Pentasa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PENTASA (PENTASA®)

Composition:

Active substance: mesalazine;

1 suppository contains mesalazine 1000 mg;

Excipients: povidone, macrogol 6000, magnesium stearate, talc.

Pharmaceutical form. Rectal suppositories.

Main physicochemical properties: oval-shaped suppositories of white to yellowish-brown color with speckles.

Pharmacotherapeutic group. Anti-inflammatory agents used in intestinal diseases. Aminosalicylic acid and related agents.

ATC code A07EC02.

Pharmacological properties.

Pharmacodynamics.

Mesalazine is the active component of sulfasalazine, which is used for the treatment of ulcerative colitis and Crohn's disease.

Clinical studies indicate that the therapeutic effects of mesalazine following oral or rectal administration are primarily due to its local action on inflamed areas of the intestinal mucosa rather than systemic effects. Available data suggest that the severity of intestinal inflammation in patients with ulcerative colitis is reversibly correlated with mesalazine concentration in the intestinal mucosa.

In patients with inflammatory bowel diseases, increased leukocyte migration, abnormal cytokine production, elevated generation of arachidonic acid metabolites (particularly leukotriene B4), and increased formation of free radicals in inflamed intestinal tissues are observed.

The exact mechanism of action of mesalazine is not fully understood, although several mechanisms may be involved, including stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and inhibition of nuclear factor kappa-B (NF-κB) in the intestinal mucosa. Pharmacological effects of mesalazine observed in in vitro and in vivo studies include inhibition of leukocyte chemotaxis, reduction in cytokine and leukotriene production, and neutralization of free radicals. Although not definitively established, these processes listed above are believed to play a key role in the clinical efficacy of mesalazine.

Pharmacokinetics.

The therapeutic effect of mesalazine is primarily determined by its local contact with the inflamed areas of the intestinal mucosa.

The use of suppositories ensures high concentrations of mesalazine in the rectum and low systemic absorption.

Absorption. After rectal administration, the drug is absorbed slowly, with the rate depending on the dose, formulation, and extent of inflammation. Absorption, assessed by urinary excretion of the compound at steady state in healthy volunteers receiving 2 g (1 g × 2) of the drug daily, is approximately 10%.

Distribution. Plasma protein binding of mesalazine is approximately 50%, and for acetylmesalazine it is approximately 80%. Mesalazine and acetylmesalazine do not cross the blood-brain barrier.

Biological transformation. Mesalazine is converted to N-acetylmesalazine (acetylmesalazine) both presystemically in the intestinal mucosa and systemically in the liver, primarily via N-acetyltransferase-1 (NAT-1). A minor portion of acetylation is mediated by colonic bacteria. Acetylation of mesalazine is likely not related to the patient's acetylator phenotype. Acetylmesalazine is considered clinically inactive, although this requires further confirmation.

Elimination. Mesalazine and acetylmesalazine are excreted in urine and feces. Acetylmesalazine is the predominant form found in urine.

In patients with impaired hepatic or renal function, the risk of renal toxicity may be increased due to reduced elimination of the drug.

Clinical characteristics.

Indications.

Ulcerative proctitis.

Contraindications.

Hypersensitivity to the active substance, to salicylates, or to any of the excipients. Severe impairment of liver and/or kidney function. Gastric or duodenal ulcer. Hemorrhagic diathesis.

Interaction with other medicinal products and other forms of interaction.

Concomitant treatment with Pentasa and azathioprine, 6-mercaptopurine, or thioguanine has led to an increased frequency of myelosuppressive effects in studies; an interaction between these agents is likely. The mechanism of this interaction has not been fully elucidated. Regular monitoring of leukocyte levels is recommended, and doses of thiopurines should be adjusted accordingly.

There are unconfirmed data suggesting that mesalazine may reduce the anticoagulant effect of warfarin.

Possible potentiation of the hypoglycemic effect of sulfonylurea derivatives and of the toxic effect of methotrexate. The activity of furosemide, spironolactone, sulfonamides, rifampicin, and uricosuric agents (probenecid and sulfinpyrazone) may be reduced. Mesalazine may potentially enhance the adverse effects of glucocorticoids on gastric mucosa and may reduce digoxin absorption.

Special precautions for use

Most patients with intolerance or increased sensitivity to sulfasalazine can take Pentasa without risk of similar reactions.

However, caution is recommended in patients who have had an allergic reaction to sulfasalazine (due to the risk of allergy to salicylates). If acute intolerance symptoms occur, including abdominal cramps, acute abdominal pain, fever, severe headache, or rash, treatment with the drug must be discontinued immediately.

Patients with impaired liver function should use the drug with caution. Liver function parameters such as ALT and AST should be monitored before and during treatment, 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. serum urea and creatinine levels, urine sediment, and methemoglobin), especially at the beginning of treatment. Urinalysis (using test strips) should be performed before and during treatment, 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 agents known to have nephrotoxic effects should lead to increased frequency of renal function monitoring.

Patients with pulmonary diseases, particularly asthma, require very careful monitoring during treatment.

Very rare cases of hypersensitivity cardiac reactions (myo- and pericarditis) caused by mesalazine have been reported. Very rare cases of severe, persistent blood dyscrasias have also been observed. Blood counts with differential leukocyte count are recommended before starting treatment and during treatment, at the discretion of the treating physician. Concomitant treatment with azathioprine, 6-mercaptopurine, or thioguanine may increase the risk of persistent blood dyscrasias (see section "Interaction with other medicinal products and other forms of interaction"). If suspicion or signs confirming these adverse reactions arise, treatment should be discontinued.

Cases of nephrolithiasis, including stone formation composed entirely of mesalazine, have been reported with mesalazine use. Patients should be advised to maintain adequate fluid intake during treatment.

Blood and urine tests are recommended 14 days after starting treatment, and subsequently 2–3 times at 4-week intervals. If test results remain within normal limits, further testing should be performed every 3 months. If additional symptoms occur, these tests should be performed immediately.

Interference with laboratory tests

There have been several reports of possible interference with urinary normetanephrine measurement by liquid chromatography, leading to false-positive results in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine.

Severe skin adverse reactions

Severe skin adverse reactions (SSARs), including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment.

Mesalazine treatment should be discontinued at the first signs of severe skin reactions, such as skin rash, mucosal lesions, or any other signs of hypersensitivity.

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

Use during pregnancy or breastfeeding

Pregnancy

It is known that mesalazine crosses the placental barrier, and its concentration in umbilical plasma is lower than that in maternal plasma. The metabolite acetylmesalazine is found at equal concentrations in umbilical and maternal plasma.

Available studies/observations indicate no teratogenic effect of the drug; significant risk to humans associated with its use has not been demonstrated. Animal studies with oral administration of mesalazine have also shown no direct or indirect harmful effects on pregnancy, embryonic/fetal development, delivery, or postnatal development.

Well-controlled clinical studies on the use of Pentasa in pregnant women are lacking. Limited published data on mesalazine suggest no increased overall rate of congenital malformations. Some data suggest increased rates of preterm birth, stillbirth, and low birth weight, but these adverse pregnancy outcomes are also associated with active inflammatory bowel disease.

In newborns whose mothers received Pentasa treatment, blood disorders (pancytopenia, leukopenia, thrombocytopenia, and anemia) have been observed.

Renal failure in a newborn has been reported in only one case after prolonged use of high-dose mesalazine (2–4 g orally) during pregnancy.

Mesalazine may be used during pregnancy only when 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.

Breastfeeding period

Mesalazine passes into breast milk. The concentration of mesalazine in breast milk is lower than in maternal plasma, whereas acetylmesalazine is found in milk at similar or higher concentrations. Experience with oral mesalazine use in breastfeeding women is limited.

Controlled studies on the use of mesalazine during breastfeeding have not been conducted. Hypersensitivity reactions such as diarrhea in infants cannot be excluded. If diarrhea occurs in a breastfed infant, breastfeeding should be discontinued.

Mesalazine should be used during breastfeeding only when the expected benefit to the mother outweighs the potential risk to the infant.

Fertility

Animal studies have demonstrated no effect of mesalazine on fertility in males or females.

Ability to affect reaction speed when driving vehicles or operating machinery

Mesalazine has no effect or only a negligible effect on the ability to drive vehicles or operate machinery. If dizziness occurs during treatment, patients should refrain from driving vehicles.

Method of Administration and Dosage.

Adults – 1 g 1–2 times daily.

Elderly patients – no dose reduction required.

Immediately before administration of the suppository, evacuation of the bowel is recommended. To ensure hygienic handling, a rubber applicator should be used.

The suppository should be inserted as deeply as possible into the rectum. The suppository should be retained in the rectum as long as possible to achieve maximum therapeutic effect.

If lesions are extensive or when response to oral treatment is delayed, suppositories may be used concomitantly with tablets.

Duration of treatment is determined by the physician.

Children.

There are limited clinical data on the efficacy of the drug in children.

Overdose.

Clinical experience with overdose of Pentasa is limited and does not indicate the presence of renal or hepatic toxicity. There is no specific antidote; treatment should be symptomatic and supportive. Reports have been received of patients taking daily doses up to 8 g for a month without occurrence of any adverse effects.

Due to the pharmaceutical formulation of mesalazine, the risk of overdose is low.

Since Pentasa is an aminosalicylate, well-known symptoms characteristic of salicylic acid salt poisoning may occur: acid-base intoxication, pulmonary hyperventilation, dehydration caused by sweating and vomiting, hypoglycemia.

Treatment of overdose: in cases of acidosis or alkalosis – restoration of acid-base and electrolyte balance; in dehydration – rehydration; in hypoglycemia – administration of glucose. Additionally, intravenous infusion of electrolyte solutions should be performed to increase diuresis. Close monitoring of kidney function is required.

Adverse Reactions.

The most commonly observed adverse reactions during clinical trials were diarrhea, nausea, abdominal pain, headache, vomiting, and rash.

Hypersensitivity reactions and drug fever are occasionally observed.

Severe skin adverse reactions (SSARs) have been reported in connection with mesalazine treatment, including drug-induced eosinophilia with systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (see section "Special Warnings and Precautions for Use").

Local reactions may occur after rectal administration, such as itching, rectal discomfort, and tenesmus.

Fatigue, paresthesia, and methemoglobinemia are possible.

The frequency of adverse effects reported during clinical trials and post-marketing surveillance has been defined as follows:

common (from ≥ 1/100 to < 1/10), rare (from ≥ 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: 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 disorders: common – headache; rare – vestibular reactions, dizziness; very rare – peripheral neuropathy, benign intracranial hypertension (in adolescents during puberty).

Cardiac disorders: rare – myocarditis*, pericarditis*; very rare – pericardial effusion.

Respiratory, thoracic and mediastinal disorders: very rare – allergic and fibrotic lung changes (including dyspnea, cough, bronchospasm, allergic alveolitis, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis).

Gastrointestinal disorders: common – diarrhea, abdominal pain, nausea, vomiting, flatulence; rare – increased amylase levels (in blood and/or urine), acute pancreatitis*; very rare – pancolitis.

Hepatobiliary disorders: very rare – liver function abnormalities (including elevated liver enzymes, cholestatic parameters, 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 (Quincke's edema), erythema multiforme; frequency not known – Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced eosinophilia with systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders: very rare – myalgia, arthralgia, lupus-like reactions.

Renal and urinary disorders: very rare – renal function impairment (including interstitial nephritis* (acute and chronic), nephrotic syndrome, renal failure (acute/chronic)); frequency not known – nephrolithiasis***, change in urine color***.

Reproductive system and breast disorders: very rare – oligospermia (reversible).

General disorders and administration site conditions: common – anal discomfort, irritation at site of administration, itching, rectal tenesmus.

*The mechanism of mesalazine-induced myocarditis, pericarditis, pancreatitis, nephritis, and hepatitis is unknown, but an 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 section "Special Warnings and Precautions for Use" for detailed information.

It should be noted that some of these disorders may be explained by the intestinal inflammation itself.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children. Store protected from light at a temperature not exceeding 25 °C.

Packaging.

7 suppositories in a blister, 4 blisters in a set with hygienic applicators in a cardboard package.

7 suppositories in a blister, 4 blisters in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

Ferring GmbH, Germany / Ferring GmbH, Germany.

Manufacturer's address and location of operations.

Wittland 11, 24109 Kiel, Germany / Wittland 11, 24109 Kiel, Germany.