Composition, form of production and packaging
Tablets, covered with an enteric film coating of the film from light yellow to yellow-brown color, round, biconvex.
1 tab.
mesalazine (5-ASA) 250 mg
[PRING] sodium carbonate, glycine, povidone, microcrystalline cellulose, silicon dioxide colloid, calcium stearate, hypromellose, methacrylic acid-methacrylate copolymer (1: 1), talc, titanium dioxide, iron oxide yellow oxide, macrogol, butyl methacrylate.
10 pieces. - blisters (5) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
Tablets, covered with an enteric film membrane from light yellow to yellow-brown, oval, biconvex.
1 tab.
mesalazine (5-ASA) 500 mg
[PRING] sodium carbonate, glycine, povidone, microcrystalline cellulose, croscarmellose sodium, silicon dioxide colloid, calcium stearate, hypromellose, methacrylic acid-methacrylate copolymer (1: 1), talc, titanium dioxide, iron oxide yellow oxide, macrogol, butyl methacrylate.
10 pieces. - blisters (5) - packs of cardboard.
10 pieces. - blisters (10) - packs of cardboard.
Granules coated with enteric-coated shell, prolonged action of grayish-white color, round, cylindrical or spherical.
1 pack.
mesalazine (5-ASA) 500 mg
[PRING] microcrystalline cellulose - 200 mg, hypromellose - 18 mg, silicon dioxide, colloidal anhydrous - 0.25 mg, euradates NE40D (40% dispersion of copolymer of methyl methacrylate and ethyl acrylate (2: 1) and 2% nonoxynol) - 45 mg, magnesium stearate - 7.75 mg, dry matter 33% emulsion simethicone (composed of 92% simethicone, 7.7% methylcellulose, 0.3% sorbic acid) - 0.5 mg.
The composition of the inner shell: hypromellose - 2 mg, copolymer methacrylic acid and methyl methacrylate (1: 1) (eudrazhit L100) - 75 mg, triethyl citrate - 7.5 mg, talc - 20 mg, magnesium stearate - 5 mg, titanium dioxide - 12.5 mg.
The composition of the outer shell: carmellose sodium - 15 mg, titanium dioxide - 5 mg, aspartame - 1 mg, citric acid anhydrous - 3 mg, vanilla flavor - 2 mg, talc 5.5 mg, povidone K25 - 5 mg.
930 mg - polyethylene bags, laminated with aluminum foil (50) - packs of cardboard.
930 mg - polyethylene bags, laminated with aluminum foil (50) - packs of cardboard (2) - cardboard boxes.
Granules coated with enteric-coated shell, prolonged action of grayish-white color, round, cylindrical or spherical.
1 pack.
mesalazine (5-ASA) 1 g
[PRING] microcrystalline cellulose - 400 mg, hypromellose - 36 mg, silicon dioxide, colloidal anhydrous - 0.5 mg, eDrazhite NE40D (40% dispersion of copolymer of methyl methacrylate and ethacrylate (2: 1) and 2% nonoxynol) - 90 mg, magnesium stearate - 15.5 mg, dry matter 33% emulsion simethicone (composed of 92% simethicone, 7.7% methylcellulose, 0.3% sorbic acid) - 1 mg.
The composition of the inner shell: hypromellose - 4 mg, methacrylic acid-methyl methacrylate copolymer (1: 1) (eudrazhit L100) - 150 mg, triethyl citrate - 15 mg, talc - 40 mg, magnesium stearate - 10 mg, titanium dioxide - 25 mg.
The composition of the outer shell: carmellose sodium - 30 mg, titanium dioxide - 10 mg, aspartame - 2 mg, citric acid anhydrous - 6 mg, vanilla flavor - 4 mg, talc - 11 mg, povidone K25 - 10 mg.
1860 mg - polyethylene bags, laminated with aluminum foil (50) - packs of cardboard.
1860 mg - polyethylene bags, laminated with aluminum foil (50) - packs of cardboard (2) - cardboard boxes.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Anti-inflammatory intestinal. Has a local anti-inflammatory effect due to inhibition of neutrophilic lipoxygenase and the synthesis of prostaglandins and leukotrienes.Slows migration, degranulation, phagocytosis of neutrophils, as well as secretion of immunoglobulins by lymphocytes. Has antioxidant effects (due to the ability to bind to free oxygen radicals and destroy them). Mesalazine can also trap radicals formed from reactive oxygen compounds. The results obtained in in vitro studies indicate the possible role of inhibition of lipoxygenase. The effect on the content of prostaglandins in the intestinal mucosa is also shown.
When administered orally, mesalazine exerts a predominantly local effect in the intestinal mucosa and submucosal layer, acting from the side of the intestinal lumen.Therefore, it is important that mesalasia is available in the area of ​​inflammation. The ratio of systemic bioavailability and mesalazine concentration in plasma is not significant in terms of therapeutic effectiveness, but rather serves as a factor affecting safety.
The fact that Salofalk's granules are resistant to gastric juice and characterized by a pH-dependent (due to a coating in the form of Eudrajit L) and a delayed (due to the matrix structure of the granules) release of mesalazine helps to release the active ingredient at the right place.
PHARMACOKINETICS
Suction and distribution
The release of mesalazine occurs in the terminal section of the small and large intestine. Tablets begin to dissolve in the small intestine after 110-170 minutes and completely dissolve after 165-225 minutes after administration. The rate of dissolution is not affected by changes in the pH of the medium caused by ingestion of food or other drugs.
The release of mesalazine from the granules begins with a deceleration of 2-3 hours, C max in the plasma is reached after about 4-5 hours. Systemic bioavailability of mesalazine after oral administration is approximately 15-25%. Food intake slows down the absorption for 1-2 hours, but does not change the rate and degree of absorption.
Eating can slow the transit of the drug for 1-2 hours, while the values ​​of T lag increase (the time gap after which the content of mesalazine is first determined in the blood) and T max , however, due to the small granule size, this does not change the rate and degree of absorption.
Eating causes a slight increase in C max and AUC.
The pharmacokinetic data of granules and tablets are summarized in the following table (granules: 3 Г— 500 mg mesalazine / day, tablets: 3-2 (250 mg) mesalazine / day, equilibrium, 24 healthy volunteers):
Granules Tablets
Pharmacokinetic parameters of Mesalazine / 5-ASA N-Ac-5-ASA Mesalazine / 5-ASA N-acetyl-5-ASA
T lag (h) 2.4 В± 0.8 2.4 В± 0.8 3.4 В± 1.0 3.5 В± 0.9
T max (h) 4.3 В± 0.6 4.5 В± 0.9 4.4 В± 0.9 4.6 В± 0.9
T 1/2 (h) 4.4 В± 3.9 8.2 В± 6.0 2.8 В± 1.9 5.0 В± 2.4
C max (Ојg / ml) 0.8 В± 0.4 1.8 В± 0.7 2.0 В± 1.5 2.6 В± 1.4
AUC 0-24h (Ојg h / ml) 7.7 В± 3.3 29.0 В± 7.5 12.2 В± 6.4 34 В± 10.7
A e urine (mmol) 0.286 В± 0.28 9.4 В± 2.4 1.48 В± 1.0 10.98 В± 2.8
A e urine (%) 0.72 В± 0.7 24.03 В± 6.2 3.77 В± 2.5 28.02 В± 7.0
? A e 5-ASA + Ac-5-ASA (mmol) 9.7 В± 2.6 12.5 В± 3.4
? A e 5-ASA + Ac-5-ASA (%) 24.8 В± 6.5 31.8 В± 8.8
The total amount of mesalazine and N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) excreted by the kidneys within 24 hours is equivalent to approximately 25-32%, respectively, of the prescribed dose of the pellets and Salofalk tablets. Approximately 30% of this amount is absorbed in the ileocecal zone, and approximately 90% in the whole in the ileocecal zone and the ascending colon. Thus, approximately 80-90% of the 5-ASA of the prescribed dose is present in the descending colon, sigmoid and rectum, where the rate of their absorption is low.
The distribution of radiolabeled 153 Sm (samarium) pellets and tablets in the gastrointestinal tract was as follows (mean В± SD (confidence interval)):
Granules Tablets
Emptying of the stomach 0.94 В± 0.70 h 0.56 В± 0.71 h
Appearances in the small intestine 0.65 В± 0.40 h 0.79 В± 0.71 h
Time of transit in the small intestine 3.07 В± 0.88 h 3.00 В± 0.84 h
Disappearance from the small intestine 3.71 В± 1.08 h 3.79 В± 1.17 h
Appearance in the ileocecal region 3.31 В± 1.03 h 3.83 В± 0.89 h
Disappearance from the ileocecal region 6.15 В± 2.48 h 5.56 В± 1.57 h
Appearance in the ascending colon 4.08 В± 1.39 h 4.74 В± 1.5 h
Disappearance from the ascending colon 13.57 В± 4.45 h 10.88 В± 1.48 h
Total transit time for the colon 19.92 В± 1.39 h 17.37 В± 4.80 h
The values ​​of serum Cmax 5-ASA and Ats-5-ASA in the equilibrium state were approximately 1.4 and 1.2 times higher after taking 1 time / day in comparison with the values ​​observed when taking the drug 3 times / day in the same daily dose. With ss in the serum, at the end of the dosing period, once taken 1 time / day was only slightly lower than when administered 3 times / day (0.3 and 0.4 times for 5-ASA and ACh-5-ASA, respectively). When taking the drug 1 time / day, there were no signs of systemic cumulation.
Due to the size of the granules (about 1 mm), transit from the stomach to the small intestine occurs quickly. Combined pharmaco-cintigraphic and pharmacokinetic study showed that the drug reaches the ileocecal region after about 3 hours, and the ascending part of the colon approximately 4 hours later. The total transit time in the colon is about 20 hours. Approximately 80% of the oral dose taken reaches a thick, sigmoid and rectum.
The binding to plasma proteins of mesalazine and N-Ats-5-ASA is 43% and 78% (75-83%), respectively.
The mother's milk penetrates (in the form of a metabolite) 0.1% of the dose.
Metabolism
Mesalazine is metabolized both by the pre-systemic route in the intestinal mucosa, and systemically in the liver, turning into a pharmacologically inactive N-Ac-5-ASA. The nature of acetylation does not depend on the acetylating phenotype of the patient. To a small extent, acetylation can be carried out by the action of bacterial microflora of the colon.
Excretion
With the administration of mesalazine at a dose of 500 mg 3 times / day, the total elimination of mesalazine and N-Ats-5-ASA by the kidneys at a saturating concentration was about 25%. The excretion of the unmetabolized portion of mesalazine was less than 1% of the orally administered dose. T 1/2 in this study was 4.4 hours.
Pharmacokinetics in special clinical cases
With a single oral administration of Salofalk pellets at a dose of 20 mg / kg to 13 children with an active inflammatory disease of the large intestine (age from 5.9 to 15.8 years), the pharmacokinetics of systemic exposure of the drug corresponded to that of adults. Salofalk was safe and well tolerated.
Data on the pharmacokinetics of Salofalk in the elderly with its use, both in tablets and in granules are absent.
INDICATIONS
Pills
- Nonspecific ulcerative colitis (NNC);
- Crohn's disease (prevention, treatment of exacerbations).
Granules
- exacerbation of ulcerative colitis of medium and mild severity;
- maintenance of remission and or long-term therapy of ulcerative colitis.
DOSING MODE
Pills
The drug is prescribed by adults for 500 mg 3 times / day. In severe forms of the disease, the dose can be increased to 3-4 g / day for 8-12 weeks.
To prevent recurrence, the drug is prescribed 500 mg 3 times / day, if necessary - for several years.
Children with a body weight of up to 40 kg are prescribed a 1/2 day dose for adults - 250 mg three times a day (250 mg tablets should be used), children with a body weight of more than 40 kg should take 500 mg three times a day.
For the prevention of recurrence, the drug is prescribed 250 mg 3 times / day, if necessary - for several years.
Tablets should be taken whole, not liquid, after eating and drink with a lot of water. In distal forms of NNC, rectal administration of the drug in the form of suppositories rectal or rectal suspension is preferred.
Granules
The dosing regimen for treating ulcerative colitis exacerbation depends on the clinical need and in each case is individual. Assign 1 packet of 500-1000 mg mesalazine 3 times / day or 3 bags 1 time / day (corresponding to 1.5-3.0 g mesalazine per day).
To maintain remission of ulcerative colitis appoint 500 mg (1 pack.) Of mesalazine 3 times / day or 3 packets of 500 mg 1 time / day (corresponding to 1.5 g of mesalazine per day).
Children older than 6 years and adolescents with an exacerbation of the disease , depending on its severity, mesalazine is prescribed in a dose of 30-50 mg / kg of body weight / day with the distribution of the daily dose for 3 doses or for 1 reception. To maintain remission, mesalazine is administered at a dose of 15-30 mg / kg body weight / day, and the daily dose can be divided into 2 divided doses. Children with body weight up to 40 kg are usually recommended to appoint a half dose of adults, children with a body weight of more than 40 kg - a dose of adults.
Granules of Salofalk can not be chewed. The prescribed dose of Salofalk in granules should be taken in the morning, at lunch time and in the evening or the entire dose once in the morning. Granules Salofalk should be put on the tongue and swallowed, without chewing, squeezed a lot of liquid.
As in the treatment of exacerbation of the inflammatory process, and with prolonged use to maintain remission, granules should be taken regularly and consistently, which allows to achieve the desired therapeutic effect. Exacerbation of ulcerative colitis usually subsides in 8-12 weeks, after which the dose of mesalazine in most patients can be reduced to 1.5 g / day.
SIDE EFFECT
Reactions associated with hypersensitivity: skin rash, itching, erythema, fever, bronchospasm, pericarditis, myocarditis, acute pancreatitis, interstitial nephritis, nephrotic syndrome. There were individual cases of allergic alveolitis and pancolitis. Under certain conditions, mesalazine and preparations having a similar chemical structure can lead to the development of a syndrome similar to that of systemic lupus erythematosus.
On the part of the digestive system: loss of appetite; rarely (<1/1000, but> 1/10 000) - diarrhea, nausea, abdominal pain, flatulence, vomiting; Very rarely (<1/10 000) - severe abdominal pain due to pancreatitis, severe diarrhea and abdominal pain due to allergic inflammation of the intestines, jaundice and abdominal pain due to bile secretion disorders, increased level of hepatic enzymes in the blood, hepatitis.
From the nervous system: rarely (1/10 000) - headache, dizziness; very rarely (<1/10 000) - peripheral neuropathy; possibly - depression, sleep disorders, malaise, paresthesia, convulsions, tremor, tinnitus.
From the cardiovascular system: it is possible - tachycardia, arterial hypertension or hypotension; Very rarely (<1/10 000) - chest pain, shortness of breath.
From the musculoskeletal system: very rarely (<1/10 000) - myalgia, arthralgia.
From the hemopoietic system: in some cases - anemia, leukopenia, agranulocytosis, thrombocytopenia.
From the coagulation system: in some cases - hypoprothrombinemia.
From the urinary system: in some cases - proteinuria, hematuria, crystalluria, oliguria, anuria.
Other: in some cases, a decrease in the production of tear fluid; Very rarely (<1/10 000) - alopecia, fever, sore throat, reversible decrease in motility of spermatozoa.
Taking into account the chemical structure of the active substance, it is impossible to exclude the possibility of increasing the level of methaemoglobin.
If acute signs of intolerance arise, treatment should be stopped immediately.
CONTRAINDICATIONS
- Blood diseases;
- Stomach ulcer and duodenal ulcer;
- hemorrhagic diathesis (with a tendency to bleeding);
- severe renal insufficiency;
severe hepatic impairment;
- deficiency of glucose-6-phosphate dehydrogenase;
- phenylketonuria (for granules);
- Children under 3 years old (for tablets);
- Children under 6 years (for pellets);
- Hypersensitivity to the components of the drug and other derivatives of salicylic acid.
Caution should be given Salofalk with renal / hepatic insufficiency of mild and moderate severity, lung diseases (especially bronchial asthma), in the first trimester of pregnancy.
PREGNANCY AND LACTATION
In the first trimester of pregnancy, the prescription of the drug is only possible on strict indications. If the course of the disease allows, in the last 2-4 weeks of pregnancy the drug should be stopped.
In the second and third trimesters, Salofalk should be used only in cases where the potential benefit of therapy for the mother exceeds the possible risk to the fetus.
Salofalk in the form of granules can be used during breastfeeding only if the potential effect of its use on the mother exceeds the possible risk of adverse effects on the child. If a newborn breastfed has diarrhea, breastfeeding should be stopped.
If it is necessary to appoint Salphalic in the form of tablets during lactation, breastfeeding should be discontinued.
Before the planned pregnancy, it is recommended, if possible, to stop Salofalkom treatment or to apply the drug in reduced doses.
APPLICATION FOR FUNCTIONS OF THE LIVER
The drug is contraindicated in severe impairment of kidney function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The drug is contraindicated in severe violations of liver function.
APPLICATION FOR CHILDREN
The drug is contraindicated in children under the age of 3 years.
Children with a body weight of up to 40 kg are prescribed a 1/2 day dose for adults - 250 mg 3 times / day, children with a body weight of more than 40 kg - 500 mg 3 times / day.
For the prevention of recurrence, the drug is prescribed 250 mg 3 times / day, if necessary - for several years.
SPECIAL INSTRUCTIONS
Before the beginning of treatment, during, and after treatment, a general analysis of blood and urine is necessary.
Before and during the treatment, it is necessary to determine the parameters of the functional state of the liver (such as ALT or ACT activity) and monitor urinalysis (by dipping test strips). The control is recommended usually 14 days after the start of treatment, then 2-3 more times with an interval of 4 weeks. If the results of the tests are normal, control studies should be performed every 3 months. If additional symptoms appear, follow-up studies should be performed immediately.
Use with caution in patients with impaired liver function.
Purpose Salofalka is not recommended for patients with severe renal dysfunction. If renal dysfunction has developed during treatment, one should think about the nephrotoxic effect of mesalazine. During the treatment should monitor the function of the kidneys.
When Salofalk is prescribed to patients with lung diseases, in particular bronchial asthma, careful monitoring is necessary during the treatment.
Patients with a history of indication of adverse reactions when prescribing drugs containing sulfasalazine are subject to close monitoring during the initial period of treatment with Salofalkom. If Salofalk treatment is associated with acute intolerance, such as convulsions, acute abdominal pain, fever, severe headache and rash, the drug should be discontinued immediately.
Patients who are "slow acetylators" have an increased risk of side effects.
There can be staining of urine and tears in a yellow-orange color, staining of soft contact lenses.
If multiple doses are missed, the patient should consult a doctor without discontinuing treatment.
When prescribing the drug for patients with phenylketonuria, it should be remembered that Salofalk in the pellets contains aspartame in doses equivalent to the following amount of phenylalanine: 0.56 mg (Salofalk granules 500 mg), 1.12 mg (Salofalk granules 1 g).
Use in Pediatrics
Salofalk in granules should not be given to children under 6 years of age , since the experience of using the drug in patients of this age group is very limited.
Impact on the ability to drive vehicles and manage mechanisms
Care should be taken when driving a vehicle and engaging in potentially dangerous activities that require increased concentration and speed of the psychomotor reaction.
OVERDOSE
Symptoms: nausea, vomiting, gastralgia, weakness, drowsiness.
Treatment: gastric lavage, laxatives, symptomatic therapy. In cases of overdose, if necessary, an infusion of electrolytes is performed (forced diuresis).
DRUG INTERACTION
With the simultaneous use of Salofalk causes an increase in the effect of anticoagulants of indirect action (increased risk of gastrointestinal bleeding).
With the simultaneous use of GCS with Salofalkom, there may be an increase in undesirable reactions from the side of the gastric mucosa.
With the simultaneous use of Salofalk increases the toxicity of methotrexate.
With the simultaneous use of probenecid and sulfinpyrazone with Salofalkom, a reduction in the excretion of uric acid is possible.
With the simultaneous use of Salofalk reduces the diuretic effect of spironolactone and furosemide.
At simultaneous application with Salofalkom weakening of tuberculostatic action of rifampicin is possible.
With the simultaneous use of Salofalk enhances the hypoglycemic effect of sulfonylurea derivatives.
When used simultaneously with lactulose or other drugs that lower the pH of the intestinal contents, it is possible to reduce the release of mesalazine from the granules due to a decrease in the pH due to the metabolism of the bacteria.
In patients who are concurrently receiving treatment with azathioprine or 6-mercaptopurine should be aware of the possible strengthening of myelosuppressive effect of azathioprine and 6-mercaptopurine.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in a dry, protected from light, out of reach of children at a temperature of no higher than 25 В° C. The shelf life of tablets - 3 years, granules - 4 years.
