Asacol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASACOL®

Composition:

Active substance: mesalazine;

1 suppository contains 500 mg of mesalazine;

Excipient: hard fat.

Pharmaceutical form. Rectal suppositories.

Main physicochemical characteristics: torpedo-shaped suppositories of light gray-brown color.

Pharmacotherapeutic group. Anti-inflammatory agent used in intestinal diseases. ATC 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 has not yet been fully elucidated. Mesalazine reduces pro-inflammatory processes in the intestinal mucosa affected by inflammation.

Pharmacodynamic effects

At therapeutic concentrations, mesalazine inhibits the migration of polymorphonuclear leukocytes and inhibits lipoxygenase activity. As a result, the synthesis of pro-inflammatory leukotrienes (LTB4, 5-HETE) in macrophages of the intestinal wall is suppressed. In experimental conditions, inhibition of cyclooxygenase and, consequently, release of thromboxane B2 and prostaglandin E2 has been observed; however, the clinical significance of this effect remains unclear. Mesalazine inhibits the formation of platelet-activating factor (PAF). Recently, it has been shown that mesalazine also activates PPAR-γ receptors, which counteract nuclear activation of intestinal inflammatory responses. In addition, mesalazine acts as an antioxidant: it reduces the synthesis of substances containing active oxygen and scavenges free radicals.

Clinical efficacy and safety

The efficacy of mesalazine administered rectally (Asacol®, suppositories) was evaluated in four double-blind studies involving 318 patients. In three studies, efficacy was assessed in the acute treatment of proctitis and proctosigmoiditis of mild to moderate severity; two studies were placebo-controlled, and one was comparative. Treatment lasted four weeks. In both placebo-controlled studies, statistically significant results in favor of mesalazine use were obtained. In the fourth controlled study, the effect on maintenance of remission over one year was evaluated. For mesalazine at doses of 0.5 g and 1 g, significantly better outcomes were observed compared to placebo.

Pharmacokinetics.

Absorption

Following a single rectal dose of 0.5 g mesalazine (Asacol®), the following plasma concentrations of the active substance and its major metabolite, N-acetyl-mesalazine [values in brackets], were determined: Cmax 271 ± 26 ng/mL [528 ± 50 ng/mL], Tmax 2.4 ± 0.3 hours [3.9 ± 0.4 hours], AUC 1737 ± 381 ng/mL × hour [5756 ± 1657 ng/mL × hour].

Distribution

Distribution studies have not been conducted.

Biotransformation

Prior to reaching the intestinal mucosa, mesalazine undergoes presystemic metabolism, forming N-acetyl-mesalazine. A portion of free mesalazine undergoes N-acetylation in the liver and intestinal mucosa.

Elimination

Mesalazine and N-acetyl-mesalazine are primarily excreted in feces. Renal excretion occurs mainly as N-acetyl-mesalazine, exclusively from the absorbed fraction, which is approximately 26% of the oral dose.

Pharmacokinetics in special patient populations

Pharmacokinetics in special patient populations (e.g., patients with hepatic or renal impairment, genetic polymorphisms) has not been studied.

Clinical characteristics.

Indications.

This medicinal product is intended for use in adults:

• for the treatment of mild to moderate proctitis and proctosigmoiditis (up to 20 cm from the anal opening);
• in severe forms of generalized ulcerative colitis affecting the rectum or rectosigmoid colon, as an adjunctive therapy to oral treatment.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Known hypersensitivity to salicylates.

Severe impairment of liver function.

Severe impairment of kidney function (GFR (glomerular filtration rate) < 30 mL/min/1.73 m²).

Age under 2 years.

Special precautions.

Prior to and during treatment, as decided by the treating physician, blood tests (leukocyte count, liver function parameters such as ALT or AST; serum creatinine) and urine output (test strips) should be performed. As a general guideline, repeat testing is recommended 14 days after initiation of treatment, then every 4 weeks during the following 12 weeks. If results are normal, repeat testing should be performed every three months. If additional signs (adverse reactions) occur, such tests should be performed immediately.

Cases of nephrolithiasis, including stones composed 100% of mesalazine, have been reported with mesalazine use. Adequate fluid intake should be ensured during treatment with this medicinal product.

Renal function impairment

Caution should be exercised in patients with elevated serum creatinine or proteinuria. In patients who develop renal impairment during treatment, mesalazine-induced nephrotoxicity should be suspected. If signs of developing renal dysfunction occur, treatment with Asacol® should be discontinued immediately and medical advice should be sought.

Mesalazine may cause red-brown discoloration of urine after contact with sodium hypochlorite-based bleach (e.g., in toilets cleaned with sodium hypochlorite-containing bleaches).

Hematological disorders

Severe hematological disorders have been reported very rarely. Treatment with Asacol® should be discontinued immediately in case of hematological disorders (signs of unexplained bleeding, bruising, purpura, anemia, persistent fever or sore throat). Patients should seek immediate medical attention if they suspect or detect hematological disorders.

Hepatic function impairment

Elevated liver enzyme levels have been reported in patients taking mesalazine-containing medicinal products. Caution should be exercised when using Asacol® in patients with liver disorders.

Cardiac hypersensitivity reactions

Cardiac hypersensitivity reactions induced by mesalazine (myo- or pericarditis) have been reported rarely with Asacol®. Asacol® should not be used in patients with a known history of mesalazine-induced cardiac hypersensitivity reactions. Caution should be exercised in patients with previous allergic myo- or pericarditis, regardless of the cause.

Lung disorders

Patients with lung disorders, especially asthma, should be monitored particularly carefully during treatment with Asacol®.

Hypersensitivity to sulfasalazine

Treatment with Asacol® in patients with known hypersensitivity to sulfasalazine should be initiated only under strict medical supervision. Treatment should be discontinued immediately if acute intolerance symptoms occur, such as abdominal cramps, acute abdominal pain, elevated body temperature, severe headache, or skin rash.

Gastric and duodenal ulcers

Due to theoretical considerations, treatment of patients with gastric or duodenal ulcers should be initiated cautiously.

Elderly patients

Use of Asacol® in elderly patients is recommended only if renal and hepatic functions are normal; treatment should be continued with caution.

Severe skin adverse reactions

Severe skin adverse reactions have been reported, including drug-induced eosinophilia with systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome, and toxic epidermal necrolysis, which have been observed during mesalazine treatment. Mesalazine should be discontinued at the first signs or symptoms of severe skin reactions, such as skin rash, mucosal lesions of the gastrointestinal tract, or any other signs of hypersensitivity.

Children

There is limited experience and only scarce documented data on the efficacy of this medicinal product in children.

Interaction with other medicinal products and other types of interactions.

No drug interaction studies have been conducted.

There is insufficient evidence that mesalazine may reduce the anticoagulant effect of warfarin and phenprocoumon.

Mesalazine may enhance the myelosuppressive effect of azathioprine, 6-mercaptopurine, or thioguanine. Life-threatening infections may occur. Patients should be carefully monitored for signs of infection and myelosuppression. Blood counts, particularly leukocyte, platelet, and lymphocyte counts, should be monitored at the beginning of such combination therapy and then at regular intervals (once weekly). If the leukocyte count remains stable after one month, monthly blood tests during the following 3 months are considered sufficient, after which repeat testing should be performed once every quarter.

Except for interaction studies with purine metabolism inhibitors in adults and children, no other interaction studies have been conducted in adults or children.

Special precautions for use.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate data on the use of Asacol® in pregnant women. However, in a limited number of pregnant women (627) who received mesalazine, no adverse effects on pregnancy or fetal/neonatal health have been observed. To date, other relevant epidemiological data are not available.

In one single case, renal failure in a newborn was reported whose mother had taken high doses of mesalazine (2–4 g orally) during pregnancy. Animal studies with oral administration of mesalazine have not indicated any direct or indirect harmful effects on pregnancy, embryonic/fetal development, labor, 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 observation is unknown. Currently, experience with use in breastfeeding women is limited. Hypersensitivity reactions such as diarrhea in infants cannot be excluded. Therefore, Asacol® should be used during breastfeeding only if the expected benefit outweighs the potential risk. If diarrhea develops in the infant, breastfeeding should be discontinued.

Ability to affect reaction rate while driving or operating machinery.

Asacol® has no effect or may have a negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Suppositories are intended for rectal use only. If one or more doses are missed, the next dose should be taken according to the usual schedule.

Dosage

Adults

Induction of remission: 1 suppository three times daily after defecation.

In severe generalized ulcerative colitis affecting the rectum or rectosigmoid region of the large intestine, and in cases of slow response to oral therapy, one suppository may be administered in the morning and evening in addition to oral treatment.

Maintenance therapy during remission: long-term treatment is recommended to prevent relapses: administer 1 suppository of Asacol® in the morning and evening. Suppositories should be inserted deeply into the anal canal after defecation.

Geriatric Patients

Elderly patients, in the absence of severe hepatic or renal impairment, may use the standard adult dosage. Studies in elderly patient populations have not been conducted.

Children

At present, the use and safety of the drug in children and adolescents have not been sufficiently studied.

Overdose

There is limited data on overdose (e.g., suicide attempts involving high oral doses of mesalazine), which does not indicate renal or hepatic toxicity. There is no specific antidote. Treatment is symptomatic and supportive.

Adverse Reactions

Summary of Safety Profile

Allergic reactions affecting 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 intolerance symptoms occur, such as seizures, abdominal pain, fever, severe headache, or rash.

Severe cutaneous adverse reactions have been reported, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens–Johnson syndrome, and toxic epidermal necrolysis, associated with mesalazine treatment (see section "Special Precautions").

Summary Table of Adverse Reactions

The following frequency categories are used to assess adverse reactions:

Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Blood and Lymphatic System Disorders

Uncommon: eosinophilia (as part of an allergic reaction).

Very rare: blood dyscrasias (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia, blood dyscrasia).

Immune System Disorders

Very rare: hypersensitivity reactions such as allergic rash, drug fever, erythematous lupus, pancolitis.

Nervous System Disorders

Very common: headache.

Common: dizziness.

Uncommon: paraesthesia.

Very rare: peripheral neuropathy.

Cardiac Disorders

Rare: myocarditis, pericarditis.

Respiratory, Thoracic and Mediastinal Disorders

Very rare: allergic and fibrotic lung reactions (including dyspnea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), interstitial pneumonia, lung disease.

Frequency not known: pleuritis.

Gastrointestinal Disorders

Common: vomiting, nausea, dyspepsia, abdominal pain, diarrhea.

Uncommon: flatulence.

Very rare: acute pancreatitis.

Hepatobiliary Disorders

Very rare: changes in liver function tests (elevated transaminases and cholestatic parameters), hepatitis, cholestatic hepatitis.

Skin and Subcutaneous Tissue Disorders

Common: rash.

Uncommon: urticaria, pruritus.

Rare: photosensitivity (see section "Description of Selected Adverse Effects").

Very rare: alopecia.

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens–Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and Connective Tissue Disorders

Common: arthralgia.

Uncommon: myalgia.

Frequency not known: lupus-like syndrome with characteristic symptoms such as pericarditis and pleuropericarditis, as well as rash.

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 resolve upon early discontinuation of treatment.

Frequency not known: nephrolithiasis.

Reproductive System and Breast Disorders

Very rare: oligospermia (reversible).

General Disorders and Administration Site Conditions

Common: pyrexia (fever).

Uncommon: chest pain.

Frequency not known: intolerance to mesalazine with elevated C-reactive protein and/or worsening of symptoms of the underlying disease, local reaction.

Investigations

Frequency not known: increased blood creatinine, weight loss, decreased creatinine clearance, increased amylase levels, increased erythrocyte sedimentation rate, increased lipase levels, increased blood urea nitrogen (BUN).

Description of Selected Adverse Effects

Some (number unknown) of the adverse reactions listed above are likely associated with the underlying inflammatory bowel disease rather than with treatment with Asacol®. This is particularly true for gastrointestinal adverse reactions and arthralgia.

If renal dysfunction occurs during treatment, mesalazine-induced nephrotoxicity should be considered, which may be reversible upon discontinuation of treatment.

To avoid blood dyscrasias due to bone marrow suppression, patients should be closely monitored (see section "Special Precautions").

Concomitant use of azathioprine, 6-mercaptopurine, or thioguanine may lead to leukopenia due to enhanced myelosuppressive effects.

Photosensitivity

More severe reactions have been reported in patients with pre-existing skin disorders such as atopic dermatitis and atopic eczema.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. Store in a light-protected place at a temperature not exceeding 25 °C. Do not store in the refrigerator and do not freeze. Keep out of reach of children.

Packaging. 500 mg rectal suppositories; 5 suppositories in a blister; 4 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer/Marketing Authorization Holder.

Tillotts Pharma AG.

Address of Manufacturer and/or Marketing Authorization Holder.

Manufacturer: Hauptstrasse 27, 4417 Ziefen, Switzerland.

Marketing Authorization Holder: Baslerstrasse 15, 4310 Rheinfelden, Switzerland.