Instructions Asacol rectal suppositories 500 mg No. 20
Composition
active ingredient: mesalazine;
1 suppository contains mesalazine 500 mg;
excipient: solid fat.
Dosage form
Rectal suppositories.
Main physicochemical properties: torpedo-shaped suppositories of light gray-brown color.
Pharmacotherapeutic group
Anti-inflammatory agent used for intestinal diseases. ATX code A07E C02.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Asacol® contains mesalazine (5-aminosalicylic acid), which exerts an anti-inflammatory effect through a mechanism that is not fully understood. Mesalazine reduces pro-inflammatory processes in the intestinal mucosa affected by inflammation.
Pharmacodynamic effects
Mesalazine in therapeutic concentrations inhibits the migration of polymorphonuclear leukocytes and inhibits the activity of lipoxygenase. As a result, the synthesis of pro-inflammatory leukotrienes (TTB4, 5-HETE) in macrophages of the intestinal wall is suppressed. In experimental conditions, inhibition of cyclooxygenase and, accordingly, the release of thromboxane B2 and prostaglandin E2 was observed, but the clinical significance of this effect remains unclear. Mesalazine inhibits the formation of platelet-activating factor (PAF). Recently, it has been found that mesalazine also activates PPAR-ү receptors, which counteract the nuclear activation of intestinal inflammatory reactions. In addition, mesalazine is also an antioxidant: it reduces the synthesis of substances containing active oxygen and binds free radicals.
Clinical efficacy and safety
The efficacy of rectal mesalazine (Asacol®, suppositories) was tested in four double-blind studies involving 318 patients. Three studies examined the efficacy in the emergency treatment of mild to moderate proctitis and proctosigmoiditis; two studies were placebo-controlled and one was a comparator. Treatment lasted four weeks. Both placebo-controlled studies showed statistically significant results in favour of mesalazine. The fourth controlled study examined the effect on maintaining remission over one year. Mesalazine doses of 0.5 g and 1 g were significantly superior to placebo.
Pharmacokinetics
Absorption
After a single rectal dose of 0.5 g of mesalazine (Asacol®), the following concentrations of the active substance and the main metabolite N-acetyl-mesalazine were determined [values in brackets]: Cmax 271 ± 26 ng/ml [528 ± 50 ng/ml], Tmax 2.4 ± 0.3 h [3.9 ± 0.4 h], AUC 1737 ± 381 ng/ml × h [5756 ± 1657 ng/ml × h].
Distribution
Distribution studies have not been conducted.
Biotransformation
Before reaching the intestinal mucosa, mesalazine undergoes presystemic metabolism to form N-acetyl-mesalazine. Part of the free mesalazine undergoes N-acetylation in the liver and intestinal mucosa.
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.
Kinetics in special patient groups
Kinetics in special patient groups (e.g., patients with hepatic and renal impairment, genetic polymorphisms) have not been studied.
Indication
This medicine is intended for use by adults:
for the treatment of mild to moderate proctitis and proctosigmoiditis (up to 20 cm from the anus); in severe forms of generalized ulcerative colitis affecting the rectum or rectosigmoid colon, as an adjunct to oral treatment.
Contraindication
Hypersensitivity to the active substance or any of the components of the drug. Known hypersensitivity to salicylates. Severe liver dysfunction. Severe renal dysfunction (GFR (glomerular filtration rate) < 30 ml/min/1.73 m2). Children under 2 years of age.
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 performed 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 (adverse reactions) are detected, such tests should be performed immediately.
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.
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 develop, Asacol® treatment should be discontinued immediately and medical attention sought.
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. Caution should be exercised when using Asacol® in patients with liver disorders.
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 allergic myo- and pericarditis, regardless of the cause.
Lung disease
Patients with lung disease, especially asthma, should be monitored particularly carefully during treatment with Asacol®.
Hypersensitivity to sulfasalazine
In patients with known hypersensitivity to sulfasalazine, treatment with Asacol® should only be initiated under strict medical supervision. If acute symptoms of intolerance occur, such as abdominal cramps, 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.
Elderly patients
The use of Asacol® in elderly patients is recommended only if renal and hepatic function are normal; and it should be continued with caution.
Children
There is little experience and only limited documented data on the effectiveness of the drug in children.
Interaction with other medicinal products and other types of interactions
Drug interaction studies have not been conducted.
There is insufficient evidence that mesalazine may reduce the anticoagulant effect of warfarin and phenprocoumon.
Mesalazine may potentiate the myelosuppressive effect of azathioprine, 6-mercaptopurine or thioguanine. Life-threatening infections may occur. Patients should be closely monitored 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.
Ability to influence reaction speed when driving vehicles or other mechanisms
Asacol® has no or negligible influence on the ability to drive and use machines.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate data from the use of Asacol® in pregnant women. However, a limited number of pregnant women (627) exposed to mesalazine did not reveal any adverse effects on pregnancy or on the health of the fetus/newborn. No other relevant epidemiological data are available.
In one isolated case, renal failure was reported in a newborn whose mother had taken high doses of mesalazine (2-4 g, orally) during pregnancy. Animal studies with oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Therefore, Asacol® should be prescribed during pregnancy only if the expected benefit outweighs the potential risks.
Breastfeeding
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.
Method of administration and doses
Suppositories are for rectal use only. If one or more doses are missed, the next dose should be taken as usual.
Dosage
Adults
Remission induction: 1 suppository 3 times a day after defecation.
Maintenance treatment during remission: Long-term treatment is indicated to prevent relapses: 1 suppository of Asacol® is used in the morning and evening. The suppositories should be inserted deep into the anus after defecation.
Elderly patients
Elderly patients, in the absence of severe liver or kidney disorders, can use the usual adult dose. Studies in the elderly group have not been conducted.
Children
At this time, the use of the drug and its safety for children and adolescents have not been sufficiently studied.
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.
Adverse reactions
Summary of safety profile
Allergic reactions involving the heart, lungs, liver, kidneys, pancreas, skin, and subcutaneous tissues have been reported.
Treatment should be discontinued immediately in patients with known hypersensitivity to sulfasalazine if acute symptoms of intolerance occur, such as cramps, abdominal pain, fever, severe headache, or rash.
Summary of adverse reactions
The following frequency criteria are used to evaluate adverse reactions:
very common (≥ 1/10); common (≥ 1/100 - < 1/10), uncommon (≥ 1/1,000 - < 1/100), rare (> 1/10,000 - < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).
Blood and lymphatic system disorders
Uncommon: eosinophilia (as a manifestation of an allergic reaction).
Very rare: Abnormal blood count (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia, blood dyscrasia).
Immune system disorders
Very rare: hypersensitivity reactions such as allergic rashes, drug fever, lupus erythematosus, pancolitis.
Nervous system disorders
Very common: headache.
Common: dizziness.
Uncommon: paraesthesia.
Very rare: peripheral neuropathy.
Cardiovascular system disorders
Rare: myocarditis, pericarditis.
Respiratory, thoracic and mediastinal disorders
Very rare: allergic and fibrotic pulmonary reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), interstitial pneumonia, lung disease.
Frequency unknown: pleurisy.
Gastrointestinal disorders
Common: vomiting, nausea, dyspepsia, abdominal pain, diarrhea.
Infrequent: flatulence.
Very rare: acute pancreatitis.
Hepatobiliary system disorders
Very rare: changes in liver function tests (increased transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis.
Skin and subcutaneous tissue disorders
Common: rash.
Uncommon: urticaria, pruritus.
Rare: photosensitivity (see section “Description of selected side effects”)
Very rare: alopecia.
Musculoskeletal, connective tissue and bone disorders
Common: arthralgia.
Uncommon: myalgia.
Frequency unknown: lupus-like syndrome with characteristic symptoms such as pericarditis and pleuropericarditis, as well as rashes.
Renal and urinary system disorders
Very rare: renal dysfunction, including acute and chronic interstitial nephritis and renal failure, nephrotic syndrome, renal failure, which may be reversible and disappear upon early discontinuation of treatment.
Frequency unknown: nephrolithiasis.
Reproductive system and mammary gland disorders
Very rare: oligospermia (reversible).
General disorders and administration site conditions
Common: fever.
Uncommon: chest pain.
Frequency unknown: mesalazine intolerance with increased C-reactive protein and/or worsening of symptoms of the underlying disease, local reaction.
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 side effects
Some (number unknown) of the above adverse reactions are likely to be associated with the underlying inflammatory bowel disease and not with Asacol® treatment. This is particularly true for gastrointestinal adverse reactions and arthralgia.
In the event that 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 (see section 4.4).
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
Do not use after the expiry date stated on the packaging.
Storage conditions
Store in a dark place at a temperature not exceeding 25 ° C. Do not refrigerate or freeze. Keep out of the reach of children.
Packaging
Rectal suppositories 500 mg; 5 suppositories in a blister; 4 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Tilots Pharma AG.
Location of the manufacturer and its business address
Manufacturer: Hauptstrasse 27, 4417 Ziefen, Switzerland.
