Asakol of the tab. of p/o of 800 mg No. 60

Structure and form of release

Ingredients:

active ingredient: mesalazin;

1 tablet contains mesalazin 400 mg or 800 mg;

other components: lactoses monohydrate, sodium krakhmalglikolit (type A), magnesium stearate, talc, povidone;

cover: methacrylic copolymer (type B), talc, triethyl citrate, ferrous oxide yellow (E 172), ferrous oxide red (E 172), macrogoal 6000.

Packaging:

Tablet, coated, kishechnorastvorimy.

Pharmacological properties

Pharmacodynamics. action mechanism. tablets asakol contain mesalazin that represents 5-pask which has anti-inflammatory effect. the action mechanism is completely not found out so far. mesalazin suppresses migration of polymorphonuclear leukocytes therefore inflammation in intestines by restriction of migration of macrophages to the inflamed sites is stopped. synthesis of anti-inflammatory leukotrienes (ltb4 and 5-hete) in macrophages of a wall of intestines is as a result oppressed. in the last researches it is established what mesalazin activates receptors of ppar-γ which counteract nuclear activation of inflammatory reactions in intestines.

Pharmakodinamichesky effects. During the researches it is established what mesalazin also inhibits action of COG and consequently, and release of thromboxane In ₂ and prostaglandin E ₂ , however the clinical value of this effect is not established so far. Mesalazin inhibits synthesis of a factor of activation of thrombocytes. Besides, mesalazin is also antioxidant: reduces synthesis of the substances containing active oxygen and connects free radicals.

with participation of 1932 patients with ulcer colitis (334 cases of a colorectal cancer and 140 cases of a dysplasia) confirmed to

This 9 researches of the metaanalysis (the 3rd cohort researches, 6 researches a case — control) reduction of risk of development of a colorectal cancer for 49% at those patients who regularly accepted mesalazin. This effect was absent at patients with ulcer colitis who did not receive mesalazin or accepted it irregularly.

Clinical performance and safety. Induction of remission at patients with a proctitis or a proctosigmoiditis of light or moderate severity.

Supporting treatment in a remission stage at patients with a proctitis of light or moderate severity.

Clinical trials of suppositories Asakol included

: one comparative research of bioavailability, one not large-scale research of shipping and four double blind clinical trials. These researches of bioavailability confirmed an acceptable profile in comparison with other licensed medicament containing mesalazin in the form of suppositories. During the researches of shipping and clinical trials the data confirming safety and efficiency of use of this medicament are obtained. Proofs of clinical performance consist in statistically reliable improvement of clinical, sigmoidoskopichesky and histologic indicators of a disease.

mesalazin affects with

At oral administration mainly locally a mucous membrane of intestines and submucosal fabric from an intestines cavity. Therefore, it is important that mesalazin it is available in inflammation zones. The system bioavailability and concentration in blood plasma are not essential to therapeutic effect, and most likely act as a harmlessness factor.

Pharmacokinetics. Absorption. Only a part of the mesalazin which is contained in a suppository is absorbed and circulates in a system blood-groove. The mechanism of action of a mesalazin is local, but not system. After use of one suppository Asakol in a dose of 500 mg at healthy volunteers average _{value C max} and Tmax made 211 ng/ml and 2.0 h for a mesalazin and 443 ng/ml and 3.0 h for N-acetyl-mesalazina respectively. Mesalazin and N-acetyl-mesalazin contact proteins of blood plasma for 43 and 78% respectively.

Distribution. In breast milk of the person low concentration of a mesalazin and his metabolite of N-acetyl are established. The clinical value of this phenomenon is not defined.

Biotransformation. Metabolism of a mesalazin is carried out in a mucous membrane of intestines and a liver therefore the inactive metabolite N-acetyl-mesalazin is formed.

Excretion of a mesalazin happens generally to a stake and urine in not changed look and in the form of a N-acetyl metabolite. After use of one suppository Asakol in a dose of 500 mg at healthy volunteers biological T _½ mesalazina and N-acetyl-mesalazina made 4.97 and 8.32 h respectively.

Tablet Asakol, covered with an enterosoluble cover, rezistentna to gastric juice. The polymeric cover of tablets provides release of active ingredient depending on rn Wednesdays in a lower part of an ileal gut and a large intestine which are the main centers of inflammation. The structure of tablets is picked up so that to minimize absorption of a mesalazin in a digestive tract. Absorption of a mesalazin is the highest in a proximal part of intestines below — in a distal part. Absorption after oral administration is about 24%. Respectively, 76% of the entered dose remain in a lower part of an ileal gut and a large intestine and also in a rectum, having local anti-inflammatory effect.

Linearity/nonlinearity. Special researches were not conducted.

Interrelation between pharmacokinetic / pharmakodinamicheskimi data. Special researches were not conducted.

Indication

Nonspecific ulcer colitis easy and moderate severity; the supporting treatment in a remission stage. Crohn's disease.

Use

Tablet

Adult. Ulcer colitis. At treatment of a disease in an aggravation phase the dose is selected individually and makes up to 4 g of a mesalazin a day which is divided into several receptions.

recommended dose makes

At the supporting treatment in a remission stage to 2 g of a mesalazin of 1 times a day, is selected individually. Perhaps also division of a dose into several receptions.

Crohn's disease. At treatment of a disease in a phase of aggravation and maintenance therapy the dose is selected individually and makes up to 4 g of a mesalazin a day which is divided into several receptions.

to

to Patients of advanced age does not need dose adjustment if function of kidneys is not broken.

Children are aged more senior than 6 years

At treatment of ulcer colitis and Crohn's disease in an aggravation stage the dose is selected individually, since 30–50 mg/kg/days, it is divided into several receptions. The maximum dose makes 75 mg/kg/days which is divided into several receptions. The general daily dose should not exceed 4 g of a mesalazin.

At maintenance therapy a dose is selected individually, since 15–30 mg/kg/days, divided into several receptions. The general daily dose should not exceed 2 g of a mesalazin.

by

As a rule, to children with the body weight of 40 kg appoint a half of a dose for adults, and to children with the body weight of 40 kg — a full dose.

should take the Pill entirely, without chewing, washing down with enough liquid, for 1 h before meal. Both at exacerbation of a disease, and at the supporting treatment in a remission stage for achievement of desirable therapeutic effect the pill Asakol should be taken regularly and constantly. Duration of use is determined by the doctor. Usually aggravation in ulcer colitis and Crohn's disease disappears in 8–12 weeks

Patients of advanced age can apply a usual dose to adults if they have no renal failures. Researches in group of patients of advanced age were not conducted.

Contraindication

Hypersensitivity to active ingredient, any other component of medicament or salicylates; heavy abnormal liver functions and kidneys (clearance of creatinine of 30 ml/min.); ulcer of stomach and duodenum; hemorrhagic diathesis.

Side effects

Database of clinical trials includes 246 patients who applied asakol, suppositories 500 mg. range of doses of a mesalazin fluctuated from 1.0 to 1.5 g/days, duration of treatment was of 4 weeks up to 12 months

At use of the oral or combined oral and rectal therapy mesalaziny organospetsifichesky side effects are registered, in particular, from heart, lungs, a liver, kidneys, a pancreas, skin and hypodermic fabrics.

Should stop immediately treatment in the presence at the patient of signs of acute intolerance of Sulfasalazinum, such as abdominal gripes, acute pain in a stomach, fervescence, the profound headache or rash.

by

Side effects registered in two double blind clinical trials and one open clinical trial and also in spontaneous messages or sources of literature which emergence can be connected with use of a mesalazin or cannot be excluded, are given below according to a class of a system of bodies: often (≥1/100, 1/10), infrequently (≥1/1000, 1/100), it is rare (≥1/10,000, 1/1000), is very rare (1/10,000).

• from blood and lymphatic system: very seldom — deviations of indicators of blood test (aplastic anemia, an agranulocytosis, a pancytopenia, a neutropenia, a leukopenia, thrombocytopenia).
• from the immune system: very seldom — reactions of hypersensitivity, such as allergic rashes, medicinal fever, system lupus erythematosus, pan-colitis.
• from nervous system: seldom — a headache, dizziness; very seldom — peripheral neuropathy.
• from a cardiovascular system: seldom — myocarditis, a pericarditis.
• from the respiratory system, bodies of a thorax and mediastinum: very seldom — allergic and fibrous reactions from lungs (including short wind, cough, a bronchospasm, an alveolitis, a pulmonary eosinophilia, infiltration of lungs, a pneumonitis).
• from digestive system: seldom — an abdominal pain, diarrhea, a meteorism, nausea, vomiting; very seldom — acute pancreatitis.
• from a gepatobiliarny system: very seldom — an abnormal liver function (increase in level of transaminases and parameters of a cholestasia), hepatitis, cholestatic hepatitis.
• from skin and hypodermic fabrics: very seldom — an alopecia.
• from a musculoskeletal system and connective tissue: damage of bones; very seldom — myalgia, an arthralgia.
• from an urinary system: very seldom — a renal failure, including acute and chronic interstitial nephrite and a renal failure.
• from a reproductive system and mammary glands: very seldom — an oligospermatism (reversible).
• System disturbances: infrequently — lack of effect of drug.

Description of separate side effects. Some (the quantity is not established) of the side effects stated above are probably connected with a basic disease (inflammatory bowel disease), but not using the medicament Asakol. Especially it concerns disturbances from digestive system.

Should be watched carefully patients for the purpose of avoidance of a dyscrasia of blood which can be caused by oppression of function of marrow.

Simultaneous use of myelosuppressive drugs, such as Azathioprinum, 6 Mercaptopurinum or thioguanine, can cause a leukopenia.

At simultaneous use with NPVP, Azathioprinum or a methotrexate the increase in risk of undesirable reactions from kidneys is possible

.

Other special groups of patients. Patients with a renal failure. Rare messages about acute disorders of function of kidneys are received. It is necessary to consider possibility of the mesalazin-induced nephrotoxicity at patients at whom during treatment the renal dysfunction developed. This nephrotoxicity usually disappears after the treatment termination.

Patients with an abnormal liver function. There are messages about increase in level of enzymes of a liver and developing of hepatitis. At some patients these symptoms disappeared after cancellation of a mesalazin.

Patients of advanced age. To patients of advanced age suppositories Asakol are appointed with care. Asakol can be appointed only when at the patient the function of kidneys is not broken.

Special instructions

Renal failure. for assessment of a functional condition of kidneys the doctor can appoint the analysis of urine (by means of a test strip) before and during treatment. with care patients should appoint this medicament with the increased concentration of creatinine in blood plasma and a proteinuria. if during treatment mesalaziny the renal failure is noted, it can be manifestation of nephrotoxic action of a mesalazin.

recommends to carry out

control of function of kidneys for all patients before an initiation of treatment the medicament Asakol and also during therapy. Also carrying out control tests in 14 days after an initiation of treatment, and then each 4 weeks during the following 12 weeks is recommended. By means of control which is carried out with short intervals of time after the beginning of therapy by the medicament Asakol the identification of rare acute renal reactions is possible. In the absence of acute renal reactions the intervals between tests can be increased up to 3 months, and then up to 1 time a year within the next 5 years. With accessory laboratory or clinical signs of a renal failure it is necessary to carry out these analyses immediately. With symptoms of a renal failure the patient should stop immediately therapy by the medicament Asakol and to see urgently a doctor.

blood Dyscrasia. Cases of a serious dyscrasia of blood are very exceptional. At suspicion or reliable developing of a dyscrasia (symptoms of bleeding of not clear origin, bruises, a purpura, anemia, not fading fevers or a sore throat) the patient has to stop immediately the Asakol medicament treatment and see urgently a doctor. Before the beginning and during therapy carrying out hematologic researches (calculation of separate types of leukocytes) which date is defined by the doctor is recommended. Carrying out control tests in 14 days after an initiation of treatment, and then 2-3 more times with 4 weeks intervals is recommended. If results of researches normal, such analyses it is enough to spend each 3 months. In the presence of additional symptoms immediate carrying out these analyses is necessary.

Abnormal liver function. Among the patients taking the medicaments containing mesalazin cases of increase in level of enzymes of a liver are registered. It is necessary to appoint with care Asakol to patients with an abnormal liver function. It is recommended to carry out blood tests (parameters of function of a liver, such as AlAT or AsAT) to and during treatment. Time of carrying out these analyses is defined by the doctor. Carrying out control tests in 14 days after an initiation of treatment, and then 2-3 more times with 4 weeks intervals is recommended. If results of researches normal, such analyses it is enough to spend each 3 months. In the presence of additional symptoms immediate carrying out these analyses is necessary.

Hypersensitivity reaction from heart. Cases of the hypersensitivity reactions from heart caused mesalaziny (myocarditis or a pericarditis) very rare at the patients accepting Asakol. In case of the hypersensitivity reactions from heart caused mesalaziny at patients it is not necessary to apply Asakol for the second time. Drug is used with care at patients with allergic myocarditis or a pericarditis in the anamnesis regardless of which medicament caused such reaction.

Disease of lungs. Patients who have diseases of lungs in particular OH, have to be under careful observation during treatment by Asakol.

Hypersensitivity to Sulfasalazinum. In the presence at the patient of hypersensitivity to Sulfasalazinum the treatment is carried out only under constant medical control. It is necessary to stop immediately treatment with signs of acute intolerance of drug, such as abdominal gripes, acute pain in a stomach, fervescence, the profound headache or rash.

Ulcer of stomach and duodenum. Based on theoretical knowledge, it is necessary to begin with care treatment of patients with ulcer of stomach or duodenum.

Patients of advanced age. It is necessary to appoint with care medicament to patients of advanced age and only at preservation of normal function of kidneys and absence of heavy renal failures.

Children. Experience of use of medicament in pediatric group insignificant in this connection there is a limited number of documents by efficiency of medicament at use for children.

Use during pregnancy and feeding by a breast

Pregnancy. Data on use of the medicament Asakol for pregnant women are not enough. Limited data (627 pregnant women) indicate lack of undesirable influence of a mesalazin on a course of pregnancy or health of a fruit and/or the newborn. However separate data confirm increase in risk of premature births and degrowth of a body of the newborn at the women receiving mesalazin during pregnancy. For today there are no relevant epidemiological data.

to

It was reported about one case of a renal failure at the newborn whose mother applied a long time mesalazin in a high dose (2–4 g orally) during pregnancy. Data of researches on animals on oral administration of a mesalazin do not indicate its direct or mediated adverse influence on a course of pregnancy and childbirth, embriofetalny or post-natal development. Thus, Asakol it is possible to appoint during pregnancy only when the expected advantage for mother exceeds potential risk for a fruit.

Breastfeeding. N-acetyl-5-aminosalicylic acid and to a lesser extent mesalazin are excreted in breast milk. The clinical value of such excretion is not established. For today there is only a limited experience of use of medicament during feeding by a breast. It is impossible to exclude at newborn reactions of hypersensitivity, such as diarrhea. So, Asakol it is possible to apply during feeding by a breast only when the potential advantage of use exceeds possible risk. If at the baby the diarrhea develops, feeding by a breast should be stopped.

Reproductive function. Influence on reproductive function is not established.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Asakol does not influence or can have insignificant impact on ability to run vehicles and to work with mechanisms. If during treatment there is dizziness, it is necessary to refrain from control of vehicles.

Researches of medicinal interaction were not conducted by

Interaction

.

some data on a possibility of decrease in effect of anticoagulating effect of warfarin at simultaneous use with mesalaziny Exist.

under the influence of a mesalazin the immunosuppressive activity of Azathioprinum, 6 Mercaptopurinum or thioguanine can increase. Development of a life-threatening infection is as a result possible. It is necessary to watch carefully patients for the purpose of early detection of symptoms of infectious diseases or immunosuppression. Before combination therapy it is necessary to control hematologic parameters, especially quantity of leukocytes, thrombocytes and lymphocytes, periodically carrying out blood test (weekly) during treatment. If the indicator of quantity of leukocytes within 1 month remains stable, the analysis can be carried out with 4 weeks intervals during the following 12 weeks, and further — with a 3-month interval.

At simultaneous use with the medicines having nephrotoxic effect such as NPVP, Azathioprinum or a methotrexate, is possible increase in risk of undesirable reactions from kidneys. However side effects which are the proof of such interaction are not registered.

Overdose

Exists not enough data on overdose (for example a suicide by oral administration of high doses of a mesalazin) which do not indicate possible nephrotoxicity or hepatic toxicity. specific antidote does not exist. the symptomatic and supporting treatment is recommended.

Storage conditions

At a temperature not above 25 °C.