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Pharmacological properties

mechanism of action. Asacol tablets and suppositories contain mesalazine, which is a 5-pasque, which has an anti-inflammatory effect. the mechanism of action has not yet been fully elucidated. mesalazine inhibits the migration of polymorphonuclear leukocytes, as a result of which the inflammation in the intestine is stopped by restricting the migration of macrophages to inflamed areas. as a result, the synthesis of anti-inflammatory leukotrienes (ltb4 and 5-hete) in the macrophages of the intestinal wall is inhibited. recent studies have found that mesalazine activates ppar-γ receptors, which counteract the nuclear activation of inflammatory reactions in the intestine.

Pharmacodynamic effects. During studies, it was found that mesalazine also inhibits the action of COX, and hence the release of thromboxane B2 and prostaglandin E2, however, the clinical significance of this effect has not yet been established. Mesalazine inhibits the synthesis of platelet activating factor. In addition, mesalazine is also an antioxidant: it reduces the synthesis of substances containing active oxygen, and binds free radicals.

Meta-analysis data from 9 studies (3 cohort studies, 6 case-control studies) involving 1932 patients with ulcerative colitis (334 cases of colorectal cancer and 140 cases of dysplasia) confirmed a 49% reduction in colorectal cancer risk in those patients who regularly took mesalazine. This effect was absent in patients with ulcerative colitis who did not receive mesalazine or took it irregularly.

Clinical efficacy and safety. Induction of remission in patients with mild or moderate proctitis or proctosigmoiditis.

Supportive treatment in remission in patients with mild or moderate proctitis.

Clinical studies of Asacol suppositories included: one comparative bioavailability study, one small-scale tolerance study, and four double-blind clinical studies. These bioavailability studies have confirmed an acceptable profile compared to another licensed drug containing mesalazine in the form of suppositories. During tolerance studies and clinical studies, data confirming the safety and effectiveness of the use of this drug were obtained. Evidence of clinical efficacy is a statistically significant improvement in the clinical, sigmoidoscopic and histological parameters of the disease.

When administered orally, mesalazine acts primarily locally on the intestinal mucosa and on the submucous tissue from the intestinal cavity. Therefore, it is important that mesalazine is available in areas of inflammation. Systemic bioavailability and plasma concentration are not essential for the therapeutic effect, but most likely act as a harmless factor.

Pharmacokinetics Absorption. Only part of the mesalazine contained in the suppository is absorbed and circulated in the systemic circulation. The mechanism of action of mesalazine is local, not systemic. After application of one Asacol suppository at a dose of 500 mg in healthy volunteers, the average values ​​of Cmax and Tmax were 211 ng / ml and 2.0 hours for mesalazine and 443 ng / ml and 3.0 hours for N-acetyl-mesalazine, respectively. Mesalazine and N-acetyl-mesalazine bind to plasma proteins by 43 and 78%, respectively.

Distribution. Low concentrations of mesalazine and its metabolite N-acetyl have been found in human breast milk. The clinical significance of this phenomenon is not defined.

Biotransformation. Mesalazine metabolism occurs in the intestinal and liver mucosa, resulting in the formation of an inactive metabolite N-acetyl-mesalazine.

Mesalazine excretion occurs mainly with feces and urine unchanged and in the form of an N-acetyl metabolite. After application of one Asacol suppository at a dose of 500 mg in healthy volunteers, biological T½ mesalazine and N-acetyl-mesalazine were 4.97 and 8.32 hours, respectively.

Enteric-coated Asacol tablets are resistant to gastric juice. The polymer shell of the tablets provides the release of the active substance depending on the pH of the medium in the lower ileum and large intestine, which are the main foci of inflammation. The composition of the tablets is selected in such a way as to minimize the absorption of mesalazine in the digestive tract. Absorption of mesalazine is highest in the proximal part of the intestine and lower in the distal part. Absorption after oral administration is about 24%. Accordingly, 76% of the administered dose remains in the lower ileum and colon, as well as in the rectum, exerting a local anti-inflammatory effect.

Linearity / nonlinearity. Special studies have not been conducted.

The relationship between pharmacokinetic / pharmacodynamic data. Special studies have not been conducted.

Indications

Tablets. nonspecific ulcerative colitis of mild to moderate severity; maintenance treatment in remission. Crohns disease.

Suppositories. This medicine is intended for use in adults:

  • for the treatment of mild or moderate proctitis and proctosigmoiditis;
  • in severe forms of total ulcerative colitis, which affects the rectum or rectosigmoid part of the rectum, as an additional therapy for oral treatment.

Application

Tablets

Adults Ulcerative colitis. In the treatment of the disease in the acute phase, the dose is selected individually and amounts to 4 g of mesalazine per day, which is divided into several doses.

With supportive treatment in remission, the recommended dose is up to 2 g of mesalazine 1 time per day, selected individually. It is also possible to divide the dose into several doses.

Crohns disease. In the treatment of the disease in the phase of exacerbation and maintenance therapy, the dose is selected individually and amounts to 4 g of mesalazine per day, which is divided into several doses.

Elderly patients do not need dose adjustment if kidney function is not impaired.

Children over 6 years old

In the treatment of ulcerative colitis and Crohns disease in the acute stage, the dose is selected individually, starting from 30-50 mg / kg / day, it is divided into several doses. The maximum dose is 75 mg / kg / day, which is divided into several doses. The total daily dose should not exceed 4 g of mesalazine.

With maintenance therapy, the dose is selected individually, starting from 15-30 mg / kg / day, divided into several doses. The total daily dose should not exceed 2 g of mesalazine.

As a rule, children with a body weight of 40 kg are prescribed half the dose for adults, and children with a body weight of 40 kg are prescribed a full dose.

Tablets should be taken as a whole, without chewing, with a sufficient amount of liquid, 1 hour before a meal. As with an exacerbation of the disease, and with maintenance treatment in remission, Asacol tablets should be taken regularly and constantly to achieve the desired therapeutic effect. The duration of use is determined by the doctor. Usually, exacerbation in ulcerative colitis and Crohns disease disappears after 8-12 weeks.

Suppositories. Suppositories are for rectal use only.

Dosage. Adults Induction of remission: 1 suppository 3 times a day after bowel movement.

In severe forms of total ulcerative colitis, which affects the rectum or rectosigmoid part of the rectum, as well as in the case of a slow reaction to oral therapy, 1 suppository in the morning and in the evening as an additional therapy for oral treatment.

Supportive treatment in remission: the dosage depends on the severity of the disease and can be reduced if the patients condition improves.

Elderly patients can use the usual dose for adults if they do not have impaired renal function. Studies in a group of elderly patients have not been conducted.

Contraindications

Hypersensitivity to the active substance, any other component of the drug or salicylates; severe violations of the liver and kidneys (creatinine clearance 30 ml / min); stomach ulcer and duodenal ulcer; hemorrhagic diathesis.

Side effects

The clinical trial database includes 246 patients who used asacol, 500 mg suppositories. the dose range of mesalazine ranged from 1.0 to 1.5 g / day, the duration of treatment ranged from 4 weeks to 12 months.

When using oral or combined oral and rectal mesalazine therapy, organ-specific side effects have been reported, in particular from the heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissues. Most of these side effects were noted precisely during oral mesalazine therapy and did not occur in patients who received Asacol monotherapy, 500 mg suppositories. However, such effects cannot be ruled out with rectal monotherapy with mesalazine.

Treatment should be stopped immediately if the patient has signs of acute intolerance to sulfasalazine, such as abdominal cramps, acute abdominal pain, fever, severe headache or rash.

Side effects reported in two double-blind clinical trials and one open clinical trial, as well as in spontaneous reports or literature sources, the occurrence of which may be associated with the use of mesalazine or cannot be excluded, are presented below in accordance with the class of the organ system: often ( ≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1/1000), very rarely (1/10 000).

On the part of the blood and lymphatic system: very rarely - deviations in blood counts (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia).

From the immune system: very rarely - hypersensitivity reactions, such as allergic rashes, drug fever, systemic lupus erythematosus, pancolitis.

From the nervous system: rarely - headache, dizziness; very rarely - peripheral neuropathy.

From the cardiovascular system: rarely - myocarditis, pericarditis.

From the respiratory system, chest and mediastinal organs: very rarely - allergic and fibrotic reactions from the lungs (including shortness of breath, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis).

From the digestive system: rarely - abdominal pain, diarrhea, flatulence, nausea, vomiting; very rarely - acute pancreatitis.

From the hepatobiliary system: very rarely - impaired liver function (increased levels of transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis.

On the part of the skin and subcutaneous tissue: very rarely - alopecia.

From the musculoskeletal system and connective tissue: bone damage; very rarely - myalgia, arthralgia.

From the urinary system: very rarely - impaired renal function, including acute and chronic interstitial nephritis and renal failure.

From the reproductive system and mammary glands: very rarely - oligospermia (reversible).

Systemic disorders: infrequently - lack of drug effect.

Description of individual side effects. Some (number not determined) of the above side effects are probably associated with the underlying disease (inflammatory bowel disease), and not with the use of Asacol. This is especially true of disorders of the digestive system.

Patients should be carefully monitored in order to avoid blood dysrasion, which may be caused by inhibition of bone marrow function.

The simultaneous use of myelosuppressive drugs, such as azathioprine, 6-mercaptopurine or thioguanine, can cause leukopenia.

With simultaneous use with NSAIDs, azathioprine or methotrexate, an increased risk of adverse reactions from the kidneys is possible.

Children. There is limited safety data for the use of Asacol suppositories in pediatric practice. It is expected that in children, the same organs can be affected as in adults (heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue).

Other special patient groups. Patients with impaired renal function. Rare reports of acute renal impairment have been received. Consideration should be given to the possibility of mesalazine-induced nephrotoxicity in patients who developed renal dysfunction during treatment. This nephrotoxicity usually disappears after discontinuation of treatment.

Patients with impaired liver function. There are reports of increased levels of liver enzymes and the occurrence of hepatitis. In some patients, these symptoms disappeared after discontinuation of mesalazine.

Elderly patients. For elderly patients, Asacol suppositories are prescribed with caution. Asacol can be prescribed only when the patient has not impaired renal function.

special instructions

Impaired renal function. To assess the functional state of the kidneys, the doctor may order a urine test (using a test strip) before and during treatment. with caution, this drug should be prescribed to patients with an increased concentration of creatinine in blood plasma and proteinuria. if renal dysfunction is noted during treatment with mesalazine, this may be a manifestation of the nephrotoxic effect of mesalazine.

It is recommended to monitor renal function for all patients before starting treatment with Asacol, as well as during therapy. Control tests are also recommended 14 days after the start of treatment, and then every 4 weeks for the next 12 weeks. With the help of control, which is performed at short intervals after the initiation of therapy with Asacol, rare acute renal reactions can be detected. In the absence of acute renal reactions, the intervals between tests can be increased up to 3 months, and then up to 1 time per year for the next 5 years. If there are additional laboratory or clinical signs of kidney failure, these tests should be performed immediately. If there are signs of impaired renal function, the patient should immediately stop therapy with Asacol and immediately consult a doctor.

Blood dysrasia. Cases of severe blood dysrasia are very rare. If there is a suspicion or significant occurrence of dyskrasia (signs of bleeding of unknown origin, bruising, purpura, anemia, persistent fever or sore throat), the patient should immediately stop treatment with Asacol and immediately consult a doctor. Before starting and during therapy, it is recommended to conduct hematological studies (counting certain types of white blood cells), the date of which is determined by the doctor. Control tests are recommended 14 days after the start of treatment, and then another 2-3 times at 4-week intervals. If the results of the studies are normal, such tests are enough to carry out every 3 months. If there are additional symptoms, immediate analysis of these data is necessary.

Impaired liver function. Among patients taking drugs containing mesalazine, there have been cases of increased levels of liver enzymes. Asacol should be prescribed with caution in patients with impaired liver function. Blood tests (liver function parameters such as AlAT or AsAT) are recommended before and during treatment. The timing of these tests is determined by the doctor.Control tests are recommended 14 days after the start of treatment, and then another 2-3 times at 4-week intervals. If the results of the studies are normal, such tests are enough to carry out every 3 months. If there are additional symptoms, immediate analysis of these data is necessary.

Hypersensitivity reactions from the heart. Cases of hypersensitivity reactions from the heart caused by mesalazine (myocarditis or pericarditis) are very rare in patients taking Asacol. In the case of reactions of hypersensitivity from the heart caused by mesalazine, Asacol should not be used a second time in patients. The drug is used with caution in patients with allergic myocarditis or pericarditis in the anamnesis, regardless of which drug caused such a reaction.

Lung diseases. Patients who have lung diseases, in particular AD, should be closely monitored during treatment with Asacol.

Hypersensitivity to sulfasalazine. If the patient has hypersensitivity to sulfasalazine, treatment is carried out only under constant medical supervision. Stop treatment immediately if there are signs of acute intolerance to the drug, such as abdominal colic, acute abdominal pain, fever, severe headache or rash.

Gastric and duodenal ulcer. Based on theoretical knowledge, treatment of patients with a stomach ulcer or duodenal ulcer should be started with caution.

Elderly patients. Caution is advised to prescribe the drug to elderly patients and only while maintaining normal renal function and the absence of severe renal impairment.

Children. The experience of using the drug in the pediatric group is insignificant, and therefore there is a limited number of documents on the effectiveness of the drug when used in children.

Use during pregnancy and lactation. Pregnancy. There is insufficient data on the use of Asacol in pregnant women. Limited data (627 pregnant women) indicate the absence of undesirable effects of mesalazine on the course of pregnancy or the health of the fetus and / or newborn. However, some data indicate an increased risk of premature birth and a decrease in the body weight of the newborn in women who received mesalazine during pregnancy. To date, no relevant epidemiological data are available.

One case of renal failure was reported in a newborn whose mother had been using high-dose mesalazine (2–4 g orally) for a long time during pregnancy.

Animal studies of oral administration of mesalazine do not indicate a direct or indirect adverse effect on the course of pregnancy and childbirth, embryofetal or postnatal development.

Thus, Asacol can be prescribed during pregnancy only when the expected benefit to the mother outweighs the potential risk to the fetus.

Breast-feeding. N-acetyl-5-aminosalicylic acid and, to a lesser extent, mesalazine are excreted in breast milk. The clinical significance of such excretion has not been established. To date, there is only limited experience with the use of the drug during lactation. Hypersensitivity reactions such as diarrhea cannot be ruled out in newborns. So, Asacol can be used during breastfeeding only when the potential benefits of the application outweigh the possible risk. If the baby develops diarrhea, breast-feeding should be discontinued.

Reproductive function. Impact on reproductive function not established.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms.Asacol does not affect or may have a slight effect on the ability to drive vehicles and work with mechanisms. In case dizziness occurs during treatment, one should refrain from driving vehicles.

Interactions

No drug interaction studies have been conducted.

There is some evidence of the possibility of reducing the effect of the anticoagulant action of warfarin while using it with mesalazine.

Under the action of mesalazine, the immunosuppressive activity of azathioprine, 6-mercaptopurine, or thioguanine may increase. As a result, a life-threatening infection is possible. Patients should be carefully monitored in order to detect signs of infectious diseases or immunosuppression in a timely manner. Before starting combination therapy, hematological parameters should be monitored, especially the number of leukocytes, platelets and lymphocytes, periodically conducting a blood test (weekly) during treatment. If the leukocyte count remains stable for 1 month, the analysis can be done at 4-week intervals for the next 12 weeks, and then at a 3-month interval.

With simultaneous use with drugs that have a nephrotoxic effect, such as NSAIDs, azathioprine or methotrexate, an increased risk of adverse reactions from the kidneys is possible. However, side effects that are evidence of such an interaction have not been reported.

Overdose

There is insufficient data on overdose (for example, suicide by oral administration of high doses of mesalazine), which do not indicate possible nephrotoxicity or liver toxicity. no specific antidote exists. symptomatic and supportive treatment is recommended.

Storage conditions

At a temperature not exceeding 25 ° c. suppositories - in a dark place at a temperature of no higher than 25 ° C. Do not store in the refrigerator and do not freeze.

Tags: Mesalazine