Etamsylate

Pharmacological properties

etamzilat is a means to prevent and stop bleeding. it affects the first stage of the mechanism of hemostasis (the interaction between endothelium and platelets). dicinone increases platelet adhesion, normalizes the stability of capillary walls, thereby reducing their permeability, inhibits prostaglandin biosynthesis, which cause platelet disaggregation, vasodilation and increased capillary permeability. as a result, bleeding time is significantly reduced, blood loss is reduced.

Pharmacokinetics Ethamylate when ingested is almost completely absorbed in the digestive tract, reaching C_max in blood plasma 4 hours after administration. When taken orally, about 95% of the drug binds to blood plasma proteins.

After iv administration of the drug, the hemostatic effect is observed after 5-15 minutes, the maximum is achieved within 1 hour. After iv administration of Dicinone at a dose of 500 mg, the maximum plasma level is reached after 1 hour and amounts to 30-50 μg / ml. With iv administration, about 90% of the drug binds to blood plasma proteins.

About 72% of the administered dose is excreted during the first 24 hours with urine unchanged. T_½ etamzilate from blood plasma - about 2 hours. Ethamsylate crosses the placental barrier. It is not known whether etamzilate passes into breast milk.

Indications

Dicinon is prescribed for the prevention and control of hemorrhages in the surface and internal capillaries of various etiologies, especially if bleeding is caused by endothelial damage:

• prevention and treatment of bleeding during and after surgical operations in otolaryngology, gynecology, obstetrics, urology, dentistry, ophthalmology and plastic surgery;
• prevention and treatment of capillary bleeding of various etiologies and localizations: hematuria, metrorrhagia, primary hypermenorrhea, hypermenorrhea in women with intrauterine contraceptives, nosebleeds, gum bleeding.

In addition, injection solution: neonatology: prevention of periventricular bleeding in premature infants.

Application

Use the tablets inside. tablets are taken during or after meals with a little water.

The daily dose is usually 2 tablets 2-3 times a day (1000-1500 mg).

Before surgery, use 1-2 tablets (250-500 mg) 1 hour before surgery.

After surgery, use 1-2 tablets (250-500 mg) every 4-6 hours until the risk of bleeding disappears.

In menorrhagia, prescribe 2 tablets 3 times a day (1500 mg) for 10 days, starting from the 5th day from the expected onset of menstruation to the 5th day of the next menstrual cycle.

The daily dose for children is half the dose for adults.

Patients with hepatic or renal failure should be used with caution.

Rr for injections. The drug is used in / in (slowly) or in / m. The optimal daily dose for adults is 10–20 mg / kg of body weight, which is administered in 3-4 doses (in most cases, the contents of 1-2 ampoules are administered 3-4 times a day). The daily dose for children is half the dose for adults.

Surgical interventions: 1 hour before the surgical intervention, inject IV or IM contents of 1-2 ampoules. During the operation, inject the contents of 1-2 ampoules, the introduction of this dose can be repeated. After the operation, administer the contents of 1-2 ampoules every 4-6 hours until the risk of bleeding disappears.

Neonatology: the drug is administered intramuscularly at a dose of 10 mg / kg body weight (0.1 ml = 12.5 mg). Treatment must be started within the first 2 hours after birth. Inject the drug every 6 hours for 4 days to a total dose of 200 mg / kg body weight.

Dicinon can be applied topically (skin graft, tooth extraction) using a sterile gauze cloth moistened with the drug. Perhaps the combined use of the oral form of the drug with parenteral administration.

Impaired liver and kidney function.Clinical data regarding dosage recommendations are insufficient, therefore, in such patients, the drug should be used with caution.

Contraindications

Hypersensitivity to etamsylate or any other ingredient of the drug. acute porphyria, increased blood coagulability, thrombosis, thromboembolism. hemoblastosis (lymphatic and myeloid leukemia, osteosarcoma) in children; injection solution also: hypersensitivity to sodium sulfite; bah.

Side effects

From the nervous system: headache, dizziness, flushing, paresthesia in the lower extremities.

On the part of the cardiovascular system: thromboembolism, arterial hypotension, decreased tissue perfusion, independently recovers after some time.

From the gastrointestinal tract: nausea, pain in the epigastric region.

On the part of the immune system: allergic reactions, skin rash, urticaria, pruritus, anaphylactic shock, exacerbation of AD, a case of angioedema has been described.

Blood and lymphatic system: agranulocytosis, neutropenia, thrombocytopenia.

From the musculoskeletal system: arthralgia.

Vascular disorders: thromboembolism.

Violation at the injection site: itching, redness.

Other: asthenia, fever, bronchospasm, acute porphyria.

All side effects are mild and transient.

In children who were treated with etamsylate to prevent bleeding in acute lymphatic and myeloid leukemia, severe leukopenia was more often noted.

special instructions

It is used with caution in patients with a history of thrombosis or thromboembolism. the drug is ineffective in thrombocytopenia.

With hemorrhagic complications associated with an overdose of anticoagulants, it is recommended to use specific antidotes.

Before starting treatment, other causes of bleeding should be ruled out. If Dicinon is used to reduce excessive and / or prolonged menstrual bleeding and no improvement is noted, possible pathological causes (for example, the presence of uterine fibroids) should be ruled out.

In case of skin reactions or high body temperature, treatment should be discontinued and the doctor advised, as this may be a sign of hypersensitivity.

The drug contains lactose, so patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome should not use Dicinon.

Use with caution in patients with a history of thrombosis or thromboembolism.

Given the risk of lowering blood pressure with parenteral administration of the drug, it should be used with caution in patients with unstable blood pressure or hypotension.

If a patient needs infusion of dextrans, etamzilate should be used before infusion of the latter.

The use of etamzilate in patients with impaired indicators of the blood coagulation system is possible, but it should be supplemented by the introduction of drugs that eliminate the identified deficiency or defect of coagulation system factors.

It is forbidden to use the drug in case of a change in color of the injection solution.

Dicinone contains sodium metabisulphite (E223) as an antioxidant. In sensitive patients, sulfites can cause allergic reactions, nausea, diarrhea. Some cases of anaphylactic shock and life-threatening asthma attacks have been reported. Hypersensitivity to sulfites is more often observed in patients with AD.

Incompatibility. Dicinone solution is incompatible with sodium bicarbonate solution and sodium lactate powder. Pharmaceutically incompatible (in the same syringe) with other drugs.

Use during pregnancy and lactation. There are no reliable data on the effect of the drug on the fetus during pregnancy. The drug is contraindicated in Ι trimester of pregnancy.In ΙΙ and ΙΙΙ trimester of pregnancy, the use of the drug is possible if the benefit to the mother outweighs the risk to the fetus.

When using the drug, breast-feeding should be discontinued.

Children. Inside, the drug is used for children from the age of 6 years. It should not be prescribed to children in the presence of hemoblastosis. The drug is contraindicated in children with hemoblastosis (lymphatic and myeloid leukemia, osteosarcoma).

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. It does not affect, but when using the drug, dizziness may occur, which should be considered when driving vehicles or other mechanisms.

Interactions

Tablets: taking ethamylate before the introduction of dextrans (for example, reopoliglyukin) prevents their antiplatelet effect, after the introduction of the latter it does not have a hemostatic effect. permissible interaction with aminocaproic acid, vicasol.

Injection: Thiamine (Vitamin B₁) is inactivated by sulfite contained in the Ditsinon solution.

The use of ethamzilate 1 hour before the introduction of dextrans (for example, reopoliglyukin) prevents their antiplatelet effect, after the introduction of the latter it does not have a hemostatic effect.

The drug can be used together with other hemostatic agents.

If ethamylate solution is mixed with 0.9% sodium chloride solution, it should be used immediately.

Overdose

No data. in case of an overdose, the treatment is symptomatic.

Storage conditions

In a dry, dark place at temperatures up to 25 ° C.

Actual information

Dicinone (2,5-dihydroxybenzenesulfonate diethylammonium salt; ethamylate) is a synthetic hemostatic drug prescribed for capillary bleeding. It was discovered in 1959 by estev and others in clinical use as a hemostatic non-thrombogenic drug since 1964.

Appointment

It is prescribed for short courses to reduce menorrhagia, to eliminate surgical or postoperative capillary bleeding. In 1980, it was proved that etamzilate acts on platelet adhesion mechanisms and thus helps to reduce capillary bleeding.

One of the reviews covers more than 40 years of intensive clinical and fundamental research using etamsylate. Firstly, a large amount of medical literature is summarized regarding its clinical effectiveness. Of these, well-controlled clinical studies clearly showed the therapeutic efficacy of etamsylate in dysfunctional uterine bleeding, and the magnitude of the reduction in blood loss was directly proportional to the severity of menorrhagia (heavy menstruation). Other well-controlled clinical studies have shown the therapeutic efficacy of etamzilate in periventricular hemorrhage in children with very low birth weight and surgical or postoperative capillary bleeding. However, this fact in the future, unfortunately, was not used in the appointment. Secondly, numerous studies were conducted to determine the mechanism of action of etamzilate.

Dicinon (etamzilate) acts at the first stage of hemostasis, improving platelet adhesion and restoring capillary resistance. Recent studies have shown that etamsylate promotes the development of P-selectin-dependent platelet adhesion mechanisms. Finally, etamzilate was compared with other hemostatic agents. It is believed that etamzilate as a hemostatic agent is considered to be mild in its action, but well tolerated, especially useful for dysfunctional uterine bleeding when contraception is not required (Garay R.P., 2006).

Research

In recent experimental studies, protein adhesion mechanisms have been well characterized using etamsylate as an example.In recent years, new hemostatic agents have appeared with a certain number of studies published in scientific journals, and already comprehensively reviewed. Animal studies have clearly demonstrated the efficacy of etamsylate as a hemostatic agent, while clinical efficacy has been clearly shown in certain, but not all, blood clotting disorders. In 1964, a double-blind, placebo-controlled study of the effect of oral and intramuscular administration of etamsylate was conducted in 60 patients, most of whom were diagnosed with tuberculosis. Ethamsylate reduced mean bleeding time by 33.8 and 32.9%. Assigned (250 mg every 6 hours for 2 days) and intramuscularly (500 mg), respectively; whereas the placebo values ​​were 8.1 and 4.5%.

Further studies confirmed such hemostatic reactions in patients with various coagulation disorders, while the effects were less noticeable or tended to zero in healthy subjects under normal conditions. In healthy people, taken orally Dicinon (etamzilate) (1 tablet of 500 mg, 4 times a day for 2 days) noticeably reduces the increase in bleeding time and blood loss caused by acetylsalicylic acid. Finally, the magnitude of the reduction in etamzilate blood loss was proportional to the severity of the bleeding. Four double-blind studies were conducted to study the therapeutic efficacy of etamsylate in dysfunctional uterine bleeding. Positive results were obtained in all 4 studies. It was found that etamsylate reduces menstruation (blood loss) more in patients with primary menorrhagia (50%) than in women using intrauterine devices (19%). Dicinon (etamzilate) was prescribed 2 tablets of 250 mg 4 times a day, starting from the 5th day before the expected onset of menstruation and continued for 10 days. Interestingly, the difference between the two groups is explained by different values ​​of the initial blood loss, which were significantly higher in the group with primary amenorrhea.

The effects of etamsylate and mefenamic acid on menstrual blood loss were compared in a double-blind study in 34 women with menorrhagia. Both drugs caused a statistically significant reduction in blood loss within 3 months of treatment; the overall decrease was 20% in the etamsylate group and 24% in the mefenamic acid group. Compared with the values ​​before treatment, blood loss was significantly less in each of the 3 months of treatment in the mefenamic acid group, but only in the 2nd and 3rd months of treatment in the etamsylate group. Nevertheless, if we consider the overall result, then a greater number of women noted a clinically useful decrease in blood loss (more than 40%) in the etamsylate group. The onset of mefenamic acid was rapid, but ethamylate showed a relatively greater effect during the studies. Discontinuation of treatment was accompanied by an increase in blood loss, more pronounced in the mefenamic acid group, which returned to the level before treatment. More side effects have been reported with mefenamic acid (Chamberlain G., 2006).

However, other researchers, by contrast, have shown superiority of mefenamic acid (as well as tranexamic acid) over ethamylate. Indeed, a study negative for etamsylate was conducted in women who use intrauterine devices. It was found that in this condition, etamzilate reduces menstrual blood loss less than in patients with primary menorrhagia. Unfortunately, no placebo group was included in these comparative studies.

Experience in treating menorrhagia with Dicinon

It is interesting to note that 30 years of experience in treating menorrhagia with etamzilate has been confirmed by doctors around the world. They expressed their satisfactory opinion and demonstrated results.

The estimate of the amount of blood loss during surgery is very variable due to various technical factors (occurring during the operation), propensities to diseases (diabetes mellitus, arterial hypertension) and a number of other reasons. In the 1960-1970s, experimental studies were conducted on the use of etamsylate in surgical or postoperative bleeding. The results were favorable. The efficacy of the drug was observed in a number of surgical interventions. These included cataract surgery, 32 major intra-abdominal, 33 prosthetic (piezotraumatic) surgeries, 34 surgical interventions on the vessels and middle ear. These positive findings were prerequisites for more well-controlled clinical trials. In the 1950s and 1960s, several attempts were made to control surgical bleeding, reducing blood pressure and blood flow. Therefore, it was a natural decision to study the effect of etamsylate on the bloodstream.

In patients receiving a single oral dose of 500 mg of ethamsylate, the maximum concentration of ethamsylate in the blood plasma was 60 mmol / l after 4 hours; 95% of the drug binds to plasma proteins. Ethamylate is excreted from the body mainly unchanged by the kidneys. The plasma half-life is about 8 hours after oral administration and 2 hours after intravenous administration.

Animal studies have shown that dogs and cats tolerate intravenous injection of etamsylate at a dose of up to 200 mg / kg body weight. In mice and rats, the lethal dose of intravenous administration of etamsylate (LD50) is 800 and 1350 mg / kg body weight, respectively.

In conditions of endothelial damage, etamzilate can act as a hemostatic agent, increasing cross-talk between platelets, leukocytes and endothelium through membrane interactions (American Journal of Therapeutics, 13/2006).

Excellent tolerance of dicinone

In patients, most researchers have confirmed the excellent tolerance of etamzilate. However, etamzilate can sometimes cause nausea, headache, and a rash. A convincing connection between etamsylate therapy and deep vein thrombosis has not been established. A double-blind study was performed on 76 patients with no clinical signs of deep vein thrombosis. No differences were found between the etamzilate group and the placebo group.

Well-controlled clinical studies have shown the therapeutic efficacy of etamsilate in dysfunctional uterine bleeding with a decrease in blood loss without directly proportional to the severity of menorrhagia (Garay R.P., 2006).

Other studies examine benign but debilitating conditions of menorrhagia, dysmenorrhea, and irregular menstrual bleeding. In the literature there are reports of these common ailments that can worsen the quality of life of women in the reproductive period. Both dysmenorrhea and menorrhagia are subjective complaints, but, despite the exact means of measuring menstrual blood loss, such a quantitative determination is rarely performed. It is the lack of diagnostic accuracy that is cause for concern, especially since the conduct of medical and surgical treatment is not without risk. Therapeutic alternatives that are usually prescribed in an attempt to correct such menstrual irregularities are discussed. These include non-steroidal anti-inflammatory drugs, combined oral contraceptives, danazole, progestogens, antifibrinolytics, hemostatics, analogues of luteinizing hormone, releasing hormone and clomiphene. The results of clinical studies in which these agents were studied are considered in terms of both the effectiveness of the treatment and its potential side effects (Higham J.M., Shaw R.W., 2014).

Other well-controlled clinical trials have shown the therapeutic efficacy of etamzilate in preterm birth, in babies with very low birth weight and surgical or postoperative capillary bleeding. Ethamsylate acts on the first step of hemostasis by improving platelet adhesion and restoring capillary resistance.

Dicinon used in all births of premature babies with a preventive purpose since 1987. The drug is taken before or during childbirth. A diagnosis of cerebral hemorrhage was made at autopsy, and cases were compared with previous periods when dicinone was not used. With the prophylactic use of dicinone, the risk of cerebral hemorrhage is significantly reduced in premature babies. It is well known that the etiology of cerebral hemorrhages is multifactorial. And favorable experience is confirmed by the literature, while application Dicinon may be one of the effective prophylactic against paralysis in premature babies (Györe F., 2009).

Premature babies are at risk of bleeding in the brain in the first few weeks of life. This is called intraventricular hemorrhage. Children born at less than 32 weeks of gestation are most at risk. Many potential treatments have been studied to determine if they can reduce the risk of this bleeding. One such treatment has been proposed drug called Dicinon (etamzilat). Before that, it was precisely known how it works - it reduces bleeding in other clinical situations, such as excessive menstrual bleeding and some types of surgical intervention.

A total of 7 studies with 1,410 premature babies were included in this review. Most of these initial studies were conducted between 1980 and 1990. Premature infants receiving ethamsilate had the same results for death and disability at the age of 2 years compared with infants treated with placebo. In children born after less than 35 weeks of pregnancy, intraventricular hemorrhage was less with etamsylate compared with the control group, but this did not lead to an improvement in later childhood. When using etamzilat side effects were not observed. Based on these results, unfortunately, the routine use of etamzilate in premature infants to prevent intraventricular hemorrhage cannot be recommended. It is unlikely that any further studies will be conducted to study this clinical issue (Hunt R., Hey E., 2010).

Synergism of Dicinon with other drugs

Desmopressin and etamsylate were evaluated for possible synergistic effects on bleeding time. The drugs were administered separately and concomitantly to 12 patients with a markedly increased bleeding time. Studied bleeding disorders included Glanzmann thrombasthenia (1), other platelet dysfunction (4), pseudo-von Willebrand disease (1) and von Willebrand disease type I (3), type II (2) and type III (1)). Desmopressin in the form of monotherapy reduced the bleeding time from 23.9 ± 1.5 to 19.5 ± 2.3 minutes (p = 0.03). Ethamsylate as monotherapy did not show effect. Desmopressin and etamsylate combined reduced bleeding time to 11.2 ± 1.4 minutes (p0.01 compared to baseline, p = 0.02 compared to desmopressin alone). The combination was ineffective in 3 patients with Glanzmann thrombasthenia and von Willebrand disease type I (1) and type III (1). No toxic effects of drugs have been identified. 5 patients received desmopressin and etamsylate before dental work with blocking the lower jaw (1), heart surgery requiring cardiopulmonary bypass (2), and adenotonsillotomy surgery (2). Normal hemostasis was achieved in each case.A synergistic reduction in bleeding time was observed with a combination of desmopressin and etamsylate with a wide range of bleeding disorders (Kobrinsky N.L., 1991).

Recent studies have shown that etamzilate stimulates P-selectin-dependent thrombocyte-adhesion mechanisms. The use of etamzilate as a hemostatic agent is supposed - mild action, but well tolerated; especially useful for dysfunctional uterine bleeding when contraception is not required (Garay R.P., 2006).