic reactions: rare – anaphylaxis or anaphylactoid reactions (changes in complexion, skin rash, urticaria, skin itching, tachypnea or dyspnea, eyelid edema, periorbital edema, shortness of breath, difficulty in breathing, heaviness in the chest, wheezing).
Other: often – edema (face, shins, ankles, fingers, feet, weight gain); less often – increased sweating, rarely – tongue swelling, fever.
Side effects associated with the use of dimedrol
Nervous system and sense organs: general weakness, fatigue, sedative effect, decreased attention, dizziness, drowsiness, headache, impaired coordination of movements, decreased speed of psychomotor reactions, anxiety, increased excitability, irritability, nervousness, insomnia, euphoria, fear of death, confusion, tremor, neuritis, seizures, paresthesias; dilated pupils, increased intraocular pressure, visual disturbances, diplopia, acute labyrinthitis, tinnitus. Patients with local brain lesions or epilepsy have activated (even when using low doses of dimedrol) convulsive discharges on EEG and this may provoke an epileptic seizure, tachycardia, extrasystole.
Blood system: agranulocytosis, thrombocytopenia, hemolytic anemia.
Gastrointestinal tract: dry mouth, transient numbness of the oral mucosa, anorexia, nausea, pain in the epigastric region, vomiting, diarrhea, constipation.
Urinary system: frequent and/or difficult urination, urinary retention, early menstruation.
Respiratory system: dry mucous membranes of the nose and throat, nasal congestion, thickening of bronchial secretion, a feeling of compression in the chest, difficulty in breathing, shortness of breath.
Skin and skin derivatives: hyperemia, itching, polymorphic rash, cyanosis of skin and mucous membranes.
Allergic reactions: rash, urticaria, anaphylactic shock.
Reactions at the injection place: local necrosis during subcutaneous and intradermal injection.
Others: increased sweating, chills, fever, hyperthermic syndrome, photosensitization.
Contraindications
Hypersensitivity to the components of the drug or other antihistamines, “aspirin” triad (combination of bronchial asthma, recurrent polyposis of the nose and sinuses, and intolerance to acetylsalicylic acid and medicines of pyrazolone series), hypovolemia (regardless of the cause), pheochromocytoma, epilepsy, prolonged Q-T interval syndrome or long-term use of drugs that may prolong the Q-T interval. Porphyria. Closed-angle glaucoma, prostatic hyperplasia, stenotic peptic ulcer disease of the stomach and duodenum, stenosis of the bladder neck, bradycardia, heart rhythm disorders. Ulcerative lesions of the gastrointestinal tract in the acute stage, hypocoagulation (including hemophilia), bleeding or high risk of bleeding, severe renal insufficiency (plasma creatinine > 50 mg/l), severe hepatic insufficiency or active liver disease, conditions after coronary artery bypass grafting, confirmed hyperkalemia, pregnancy (III trimester), inflammatory bowel disease, childbirth, lactation, children under 16 years (safety and effectiveness of use are not established).
Caution
Hypersensitivity to other NSAIDs, bronchial asthma; presence of factors that increase gastrointestinal toxicity: Alcoholism, tobacco smoking and cholecystitis; postoperative period; chronic heart failure, coronary heart disease; edema syndrome; arterial hypertension; impaired renal function (plasma creatinine below 50 mg/L); cholestasis; active hepatitis; sepsis; systemic lupus erythematosus; concomitant use with other NSAIDs, long-term use of NSAIDs, cerebrovascular disease, dyslipidemia/hyperlipidemia, diabetes, peripheral artery disease, history of peptic ulcers, presence of H. pylori, severe somatic diseases, concomitant use of oral GCS (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline), older age (over 65 years), pregnancy.
Interaction with other drugs
Ketorolac. Co-administration of ketorolac with paracetamol increases nephrotoxicity of ketorolac.
Administration with other NSAIDs, glucocorticosteroids, ethanol, corticotropin, calcium preparations increases the risk of gastrointestinal mucosal ulceration and gastrointestinal bleeding.
Concomitant administration with anticoagulant drugs – coumarin and indandion derivatives, heparin, thrombolytics (alteplase, streptokinase, urokinase), antiplatelet drugs, cephalosporins, valproic acid and acetylsalicylic acid increases the risk of bleeding.
Reduces the effect of hypotensive and diuretic drugs (reduces the synthesis of prostaglandins in the kidneys).
Administration together with methotrexate increases hepato- and nephrotoxicity (coadministration is possible only when using low doses of the latter and monitoring its plasma concentrations).
Administration with other nephrotoxic drugs (including gold drugs) increases the risk of nephrotoxicity.
Medicinal products that block tubular secretion reduce the clearance of ketorolac and increase its plasma concentrations.
Increases the effect of narcotic analgesics.
Myelotoxic drugs increase the manifestation of hematotoxicity of the drug.
Dimedrol potentiates the effects of anesthetics, sleeping pills, sedatives, narcotic analgesics and local anesthetics. When used with tricyclic antidepressants, it may increase the cholin-blocking and depressing effect on the central nervous system.
Possible risk of seizures when used with analeptics. Concomitant use of MAO inhibitors and dimedrol may lead to increased blood pressure and affect the central nervous and respiratory systems. The use of dimedrol together with hypotensive drugs may increase the feeling of fatigue. The drug increases the effect of ethanol, reduces the effectiveness of apomorphine as a vomiting agent in the treatment of poisoning. It should not be administered concomitantly with drugs containing dimedrol, including those for topical use.
Incompatibility. Do not mix with other drugs in the same container.
Use only the recommended solvent.
Special indications
Before prescribing the medicinal product, the question of previous allergy to the drug or to other NSAIDs should be ascertained. Due to the risk of allergic reactions, the first dose should be administered under close medical supervision.
Hypovolemia increases the risk of nephrotoxic adverse reactions.
If necessary, it may be administered in combination with narcotic analgesics.
It is not recommended to use as a drug for premedication, maintenance of anesthesia.
When coadministration with other NSAIDs, fluid retention, decompensation of cardiac activity, increased blood pressure may be observed. The effect on platelet aggregation stops after 24 – 48 hours. Do not use simultaneously with paracetamol for more than 5 days.
For patients with blood coagulation disorders, prescribe only with continuous monitoring of platelet count, especially important for post-operative patients who require careful hemostasis control.
The risk of drug complications increases with prolongation of treatment (in patients with chronic pain) and increasing the oral dose of the drug more than 40 mg/day.
Antacids, misoprostol, omeprazole are prescribed to reduce the risk of NSAID gastropathy.
Alcoholic beverages are contraindicated during treatment with the drug, exposure to UV radiation should be avoided. The use of diphenhydramine as an antiemetic may complicate the diagnosis of appendicitis and recognition of symptoms of overdose of other drugs.
Use in pregnancy and lactation
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system, ketorolac should not be used during pregnancy (especially in the third trimester).
The use of ketorolac is contraindicated during pregnancy, during labor and delivery.
Do not use during breastfeeding due to possible adverse effects of prostaglandin synthesis inhibitors on infants.
Influence on the ability to drive a car and operate complex mechanisms
It is recommended to avoid work requiring high attention and quick reaction (driving a vehicle, operating mechanisms and so on).
Overdose.
Symptoms: Abdominal pain, nausea, vomiting, peptic ulcer of the stomach and duodenum, erosive gastritis, impaired renal function, metabolic acidosis, dry mouth, difficulty breathing, mydriasis, face redness, CNS oppression or agitation, tachycardia, arrhythmia, depressed cardiovascular function and respiration, depression, hyperkinesia, confusion, delirium; in children – development of convulsions. A case of rhabdomyolysis after diphenhydramine overdose has been described.
Treatment: symptomatic and supportive therapy with careful control of respiratory function and blood pressure. Gastric lavage, administration of adsorbents (activated charcoal), parenterally administer diazepam if convulsions and CNS agitation symptoms develop. I/V drip administration of plasma substitute fluids, oxygen therapy. Epinephrine and analeptics should not be used. As an antidote in case of diphenhydramine overdose, physostigmine 0.02-0.06 mg/kg body weight may be administered intravenously several times if the severity of anticholinergic symptoms increases
Form of production
Solution for injection in 2 ml ampoules.
Storage conditions
Store in a dark place at temperatures not exceeding 25 C.
Keep out of reach of children!
Shelf life
2 years. Do not use after the expiration date.
Conditions of dispensing from pharmacies
Released by a doctor’s prescription.