Ketoprofen

General characteristics. Structure:

Active ingredient: 100 mg of ketoprofen in 1 ml of solution.

The drug rendering analgeziruyushchy, febrifugal, antiinflammatory and anti-aggregation action.

Pharmacological properties:

Pharmacodynamics. Inhibits activity of TsOG-1 and TsOG-2, synthesis of PG and LT oppresses. Has antibradikininovy activity, stabilizes lizosomalny membranes and release from them of the enzymes promoting destruction of fabrics at a chronic inflammation detains. Reduces release of cytokines, brakes activity of neutrophils.

The antiinflammatory effect occurs by the end of 1 week of reception. Lizinovy salt of ketoprofen possesses equally expressed antiinflammatory, analgetic, febrifugal action.

At a joint syndrome weakens a joint pain at rest and at the movement, reduces morning constraint and a swelling of joints, promotes increase in volume of movements.

Pharmacokinetics. At intake bioavailability — about 90% is soaked up quickly and rather fully. Cmax  in blood is reached in 0,5–2 h after intake, in 1,4–4 h — at rectal administration, in 15–30 min. — at parenteral administration and in 5–8 h — after drawing on skin. At reception of retardirovanny forms the minimum effective concentration is defined by 2–3 h, Cmax  is usually reached during 6–7 h. At a concomitant use with food the general bioavailability (AUC) does not change, the speed of absorption is slowed down (both for usual, and for retardirovanny forms). Absorption is followed by effect of "the first passing" through a liver. Linkng with proteins of a blood plasma, is preferential with albumine — 99%. Equilibrium concentration in plasma is reached in 24 h after the beginning of regular reception. Easily passes through gistogematichesky barriers and it is distributed in fabrics and bodies. In significant quantity does not get through GEB. Ketoprofen level in synovial fluid is lower, than in blood, but within therapeutic remains on an extent бóльшего time (6–8 h). It is metabolized in a liver by a glyukuronidation. It is removed preferential by kidneys — 80% during 24 h, mainly in the form of glucuronic derivative. T1/2  is (2,05±0,58) h later in/in introductions; 2–4 h after intake in a usual lekforma in a dose of 200 mg; (5,4±2,2) h after reception of a retardirovanny form in a dose of 200 mg. At a renal failure removal is slowed down.

Lizinovy salt of ketoprofen: Tmax  after intake in the form of granules — 15 min., at parenteral administration — 20–30 min., at rectal — 45–60 min. At reception in the form of capsules of the slowed-down release effective concentration is reached cherez20-30 mines and remains during 24 h.

Therapeutic concentration in synovial fluid sokhranyaetsya18-20ch. It is metabolized by microsomal enzymes of a liver. 60–80% — in the form of a glucuronide for 24 h are removed by kidneys.

At elderly patients the plasma and renal clearance is reduced, the size Cmax, AUC and untied fraction raise with increase in age (at women more, than at men).

At cutaneous application there is a slow transdermalny absorption of ketoprofen that provides maintenance of its concentration in the inflamed fabrics within therapeutic level for a long time. Well gets into synovial fluid and connecting fabric. Absorption in a system blood stream insignificant, bioavailability for gel, spray — about 5%.

When using solution for topical administration (solution for rinsing) in a dose of 160 mg of Tmax  — 1 h, the size Cmax  — 350 mg/ml (4% of the concentration received at oral administration of 80 mg).

Carcinogenicity, mutagenicity, influence on fertility. Researches of chronic toxicity at mice at use inside (to 32 mg/kg/days, 96 mg/sq.m/days, about 0,5 MRDCh) did not reveal cancerogenic effect of ketoprofen. In a biennial research of carcinogenicity at rats at doses to 6 mg/kg/days (36 mg/sq.m/days) of adverse oncogenous action it is not revealed. At the same time animals in all groups received HP during 104 weeks, except for the females receiving 6 mg/kg/days (36 mg/sq.m/days) during 81 weeks because of low survival. Survival in the groups receiving HP during 104 weeks made 6% in comparison with control group.

The ketoprofen mutagenicity in Ames's test is not revealed. At administration of ketoprofen to males of rats (to 9 mg/kg/days, 54 mg/sq.m/days) the significant effect on reproductive function and fertility is not revealed. At females of rats at doses of 6 or 9 mg/kg/days (36 or 54 mg/sq.m/days) decrease in number of implantations is noted.

At high doses at rats and dogs the spermatogenesis is broken and inhibited, at dogs and monkeys baboons — the mass of testicles decreases.

Indications to use:

For system use (inside, in oil, in/in, rektalno). Inflammatory and degenerative diseases of a musculoskeletal system, including pseudorheumatism, nonspecific spondylarthritis (ankylosing and psoriasis spondylitis), gouty arthritis, pseudogout, osteoarthrosis, extraarticular rheumatism (tendovaginitis, bursitis, capsulitis). Stopping of a pain syndrome of various genesis, including postoperative, posttraumatic pain, an ischialgia, a mialgiya, radiculitis, bruises and muscle strain, renal colic, pain syndromes in dental, gynecologic, neurologic, oncological practice. A symptomatic treatment of an acute pain syndrome at inflammatory diseases of a musculoskeletal system (only for introduction in oil). Primary dysmenorrhea.

For topical administration: - at application on skin — acute and chronic inflammatory diseases of a musculoskeletal system (a pseudorheumatism, a spondylarthritis, arthrosis, osteochondrosis); painful inflammatory or traumatic (including sports) damages of joints, sinews, sheaves and muscles (including arthritis, a periarthritis, a tendinitis, tendosinovit, a bursitis, bruises of muscles, sprains, ruptures of sheaves and sinews of muscles, dislocations, injuries of a meniscus of a knee, a wryneck, a lumbago), phlebitis, thrombophlebitis of superficial veins, a lymphangitis, inflammations of the skin;

- in the form of solution for rinsing — a symptomatic treatment of inflammatory diseases of an oral cavity, throat and throat (including quinsy, laryngitis, pharyngitis, stomatitis, a glossitis, an ulitis, a periodontal disease, periodontosis), for an analgesia at treatment and an exodontia (as auxiliary HP).

Route of administration and doses:

Inside, in oil, in/in, rektalno, nakozhno, locally. The dose is selected individually, depending on the nature of a disease, expressiveness of a pain syndrome, a condition of the patient. If necessary dosage forms can be used in various combinations, at the same time the total daily dose can be increased to 300 mg or is reduced to 100 mg. In an initiation of treatment a daily dose — 300 mg in 2–3 receptions, supporting — 150–200 mg/days.

Capsules, tablets, granulate it is recommended to accept during food.

Rektalno: 1–2 suppositories a day.

In oil: 100 mg 1–2 times a day; after stopping of a pain syndrome appoint inside and/or rektalno.

In/in: 100–200 mg in 100–150 ml of 0,9% of solution of sodium of chloride. Infusions of ketoprofen have to be performed only in a hospital.

Nakozhno: 2–4 times a day apply gel/cream/spray on skin over the center of an inflammation and carefully rub; imposing of a dry bandage is possible.

Locally (solution for rinsing): 2–3 rinsings a day.

Lizinovy salt of ketoprofen: solution for injections: in oil or in/in on 160 mg (2 ml) 1–3 times a day, at an electrophoresis solution is imposed on a negative pole. Suppositories: adult — 160 mg. To children weight tela15-30kg — on 30 mg, more than 30 kg — 60 mg 2–3 times a day. Granules: adult — 80 mg, to children — 40 to grastvorit in 1/2 glasses of water and to accept inside 2–3 times a day.

Features of use:

Use at pregnancy and feeding by a breast. Teratogenic effects. In researches at mice at administration of ketoprofen in doses to 12 mg/kg/days (36 mg/sq.m/days) and at rats at doses of 9 mg/kg/days (54 mg/sq.m/days) that is approximately equivalent 0,2 MRDCh (185 mg/sq.m/days), was not revealed teratogenic or embriotoksichesky effects. In separate researches at rabbits doses, toxic for females, were associated with embriotoxity, but not with teratogenecity. However reproductive researches at animals not always predict effects at the person.

Not teratogenic effects. As adverse influence of the funds inhibiting synthesis of PG for cardiovascular system of a fruit (premature closing of an arterial channel) is known, it is necessary to avoid use at pregnancy (especially on late terms).

At intake or rectal administration during pregnancy disturbance of a hemodynamics at the newborn is possible that is followed by heavy disorders of function of breath, and use shortly before childbirth can lead to their delay.

Adequate and strictly controlled researches at pregnant women are not conducted. Use at pregnancy in I and II trimesters is possible if the expected effect of therapy exceeds potential risk for a fruit, in the III trimester (especially after 36 weeks) — it is contraindicated because of possible influence on a uterus tone.

Category of action on a fruit on FDA — C. Childbirth and delivery. Effects of ketoprofen on childbirth and delivery at the person are unknown. Researches on rats showed that ketoprofen in a dose of 6 mg/kg (36 mg/sq.m/days) that it is approximately equivalent 0,2 MRDCh, prolongs pregnancy if it is applied prior to childbirth.

The women planning pregnancy should refrain from ketoprofen use since against the background of its reception the probability of implantation of an ovum can decrease.

It is unknown whether ketoprofen gets into breast milk of the person. At rats at doses of 9 mg/kg (54 mg/sq.m/days, about 0,3 MRDCh) ketoprofen did not exert impact on perinatal development. At administration of ketoprofen to the lactating dogs concentration in milk made 4–5% of concentration in plasma. Like other substances which are excreted in breast milk nursing mothers are not recommended to apply ketoprofen.

It is necessary to show care and to make careful medical observation in the presence in the anamnesis of instructions on allergic reactions to HP of a "aspirinovy" row, a "aspirinovy" triad, a peptic ulcer of a stomach and duodenum, at anemia, alcoholism, tobacco smoking, alcoholic cirrhosis, a hyperbilirubinemia, a liver failure, a diabetes mellitus, dehydration, sepsis, chronic heart failure, hypostases, arterial hypertension, blood diseases (in т.ч leukopenias, thrombocytopenia, at blood coagulation disturbance), deficit glyukozo-6-fosfatdegidrogenazy, stomatitis; with care at external use — at an aggravation of a hepatic porphyria, GIT erosive cankers, heavy abnormal liver functions and kidneys, chronic heart failure, bronchial asthma, at children up to 12 years.

At the instruction in the anamnesis on allergic reactions to NPVS apply only in urgent cases.

Risk of cardiovascular complications. NPVS can cause increase in risk of serious cardiovascular complications, including a myocardial infarction and a stroke which can lead to a lethal outcome, especially at prolonged use. At patients with cardiovascular diseases or risk factors of development of cardiovascular pathology the risk is especially high.

Risk of gastrointestinal complications. NPVS cause increase in risk of serious side effects from a GIT, including bleeding, an ulceration and perforation of a stomach or intestines which can be fatal, especially at prolonged use. These complications can arise uses without the foretelling symptoms at any time. Elderly patients have higher risk of serious complications from a GIT.

Reception of ketoprofen can mask symptoms of an infectious disease.

During treatment control of a picture of peripheral blood and a functional condition of a liver and kidneys is necessary. In need of definition of 17 ketosteroids drug should be cancelled for 48 h prior to a research.

It is necessary to avoid hit in eyes and on other mucous membranes of forms for cutaneous use; it is not recommended to apply on open wounds or the damaged sites of skin.

During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

System side effects. When carrying out clinical tests the following side effects were noted (perhaps connected using ketoprofen):

From bodies of a GIT: dyspepsia (11%); 3–9% — nausea, abdominal pain, a diarrhea/lock, a meteorism;> 1% — anorexia, vomiting, stomatitis;

From a nervous system and sense bodys: 3–9% — a headache, excitement (including an insomniya, nervousness, unusual dreams);> 1% — dizziness, oppression of TsNS (including drowsiness, an indisposition), a ring in ears, a vision disorder;

From cardiovascular system and blood (a hemopoiesis, a hemostasis):

From respiratory system:> 1% — диспноэ, a pneumorrhagia, nasal bleeding, pharyngitis, rhinitis, a bronchospasm, throat hypostasis.

From urinogenital system: 3–9% — a renal failure (hypostases, increase in ureal nitrogen of blood);> 1% — symptoms and signs of irritation of urinary tract;

From integuments:> 1% — rash, an alopecia, eczema, prurit, urticaria, violent rash, exfoliative dermatitis, a photosensitization, skin discoloration, онихолизис, a toxic epidermal necrolysis, a mnogoformny erythema, Stephens-Johnson's syndrome.

Others. The side effects meeting with frequency.

From cardiovascular system and blood (a hemopoiesis, a hemostasis): arrhythmia, myocardial infarction.

From bodies of a GIT: a bukkalny necrosis (for a peroral form), ulcer colitis, a microvesicular steatosis, pancreatitis, aggravation of a diabetes mellitus.

From a nervous system and sense bodys: dysphoria, hallucinations, dreadful dreams, changes of the personality, aseptic meningitis.

Others: septicaemia, shock, disturbance of a libido, acute tubulopatiya, gynecomastia.

Lizinovy salt of ketoprofen in comparison with ketoprofen causes side effects from a GIT less often (thanks to the fact that lizinovy salt of ketoprofen has neutral pH and, respectively, smaller irritant action on mucous a stomach).

Local side effects: at rectal use — an itch, weight in anorectal area, an exacerbation of hemorrhoids; at cutaneous use — skin allergic reactions, a photosensitization, development of system side effects (at prolonged use on the extensive surfaces of skin); when using solution for rinsing — a sensitization (at prolonged use).

Interaction with other medicines:

Pharmaceutical it is incompatible with solution of a tramadol.

Reduces efficiency of uricosuric HP, strengthens effect of anticoagulants, antiagregant, fibrinolitik, ethanol, side effects glyuko-and mineralokortikoid, estrogen; reduces efficiency of hypotensive HP and diuretics.

Joint reception with other NPVS, glucocorticoids, ethanol, corticotropin can lead to formation of ulcers and development of gastrointestinal bleedings, to increase in risk of development of disturbances of functions of kidneys.

Co-administration with peroral anticoagulants, heparin, trombolitika, antiagregant, tsefoperazony, tsefamandoly and tsefotetany increases risk of development of bleedings.

Increases hypoglycemic effect of insulin and peroral hypoglycemic HP (recalculation of a dose is necessary).

Inductors of a microsomal oxidation in a liver (Phenytoinum, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) increase products of hydroxylated active metabolites.

Joint appointment with Valproatum of sodium causes disturbance of aggregation of thrombocytes.

Increases concentration in plasma of verapamil and nifedipine, drugs of lithium, a methotrexate.

Antacids (including aluminum - and magniysoderzhashchy) do not influence the speed and size of absorption of ketoprofen.

Myelotoxic HP strengthen manifestations of a gematotoksichnost.

Contraindications:

Hypersensitivity (including to other NPVS). For system use: "aspirinovy" asthma, a peptic ulcer of a stomach and duodenum (aggravation), ulcer colitis (aggravation), a disease Krone, a diverticulitis, a round ulcer, disturbances of coagulant system of blood (in т.ч hemophilia), a renal and liver failure, children's and teenage age up to 18 years, pregnancy (the III trimester); for rectal use (in addition): hemorrhoids, proctitis, proctorrhagias; for cutaneous the primeneniya:moknushchy dermatosis, eczema infected grazes, disturbance of integrity of integuments, children's age up to 6 years.

Ketoprofen is not shown for stopping of a pain syndrome when carrying out operation of coronary shunting.

Overdose:

Symptoms: the lethargy, dizziness, nausea, vomiting, pain in epigastriums — symptoms are usually reversible. The respiratory distress, a coma, spasms can be noted. Seldom — bleeding from a GIT, hypotension/hypertensia, an acute renal failure.

Treatment: symptomatic and maintenance therapy, monitoring of respiratory and cardiovascular system. The specific antidote is not revealed. The hemodialysis is ineffective.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for injections of 100 mg/ml, on 2 ml in each ampoule. On 5 or on 10 ampoules in cardboard packaging.