Artrum® solution for intravenous and intramuscular administration 50 mg/ml

Artrum® solution for intravenous and intramuscular administration 50 mg/ml

International nonproprietary name

Ketoprofen

Pharmacological group

Нестероидные противовоспалительные препараты

Composition

Active ingredient:
Ketoprofen on a dry basis - 50 mg
Excipients:
propylene glycol - 400 mg
ethanol (ethyl alcohol) 96% - 100 mg
benzole (benzyl alcohol) - 20 mg
sodium hydroxide - for рН adjustment to 6.0-7.5
water for injection - up to 1 ml

Pharmacological action

Ketoprofen is non-steroidal anti-inflammatory drug.
The drug has anti-inflammatory analgetic and antipyretic effect. Ketoprofen inhibits the action of cyclooxygenase 1 and 2 (COX1 and COX2) and partily lipoxygenase ferments resulting in inhibition of the prostaglandin synthesis (including in the central nervous system, most probably in the hypothalamus) Stabilizes in vitro and in vivo liposomal membranes.
Ketoprofen higher concentrations inhibit bradykinin and leukotrienes synthesis. Ketoprofen has no adverse effect on the articular cartilage state.

Pharmacokinetics

Absorption
After intravenous administration of ketoprofen the mean plasma concentration after 5 minutes from the beginning of infusion and up to 4 minutes after the end is 26.4 ± 5.4 mg/ml. Bioavailability is 90%. After single intramuscular administration of 10 mg of ketoprofen the drug is identified in the plasma in 15 min. after the beginning of infusion and the peak concentration (1.3 mg/ml) is achieved after 2 hours. Bioavailability of the drug increases linearly with dose.
Distribution
99 % of ketoprofen are protein-bound, mainly with albumin fraction. Volume of distribution in the tissues is 0.1-0.2 l/kg. Ketoprofen enters the synovial fluid and its concentration after 3 hours of intravenous administration of 100 mg reaches 1.5 mg/ml, that is 50% of the plasma concentration (about 3 mg/ml). After 9 hour the concentration in the synovial fluid is 0.8 mg/ml and the plasma concentration is 0.3 mg/ml. This indicates that ketoprofen enters slowly the synovial fluid and is slower removed from it. Steady state plasma concentrations of ketoprofen are identified even after 24 hours of its administration. After single intramuscular administration of 10 mg ketoprofen is identified both in the cerebrospinal fluid and in the blood serum after 15 minutes.
Metabolism
Ketoprofen is intensively metabolized with microsomal hepatic enzymes. It is bound with glucuronic acid and removed from the body in the form of glucoronide. Ketoprofen has now active metabolites.
Recovery
Ketoprofen half-life is 2 hours. Up to 80% of ketoprofen are excreted by the kidneys during 24 hours mainly (> 90 %) in the form of ketoprofen glucoronide, and about 10% - by the intestinal tract. Ketoprofen is removed slower in patients with renal failure and its half-life is increased by 1 hour. Half-life in patients with hepatic failure is increased so ketoprofen can accumulate in the tissues. Ketoprofen metabolism and recovery proceed slower in elder patients and this is significant only for patients with renal failure.

Indications for Use

Expectant therapy of the pain syndrome including with inflammatory process ща various origin:
- rheumatic arthritis;
- seronegative arthritis: ankylosing spondylitis (Bekhterev's disease), psoriatic arthritis, Reiter disease;
- uratic arthritis, chondrocalcinosis;
- degenerative diseases of the locomotor system including osteoarthrosis; weak, moderate or severe pain syndrome headache, bilious blind headache, tendinitis, bursitis, myodynia, neurodynia, radiculitis;
- post traumatic and postsurgical pain syndrome, including associated with inflammation and raised body temperature;
- pain syndrome in case of oncology diseases;
- algodismenorrhea.
The drug is intended for expectant therapy, pain or inflammation reduction at the administration moment, has no effect on progression of the disease.

Contraindications

- hypersensitivity to ketoprofen or other components of the drug, as well as salicylates or other non-steroidal anti-inflammatory drugs;
- complete or partial composition of bronchial asthma, recurrent nasal and air cell polyposis or intolerance of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including in the past medical history);
- active gastroduodenal ulcer;
- ulcerative colitis, Crohn's disease;
- hemophilia and other blood-clotting disorders;
- pediatric use (age to 15 years old);
- severe hepatic failure;
- severe renal failure: creatine clearance less than 30 ml/min., confirmed hyperkalemia, advanced renal diseases;
- decompensated heart failure;
- postsurgical period after coronary artery bypass graft surgery;
- gastrointestinal, cerebrovascular and other haemorrhage (or suspected haemorrhage);
- chronic dyspepsia;
- III trimester of pregnancy;
- lactation period.
With care
Ulcer disease in the past medical history, Helicobacter pylori infection, bronchial asthma in the past medical history; overt cardiovascular, cerebrovascular diseases and peripheral arterial diseases; dyslipidemia, hepatic failure, hyperbilirubinemia, ging liver; chronic renal failure (creatine clearance 30-60 ml/min.); chronic heart failure, arterial hypertension, blood diseases; dehydration, diabetes mellitus; smoking; elderly age; long-term administration of non-steroidal anti-inflammatory drugs, simultaneous administration of anticoagulating agents (including Warfarin), antiaggregants (including Clopidogrel), oral glucocorticosteroids (including prednisolone), selective serotonin reuptake inhibitors (including fluoxetine, paroxetine, citalopram, sertraline) (see section “Interaction with other drugs”).
Administration during pregnancy and lactation period
Inhibition of the prostaglandin synthesis may have adverse affect on pregnancy and/or embryonal development. The data obtained during epidemiological studies of administration of the prostaglandin synthesis inhibitors during early pregnancy confirm increased risk of spontaneous miscarriage and development of valvular heart diseases (up to 105%) and congenital anterior abdominal wall defects.
The risk increases with dose and treatment duration.
The drug can be prescribed to pregnant women at the I and II trimesters of pregnancy only when potential benefit to the mother outweighs any potential risk to the fetus. In this case the minimum effective dose shall be administered with the shortest treatment course. Ketoprofen is contradicted in pregnant women during the III trimester of pregnancy because of possible development of weak uterine labor, bleeding time increment, antiaggregant effect (even at small doses) as well as affect on the fetus (cardiopulmonary toxicity including premature closing of the ductus arteriosus and pulmonary hypertension, renal dysfunction which can develop to renal failure with development of hypamnion).
At present data about ketoprofen secretion into the breast milk is not available, so if ketoprofen is prescribed to a nursing mother then breast-feeding stop shall be considered.

Cautions

Long-term administration of non-steroidal anti-inflammatory drugs requires regular assessment of clinical blood analysis as well as monitoring of kidney and liver functions especially in patients at the elderly age (more than 65 years old), faecal occult blood testing. Administration of ketoprofen for treatement of patients with arterial hypertension, cardiovascular diseases causing water retention requires special precautions and more frequent monitoring of blood pressure.
Treatment shall be immediately stopped in case of visual organ disorders.
Ketoprofen like other non-steroidal anti-inflammatory drugs may mask the symptoms of inflammatory infections. In case of identification of infection symptoms or feeling unwell after the drug administration consult the doctor immediately.
In case of any gastrointestinal contradictions in the past medical history (bleedings, perforation, ulcer disease), long-term therapy and administration of higher doses of ketoprofen the patient shall stay under careful supervision of the doctor.
Due to important role of prostaglandins supporting the renal blood flow special precautions shall be taken when prescribing ketoprofen to the patients with heart and renal failure as well as when treating elderly patients receiving diuretics and to patients with indicated depression in the circulating blood volume (for example after surgical intervention). Administration of ketoprofen may affect woman fertility so the patients with infertility (including undergoing screening) are not recommended to receive the drug.
Effects on ability to drive and use machines
During administration of the drug precautions shall be taken when driving and performing other potential hazardous activities requiring increased attention focusing and psychomotor reaction speed as the drug may cause dizziness and other adverse effects influencing the mentioned abilities.

Dosing and Administration

Intravenous and intramuscular administration.
The minimum effective dose of the drug shall be administered to reduce the adverse reaction incidence rate. Maximum daily dose is 200 mg.
The potential benefit and risk ratio shall be assessed thoroughly prior to administration of ketoprofen at dose 200 mg/day.
Intramuscular administration: 100 mg (1 ampoule) 1-2 times per day.
Intravenous infusion administration of ketoprofen shall be performed only under inpatient conditions.
Infusion duration shall be from 0.5 to 1 hour. Intravenous administration shall be applied not longer than 48 hours.
Short-term intravenous infusion: from 100 to 200 mg (1-2 ampoules) of ketoprofen deluted in 100 ml of 0.9% saline solution shall be administered during 0.5-1 hour.
Long-term intravenous infusion: from 100 to 200 mg (1-2 ampoules) of ketoprofendeluted in 500 ml of infusion solution (0.9% saline solution, Ringer's solution, 5 % dextrose solution) shall be administered during 8 hours; the repeated administration is possible after 8 hours.
Maximum daily dose is 200 mg.
Ketoprofen can be combinated with centrally acting painkillers; it can be mixed with opioids (for example Morphine) in the same vial. Pharmaceutically incompatible with tramadol solution due to precipitation.
Parenteral administration of Artrum can be combined with administration of oral dosage forms (tablets, capsules) or rectal suppositiories.

Side effect

According to the World Health Organization (WHO) the adverse effects are classified based on their frequency as follows: - very common (≥ 1/10), - common (frequent)(≥ 100, < 1/10), - uncommon (infrequent) (≥ 1/1000, < 1/100), - rare (≥ 1/10000, < 1/1000), - very rare (≥ 1/10000), - unknown frequency (frequency of adverse events cannot be determined based on the current data).
Adverse hematopoietic and lymphoid system effects: rare: hemorrhagic anemia, haemolytic anaemia, leukopenia; unknown frequency: agranulocytosis, thrombocytopenia, bone marrow dysfunction.
Adverse immune system effects: unknown frequency: anaphylactic reactions (including anaphylactic shock).
Adverse nervous system effects: common (frequent): insomnia, depression, asthenic syndrome; uncommon (infrequent): headache, dizziness, somnolency; rare: paresthesia, confused consciousness or unconsciousness, peripheral polyneuropathy; unknown frequency: convulsions, taste disturbance, emotional instability.
Adverse sense organ effects: rare: blurred vision, tympanophony, conjunctivitis, dry eye syndrome, ophthalmalgia, diminished hearing; unknown frequency: optic neuritis.
Adverse cardiovascular effects: uncommon (infrequent): tachycardia; unknown frequency: heart failure, blood pressure increase, vasodilation. Adverse respiratory system effects: rare: bronchial asthma attack, epistaxis, laryngeal edema; unknown frequency: bronchospasm (especially in patients with hypersensitivity to non-steroidal anti-inflammatory drugs), rhinitis.
Adverse gastrointestinal effects: common (frequent): nausea, vomiting, dyspepsia, abdominal pain, NSAID-gastropathy; uncommon (infrequent): constipation, diarrhea, abdominal distention, gastritis; rare: peptic ulcer, stomatitis; very rare: nonspecific ulcerative colitis attack, Crohn's disease, ulorrhagia, gastrointestinal and hemorrhoidal hemorrhage, melaena, perforation of gastrointestinal tract organs. unknown frequency: gastrointestinal discomfort, stomach ache.
Adverse liver and biliary tract effects: rare: hepatitis, increased liver ferments and bilirubin activity.
Adverse skin effects: uncommon (infrequent): exanthema, skin itching; unknown frequency: photosensitization, baldness, urticaria fever, chronic urticaria fever attack, angioneurotic edema, erythema, bullous eruption, including Steve-Johnson syndrome, toxic epidermal necrolysis, purpura. Adverse urinary system effects: rare: cystitis, urethritis, hematuria; very rare: acute renal failure, interstitial nephritis, nephrotic syndrome, abnormal values of renal function indicators; unknown frequency: water retention resulting in body weight gain, hyperkalemia.
Other: uncommon (infrequent): peripheral edemas, tiredness; rare: hemoptysis, menometrorrhagia, dyspnea, thirst, muscular twitching. Overdose
Ketoprofen overdose can be associated with headache, nausea, vomiting, abdominal pain, vomiting with blood, melaena, impairment of consciousness, respiratory depression, convulsions, renal disorders and renal failure.
In case of overdose stomach lavage and administration of activated carbon shall be applied.
Treatment - expectant and supporting therapy; ketoprofen effect on gastrointestinal tract can be mitigated with the drugs reducштп the stomach gland secretion (for example proton pump inhibitors) and prostaglandins, monitoring of respiratory and cardiovascular activity, specific antidote is not identified, haemodialysis is ineffective.

Interaction with other medicines

Undesirable combinations of drugs

Combined administration of ketoprofen with other non-steroidal anti-inflammatory drugs (including cyclooxygenase-2 selective inhibitors), salicylates at high doses is not recomended due to high risk of gastrointestinal bleeding and ulceration of the gastrointestinal tract mucosa.
Simultaneous administration with anticoagulating agents (heparine, warfarin), antiaggregants (ticlopidine, clopidogrel) increase the risk of bleeding. If administration of such combination is unavoidable the patients state shall be monitored very carefully.
Simultaneous administration with lithium agents may increase the lithium plasma concentration up to toxic values. The lithium plasma concentration shall be carefully monitored and the lithium agent dose shall be timely adjusted during and after treatment with non-steroidal anti-inflammatory drugs.
The drug increase the hematologic toxicity of methotrexate especially when administered at high doses (more than 15 mg per week). Time interval between ending or beginning the therapy with ketoprofen and administration of methotrexate shall be minimum 12 hours.
Combinations to be applied with care
The patients receiving the ketoprofen therapy together with diuretics especially with developing dehydration have higher risk of renal failure development due to reduction of the renal blood flow caused by inhibition of the prostaglandin synthesis. These patients shall take rehydration measures before administration of ketoprofen. The renal function shall be monitored after beginning the treatment.
Combined administration of the drug  with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients with renal disorders (with dehydration, in patients at the elderly age) may cause worsening of the renal disorders including development of renal failure.
Blood testing shall be conducted on a weekly basisi during the ferst weeks of simultaneous administration of ketoprofen and methotrexate at dose not exceeding 15 mg/week. The testing shall be conducted more often in patients at the elderly age and in case of any symptoms of renal disorders.
Combinations to be considered
Ketoprofen may reduce the effect of antihypertensive agents (beta-blockers, angiotensin-converting enzyme inhibitors, diuretics).
Simultaneous administration with selective serotonin reuptake inhibitors increases the risk of gastrointestinal bleeding.
Simultaneous administration with thrombolytics increases the risk of bleeding.
Simultaneous administration with potassium salts, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs, low molecular heparines, cyclosporine, tacrolimus and trimethoprim increases the risk of hyperkalemia.
Simultaneous administration with cyclosporine, tacrolimus may increase the risk of additive nephrotoxic effect especially in patients at the elderly age.
Administration of several antiaggregants (tirofiban, eptifibatide, abciximab, iloprost) increases the risk of bleeding.
The drug increases the plasma concentration of cardiac glycosides, calcium channel blocking agents, cyclosporine, methotrexate and digoxin.
Ketoprofen may increase the effect of oral hypoglycaemics and some anti-seizure medications (phenytoin).
Simultaneous administration with probenecid reduces significantly ketoprofen clearance  in the plasma.
Non-steroidal anti-inflammatory drugs may reduce efficacy of mifepristone. Administration of non-steroidal anti-inflammatory drugs shall be started not earlier than 8-12 days after withdrawal of mifepristone.
Pharmaceutically incompatible with tramadol solution due to precipitation.

Form release

Storage conditions

At temperature maximum 25 °С.

 

Expiration date

3 years