Instructions for Pentasa rectal suppositories 1000 mg No. 28
Composition
active ingredient: mesalazine;
1 suppository contains mesalazine 1000 mg;
excipients: povidone, macrogol 6000, magnesium stearate, talc.
Dosage form
Rectal suppositories.
Main physicochemical properties: oval-shaped suppositories from white to yellowish-brown with inclusions.
Pharmacotherapeutic group
Anti-inflammatory drugs used in intestinal diseases. Aminosalicylic acid and similar drugs.
ATX code A07E C02.
Pharmacological properties
Pharmacodynamics.
Mesalazine is the active ingredient in sulfasalazine, which is used to treat ulcerative colitis and Crohn's disease.
Clinical studies suggest that the therapeutic properties of mesalazine when administered orally and rectally are due to its local action on inflamed areas of the intestine rather than a systemic effect. Available information indicates that the severity of intestinal inflammation in patients with ulcerative colitis is inversely correlated with the concentration of mesalazine in the mucosa.
Patients with inflammatory bowel disease exhibit increased leukocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites (especially leukotrienes B4), and the formation of free radicals in inflamed intestinal tissues.
The mechanism of action of mesalazine is not fully understood, although mechanisms such as stimulation of the γ-form of peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor kappa-B (NF-κB) in the intestinal mucosa may be involved. The pharmacological effects of mesalazine in vitro and in vivo studies are to inhibit leukocyte chemotaxis, reduce cytokine and leukotriene production, and neutralize free radicals. Although this has not been definitively established, in any case the above processes play a major role in the clinical efficacy of mesalazine.
Pharmacokinetics.
The therapeutic effect of mesalazine is mainly determined by its local contact with the area of inflammation of the intestinal mucosa.
The use of suppositories provides a high concentration of mesalazine in the rectum and low systemic absorption.
Absorption: The drug is absorbed slowly after rectal administration, but the extent depends on the dose, composition of the drug, and distribution. Absorption, as determined from steady-state urinary excretion in healthy volunteers receiving 2 g (1 g × 2) of the drug per day, is approximately 10%.
Distribution: Mesalazine is approximately 50% bound to plasma proteins and acetylmesalazine is approximately 80%. Mesalazine and acetylmesalazine do not cross the blood-brain barrier.
Biotransformation. Mesalazine is converted to N-acetylmesalazine (acetylmesalazine) both presystemically in the intestinal mucosa and systemically in the liver, mainly by N-acetyltransferase-1 (NAT-1). Minor acetylation occurs with the participation of colonic bacteria. Acetylation of mesalazine is probably not related to the acetylation phenotype of the patient. Acetylmesalazine is believed to be clinically inactive, but this fact requires confirmation.
Excretion: Mesalazine and acetylmesalazine are excreted in the urine and feces. Acetylmesalazine is mainly found in the urine.
In patients with impaired liver and kidney function, the risk of kidney damage may increase due to a decrease in the rate of drug excretion.
Indication
Ulcerative proctitis.
Contraindication
Hypersensitivity to the active substance, to salicylates or to any of the excipients. Severe liver and/or kidney dysfunction. Gastric or duodenal ulcer. Hemorrhagic diathesis.
Interaction with other medicinal products and other types of interactions
Concomitant treatment with Pentasa and azathioprine, 6-mercaptopurine or thioguanine in studies has resulted in an increased incidence of myelosuppressive effects; an interaction between these agents is likely. The mechanism of this interaction is not fully understood. It is recommended to regularly monitor leukocyte levels and adjust the doses of thiopurines accordingly.
According to unconfirmed data, mesalazine may weaken the anticoagulant effect of warfarin.
Possible enhancement of the hypoglycemic effect of sulfonylurea derivatives, toxic effects of methotrexate. The activity of furosemide, spironolactone, sulfonamides, rifampicin, uricosuric drugs (probenecid and sulfinpyrazone) may be weakened. Mesalazine may be able to potentiate the undesirable effect of glucocorticoids on the gastric mucosa, may reduce the absorption of digoxin.
Application features
However, caution is advised in patients with an allergic reaction to sulfasalazine (due to the risk of allergy to salicylates). In the event of acute symptoms of intolerance, including abdominal cramps, acute abdominal pain, fever, intense headache and rash, treatment with the drug should be discontinued immediately.
Patients with impaired liver function are advised to take the drug with caution. Before starting treatment and during treatment with the drug, liver function parameters such as ALT or AST should be monitored at the discretion of the treating physician.
The drug is not recommended for use in patients with impaired renal function. Renal function should be monitored regularly (e.g. parameters such as serum urea and creatinine, urinary sediment and methaemoglobin), especially at the beginning of treatment. Urinalysis (using dipsticks) should be performed before and during treatment with the drug, at the discretion of the treating physician. In patients with abnormal renal function parameters during treatment, nephrotoxicity caused by mesalazine should be suspected. Concomitant use of other drugs with known nephrotoxic effects should lead to an increased frequency of renal function monitoring.
Patients with lung diseases, including asthma, require very careful monitoring during treatment.
Cardiac hypersensitivity reactions (myocarditis and pericarditis) caused by mesalazine have been reported very rarely. Severe persistent pathological changes in the cellular composition of the blood have been observed very rarely. Before starting treatment and during treatment with the drug, it is recommended to perform a blood test with the determination of the leukocyte formula, at the discretion of the attending physician. Concomitant treatment with azathioprine, 6-mercaptopurine or thioguanine may increase the risk of persistent pathological changes in the cellular composition of the blood (see section "Interaction with other medicinal products and other types of interactions"). If these undesirable reactions are suspected or signs are detected, treatment should be discontinued.
Nephrolithiasis, including the formation of stones composed of 100% mesalazine, has been reported with the use of mesalazine. Patients should be advised to drink sufficient fluids during treatment.
Blood and urine tests are recommended to be performed 14 days after the start of treatment and then 2–3 times at 4-week intervals. If the test results are within normal limits, further tests should be performed every 3 months. If additional symptoms appear, these tests should be performed immediately.
Interference with laboratory tests
There have been several reports of possible interference with the determination of urinary normetanephrine by liquid chromatography, resulting in false-positive results in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine.
Severe skin adverse reactions
Severe cutaneous adverse reactions (SCARs), including drug-induced eosinophilia with systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment.
The use of mesalazine should be discontinued at the first appearance of severe skin reactions such as skin rash, damage to the intestinal mucosa or any other signs of hypersensitivity.
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).
Use during pregnancy or breastfeeding
Pregnancy.
Mesalazine is known to cross the placental barrier and its concentration in cord plasma is lower than that in maternal plasma. The metabolite acetylmesalazine is found in the same concentration in cord plasma and maternal plasma.
From a number of studies/observations it is known that the drug has no teratogenic effect; evidence of a significant risk to humans associated with the use of the drug has also not been identified. Animal studies with oral administration of mesalazine also did not reveal direct or indirect harmful effects of the drug with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
There are no adequate and well-controlled studies of Pentasa in pregnant women. Limited published data on mesalazine suggest no increase in the overall rate of birth defects. Some data suggest an increase in preterm birth, stillbirth and low birth weight, but these adverse pregnancy outcomes are also associated with active inflammatory bowel disease.
Blood disorders (pancytopenia, leukopenia, thrombocytopenia and anemia) have been observed in newborns whose mothers were treated with Pentasa.
Only one case of neonatal renal failure has been reported after prolonged use of high-dose mesalazine (2–4 g orally) during pregnancy.
During pregnancy, mesalazine should only be used if the expected benefit to the mother outweighs the potential risk to the fetus. The disease itself (inflammatory bowel disease) may increase the risk of adverse pregnancy outcomes.
Mesalazine passes into breast milk. The concentration of mesalazine in breast milk is lower than in maternal plasma, while acetylmesalazine is found in milk at the same or higher concentrations. There is limited experience with the oral administration of mesalazine to breastfeeding women.
There are no controlled studies on the use of mesalazine during breastfeeding. Hypersensitivity reactions, such as diarrhoea, in infants cannot be excluded. If diarrhoea occurs in a breastfed infant, breastfeeding should be discontinued.
During breastfeeding, mesalazine should be used only if the expected benefit to the mother outweighs the potential risk to the child.
Fertility.
Animal studies have shown no effect of mesalazine on male and female fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Mesalazine has no or negligible influence on the ability to drive or use machines. If dizziness occurs during treatment with the drug, you should refrain from driving.
Method of administration and doses
Adults – 1 g 1–2 times a day.
Do not reduce the dose for elderly patients.
It is recommended to empty the bowel immediately before inserting the suppository. To ensure hygiene during the procedure, a rubber applicator should be used.
The suppository should be inserted as deeply as possible into the rectum. The suppository should be kept in the rectum for as long as possible to achieve maximum therapeutic effect.
If the lesion is widespread or in cases where the response to oral treatment is slow, suppositories can be used simultaneously with tablets.
The duration of use is determined by the doctor.
Children.
There is limited clinical data on the effectiveness of the drug in children.
Overdose
There is only limited clinical experience with overdose of Pentasa, which does not indicate renal or hepatic toxicity. There is no specific antidote, treatment should be symptomatic and supportive. There have been reports of patients taking daily doses of up to 8 g for a month without any adverse effects.
Given the dosage form of mesalazine, the risk of overdose is small.
Since Pentasa is an aminosalicylate, well-known symptoms characteristic of poisoning with salicylic acid salts may occur: acid-base intoxication, pulmonary hyperventilation, dehydration caused by sweating and vomiting, hypoglycemia.
Overdose treatment: in case of acidosis or alkalosis - restoration of acid-base and electrolyte balance; in case of dehydration - rehydration; in case of hypoglycemia - use of glucose. Additionally, intravenous infusion of electrolyte solutions should be carried out to increase diuresis. Careful monitoring of renal function.
Side effects
The most common adverse reactions observed during clinical studies were diarrhea, nausea, abdominal pain, headache, vomiting, and rash.
Hypersensitivity reactions and drug fever are sometimes observed.
Severe cutaneous adverse reactions (SCARs), including drug-induced eosinophilia with systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).
After rectal administration, local reactions such as itching, rectal discomfort and urge to defecate are possible.
Fatigue, paresthesia, and methemoglobinemia may develop.
The frequency of adverse reactions reported during clinical trials and post-marketing surveillance is defined as follows:
common (≥ 1/100 to < 1/10), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).
Blood and lymphatic system disorders: very rare – eosinophilia (as part of an allergic reaction), anemia, aplastic anemia, agranulocytosis, neutropenia, leukopenia (including granulocytopenia), pancytopenia, thrombocytopenia.
Immune system disorders: very rare – pancolitis, drug fever, hypersensitivity reactions including allergic exanthema, anaphylactic reactions with eosinophilia and systemic symptoms (DRESS syndrome).
Nervous system: common - headache; rare - vestibular reactions, dizziness; very rare - peripheral neuropathy, benign intracranial arterial hypertension (in adolescents during puberty).
Cardiac disorders: rare – myocarditis* and pericarditis*; very rare – pericardial effusion.
Respiratory, thoracic and mediastinal disorders: very rare - allergic and fibrotic changes in the lungs (including dyspnea, cough, bronchospasm, allergic alveolitis, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis).
Hepatobiliary disorders: very rare - liver dysfunction (including increased levels of liver enzymes, cholestasis indicators, bilirubin), hepatotoxicity (including hepatitis*, cholestatic hepatitis, cirrhosis, liver failure).
Skin and subcutaneous tissue disorders: common - rash (including urticaria, erythematous rash); rare - photosensitivity reactions**; very rare - reversible alopecia, angioedema, erythema multiforme; frequency unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced eosinophilia with systemic symptoms (DRESS syndrome).
Musculoskeletal and connective tissue disorders: very rare – myalgia, arthralgia, lupus erythematosus-like reactions.
Renal and urinary disorders: very rare - renal dysfunction (including interstitial nephritis* (acute and chronic), nephrotic syndrome, renal failure (acute/chronic)); frequency unknown - nephrolithiasis***, urine discoloration***.
From the reproductive system and mammary glands: very rare - oligospermia (reversible).
General disorders and administration site conditions: common - anal discomfort and irritation at the injection site, itching, rectal tenesmus.
*The mechanism of development of mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but its allergic origin is possible.
**Photosensitivity: More severe reactions have been reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.
***See the “Application Features” section for detailed information.
It should be noted that some of these disorders can be explained by intestinal inflammation itself.
Adverse reaction reporting
Reporting of suspected adverse reactions after the approval of a medicinal product is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
Keep out of the reach of children. Store in a place protected from light at a temperature not exceeding 25 °C.
Packaging
7 suppositories in a blister, 4 blisters complete with hygienic pads in a cardboard box.
7 suppositories in a blister, 4 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Ferring GmbH, Germany.
Location of the manufacturer and address of its place of business.
Wittland 11, 24109 Kiel, Germany.
