Instructions Asacol enteric-coated tablets 800 mg blister No. 60
Composition
active ingredient: mesalazine;
1 tablet contains 400 mg or 800 mg of mesalazine;
excipients: lactose monohydrate, sodium starch glycolate (type A), magnesium stearate, talc, povidone;
shell: methacrylic copolymer (type B), talc, triethyl citrate, iron oxide yellow (E 172), iron oxide red (E 172), macrogol 6000.
Dosage form
The film-coated tablets are enteric-coated.
Main physicochemical properties: oblong, film-coated tablets, reddish to brownish in color.
Pharmacotherapeutic group
Anti-inflammatory drugs used in intestinal diseases. ATX code A07E C02.
Pharmacological properties
Pharmacodynamics.
Mesalazine inhibits LTB4-stimulated migration of intestinal macrophages, limiting the migration of macrophages to inflamed areas. This inhibits the production of pro-inflammatory leukotrienes (LTB4 and 5-HETE) in macrophages of the intestinal wall. Recently, mesalazine has been shown to activate the PPAR-γ receptor, which counteracts the nuclear activation of intestinal inflammatory responses.
Clinical efficacy
The treatment of acute ulcerative colitis was studied in 529 patients with mild to moderate symptoms. Of the six controlled trials, two were placebo-controlled and four were comparator-controlled or dose-finding trials. The duration of treatment was four to six weeks. All patients had disease confirmed by sigmoidoscopy. Response to treatment was monitored by clinical examinations, patient self-monitoring and clinical outcomes (sigmoidoscopy results) either daily or at weekly intervals. Both placebo-controlled trials achieved a statistically significant result in favour of mesalazine.
Maintenance of remission in ulcerative colitis was studied in 503 patients. Of the four controlled trials, one was placebo-controlled and three were comparator-controlled. The duration of treatment ranged from four to eleven months. The endpoint of the study was the occurrence of relapse as evidenced by sigmoidoscopy. The placebo-controlled trial achieved a statistically significant result in favour of mesalazine.
Pharmacokinetics.
Absorption
After oral administration of mesalazine, the active substance reaches the lower ileum unchanged. The active substance begins to be released at pH > 7. Absorption was studied under stationary conditions in 38 healthy volunteers and in 14 patients with ulcerative colitis in remission. The average absorption (cumulative urinary excretion) was 26%. Plasma protein binding is 40% for mesalazine and 80% for N-acetyl-mesalazine.
Distribution
Distribution studies have not been conducted.
Metabolism
As mesalazine passes through the intestinal mucosa, it is already systemically metabolized to N-acetyl-mesalazine. Some of the free mesalazine is N-acetylated in the liver and intestinal flora.
Breeding
Mesalazine and N-acetyl-mesalazine are excreted mainly in the feces. It is excreted by the kidneys mainly in the form of N-acetyl-mesalazine exclusively within the absorbed fraction, which is approximately 26% of the oral dose.
Indication
Mild to moderate nonspecific ulcerative colitis; supportive treatment in remission. Crohn's disease.
Contraindication
Hypersensitivity to mesalazine or any other component of the drug or known allergy to salicylates; severe liver and kidney dysfunction (creatinine clearance < 30 ml/min/1.73 m2).
Children's age up to 6 years.
Special safety precautions
Before and during treatment, blood tests (white blood cell count, liver function parameters such as ALT or AST; serum creatinine) and urine output (test system) should be scheduled at the discretion of the treating physician. As a general guideline, repeat tests are recommended 14 days after the start of treatment and then every 4 weeks for the next 12 weeks. If the results are normal, repeat tests should be performed every three months. If additional signs of hepatic or renal failure are detected, such tests should be performed immediately.
Kidney dysfunction
Caution should be exercised in patients with elevated serum creatinine or proteinuria. In patients who develop renal impairment during treatment, the possibility of mesalazine-induced nephrotoxicity should be considered. If signs of renal impairment appear, Asacol® treatment should be discontinued immediately and patients should seek urgent medical attention.
Nephrolithiasis
Urolithiasis has been reported with the use of mesalazine, including cases of stones consisting of 100% mesalazine. Adequate fluid intake should be ensured during treatment with the drug.
Mesalazine may cause a red-brown discoloration of urine after contact with sodium hypochlorite-based bleach (e.g., in toilets cleaned with sodium hypochlorite, which is found in some bleaches).
Severe blood dyscrasias have been reported very rarely. In case of blood dyscrasia, Asacol® treatment should be discontinued immediately (signs of unexplained bleeding, hematoma, purpura, anemia, persistent fever or sore throat), and patients should consult a doctor immediately if blood dyscrasias are suspected or detected.
Liver dysfunction
Elevated liver enzymes have been reported in patients taking mesalazine-containing products. Asacol® should be used with caution in patients with liver damage.
Cardiac hypersensitivity reactions
Cardiac hypersensitivity reactions (myo- or pericarditis) caused by mesalazine have been reported rarely with the use of Asacol®. In case of known previous cardiac hypersensitivity reactions caused by mesalazine, Asacol® should not be used. Caution should be exercised in patients with previous myo- and pericarditis of allergic origin, regardless of its cause.
Lung disease
Patients with pulmonary diseases, especially asthma, should be closely monitored during therapy with Asacol®.
Hypersensitivity to sulfasalazine
Treatment with Asacol® in patients with known hypersensitivity to sulfasalazine should be initiated only under close medical supervision. If acute symptoms of intolerance appear, such as abdominal colic, acute abdominal pain, fever, severe headache or skin rash, treatment should be discontinued immediately.
Gastric and duodenal ulcers
Based on theoretical considerations, treatment of patients with gastric or duodenal ulcers should be initiated with caution.
Carbohydrate intolerance
Patients with rare hereditary forms of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Presence of pills in stool
There have been isolated reports of whole tablets being found in the stool. These seemingly whole tablets may in some cases be essentially empty shells from film-coated tablets. If whole tablets are frequently found in the stool, the patient should consult a doctor.
Elderly patients
Elderly patients are recommended to use Asacol® only if their renal and hepatic function are normal. In general, therapy should be continued with caution (see section "Contraindications").
Severe skin adverse reactions
Severe cutaneous adverse reactions, including drug-induced eosinophilia with systemic symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with mesalazine. Mesalazine should be discontinued at the first signs and symptoms of severe cutaneous reactions, such as skin rash, intestinal mucosal lesions, or any other sign of hypersensitivity.
Interaction with other medicinal products and other types of interactions
There have been isolated reports of an acceptable change in coagulation (INR value) after combined administration with coumarins (phenprocoumon, warfarin).
Mesalazine may potentiate the myelosuppressive effect of azathioprine, 6-mercaptopurine or thioguanine. Life-threatening infection may occur. Patients should be closely observed for signs of infection and myelosuppression. Blood counts, especially leukocyte, platelet and lymphocyte counts, should be monitored at the start of such combination therapy and at regular intervals (once a week) thereafter. If the leukocyte count is stable after one month, monthly blood tests are considered sufficient for the next 3 months, after which repeat tests should be performed once a quarter.
With the exception of interaction studies with purine metabolism inhibitors in adults and children, no other interaction studies have been conducted in adults or children.
Application features
Excipients of particular interest.
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate data from the use of Asacol® in pregnant women. However, in a limited number of pregnant women (627) exposed to mesalazine, no adverse effects on pregnancy or on the health of the fetus/newborn child were observed. No other relevant epidemiological data are available at present.
In one isolated case of long-term administration of high doses of mesalazine (2-4 g orally) to a pregnant woman, renal failure was observed in the newborn. Animal studies with oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
Therefore, Asacol® should be prescribed during pregnancy only if the expected benefit outweighs the potential risks.
Low concentrations of mesalazine and its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this phenomenon is unknown. To date, there is only limited experience in breast-feeding women. Hypersensitivity reactions, such as diarrhoea, in infants cannot be excluded. Therefore, Asacol® should be used during breast-feeding only if the expected benefit outweighs the possible risk. If diarrhoea develops in the infant, breast-feeding should be discontinued.
The ability to influence the reaction speed when driving or working with other mechanisms
No relevant studies have been conducted. No negative effect on the reaction speed when driving vehicles or other mechanisms is expected.
Method of administration and doses
Adults
Ulcerative colitis.
Start of treatment: One tablet of Asacol® 800 mg in the morning, noon and evening.
In case of a particularly severe clinical picture and resistance to treatment, the daily dose can be increased to six 800 mg tablets.
Supportive therapy.
During maintenance treatment in remission, the recommended dose can be increased to 2.4 g mesalazine per day and adjusted individually. The dose should be divided into several doses.
Crohn's disease.
When treating the disease in the acute phase and during maintenance therapy, the dosage should be selected individually, it can be increased to 4 g of mesalazine per day in several doses.
Elderly patients.
Elderly patients do not require dose adjustment unless renal and hepatic function is impaired.
Children aged six and over
Ulcerative colitis or Crohn's disease.
- Active disease: The dose is determined individually, starting from 30-50 mg/kg body weight/day in several doses. The maximum dose is 75 mg/kg body weight/day in several doses. The total daily dose should not exceed 4 g of mesalazine.
Maintenance therapy: the dose is determined individually, starting from 15-30 mg/kg body weight/day in several doses. The total daily dose should not exceed 2 g of mesalazine.
It is usually recommended that children weighing up to 40 kg receive half the dose recommended for adults, and children weighing more than 40 kg receive the normal dose recommended for adults.
Method of application
The tablets are for oral use and should be swallowed whole. The tablets should not be chewed, broken or crushed under any circumstances. If possible, they should be taken before meals with a glass of liquid.
If one or more doses are missed, the next dose should be taken as usual.
The duration of use is determined by the doctor. Usually, remission in ulcerative colitis and Crohn's disease occurs after 8–12 weeks of taking Asacol®.
Children
Asacol® tablets should not be used in children under 6 years of age, as experience with the use of the drug in this age group is insufficient.
Overdose
There are few data on overdose (e.g. suicide attempt with high oral doses of mesalazine) which do not indicate renal or hepatic toxicity. There is no specific antidote. Treatment is symptomatic and supportive.
Side effects
Summary of safety profile
Allergic reactions involving the heart, lungs, liver, kidneys, pancreas, skin, and subcutaneous tissues have been reported.
Treatment of patients with known hypersensitivity to sulfasalazine should be discontinued immediately if acute symptoms of intolerance occur, such as cramps, abdominal pain, fever, severe headache or rash.
Serious cutaneous adverse reactions, including drug-induced eosinophilia with systemic symptoms (DRESS), Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with mesalazine treatment (see section 4.4).
Summary of adverse reactions
The following frequency criteria are used to evaluate adverse reactions: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).
Disorders of the hematopoietic and lymphatic systems
Uncommon: eosinophilia (as a manifestation of an allergic reaction).
Very rare: altered blood counts (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia), bone marrow depression, blood dyscrasia.
Immune system disorders
Very rare: hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis, angioedema, lupus-like syndrome.
Nervous system disorders
Very common: headache.
Common: dizziness.
Uncommon: paraesthesia.
Very rare: peripheral neuropathy, benign intracranial hypertension (in children during puberty).
Cardiovascular system disorders
Rare: myocarditis, pericarditis.
Respiratory, thoracic and mediastinal disorders
Very rare: allergic and fibrosing pulmonary reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), interstitial pneumonia, eosinophilic pneumonia, lung disease.
Gastrointestinal disorders
Common: vomiting, nausea, dyspepsia, abdominal pain, diarrhea.
Rare: flatulence.
Very rare: acute pancreatitis.
Hepatobiliary system disorders
Very rare: changes in liver function tests (increased transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis, hepatic failure.
Skin and subcutaneous tissue disorders
Common: rash.
Uncommon: urticaria, pruritus.
Rare: photosensitivity (see below "Description of selected adverse reactions").
Very rare: alopecia.
Frequency not known: Drug-induced eosinophilia with systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal, connective tissue and bone disorders
Common: arthralgia.
Uncommon: myalgia.
Frequency not known: Lupus-like syndrome with pericarditis and pleuropericarditis as the main symptoms, as well as rashes.
Renal and urinary disorders
Very rare: renal dysfunction, including acute and chronic interstitial nephritis and renal failure, nephrotic syndrome, renal failure, which may be reversible and disappear with early discontinuation of treatment.
Frequency not known: nephrolithiasis (see section "Special precautions").
Reproductive system and mammary gland disorders
Very rare: oligospermia (reversible).
General violations
Common: fever.
Uncommon: chest pain.
Frequency unknown: mesalazine intolerance with increased C-reactive protein levels and/or worsening of symptoms of the underlying disease.
Research
Frequency unknown: increased blood creatinine, decreased body weight, decreased creatinine clearance, increased amylase, increased erythrocyte sedimentation rate, increased lipase, increased blood urea nitrogen (BUN).
Description of selected adverse reactions
An unknown number of the above adverse reactions are more likely to be associated with the underlying inflammatory bowel disease than with Asacol® treatment. This is particularly true for gastrointestinal and arthralgia adverse reactions.
If patients develop renal dysfunction during treatment, the possibility of mesalazine-induced nephrotoxicity should be considered, which may be reversible and disappear after discontinuation of treatment.
Patients should be closely monitored to avoid blood dyscrasias due to bone marrow suppression.
Concomitant use of azathioprine, 6-mercaptoprine or thioguanine may cause leukopenia due to increased myelosuppressive effect.
Photosensitivity
More severe reactions have been reported in patients with pre-existing skin disorders such as atopic dermatitis and atopic eczema.
Expiration date
3 years.
Do not use after the expiry date stated on the packaging.
Storage conditions
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging
400 mg tablets: 10 tablets in a blister; 10 blisters in a cardboard box;
800 mg tablets: 10 tablets in a blister; 5 or 6 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Tillotts Pharma AG.
Location of the manufacturer and its address of place of business
Hauptstrasse 27, 4417 Ziefen, Switzerland.
