Pentasa

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

Composition:

Active ingredient: mesalazine;

100 ml of suspension contain 1 g of mesalazine;

Excipients: disodium edetate (Trilon B); sodium metabisulphite (E 223); sodium acetate trihydrate; hydrochloric acid concentrated; purified water.

Pharmaceutical form. Rectal suspension.

Main physico-chemical properties: white to yellowish-colored suspension.

Pharmacotherapeutic group. Anti-inflammatory agents used in gastrointestinal disorders. Aminosalicylic acid and related substances. Mesalazine.

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 properties of mesalazine following oral and rectal administration are primarily due to its local action on inflamed areas of the intestinal mucosa rather than systemic effects.

There is evidence that the severity of intestinal inflammation in patients with ulcerative colitis receiving mesalazine is inversely correlated with mesalazine concentration in the mucosa.

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

The mechanism of action of mesalazine is not fully understood, but several mechanisms have been proposed, including activation of the gamma isoform of peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor-kappa B (NF-κB) in the intestinal mucosa.

The pharmacological effect of mesalazine observed in in vitro and in vivo studies includes inhibition of leukocyte chemotaxis, reduction in cytokine and leukotriene production, and scavenging of free radicals. To date, it is not known which of these mechanisms play the predominant 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.

Administration of rectal suspension provides high concentrations of mesalazine in the distal portion of the gastrointestinal tract and low systemic absorption. It has been established that rectal suspension reaches the descending colon and spreads over its mucosal surface.

Absorption. Absorption after rectal administration is low and depends on dosage and degree of dispersion. Measurements of mesalazine excreted in urine in healthy volunteers receiving 2 g daily (twice daily 1 g) of Pentasa showed that approximately 15–20% of the dose is absorbed.

Distribution. Plasma protein binding of mesalazine is approximately 50%, and for acetyl-mesalazine it is approximately 80%.

Metabolism. Mesalazine is metabolized to N-acetyl-mesalazine (acetyl-mesalazine) both presystemically in the intestinal mucosa and systemically in the liver, primarily by NAT-1. Minor acetylation occurs via colonic bacteria. Acetylation of mesalazine is probably not related to the acetylator phenotype of the patient.

Acetyl-mesalazine is considered to be clinically and toxicologically inactive, although this has not been definitively confirmed.

Elimination. Due to the continuous release of mesalazine from Pentasa in the gastrointestinal tract after oral administration, the elimination half-life cannot be determined. However, once the compound disappears from the gastrointestinal tract, the plasma elimination half-life of mesalazine after oral or intravenous administration is 40 minutes, and for acetyl-mesalazine it is approximately 70 minutes.

Special patient groups

Pathophysiological changes such as diarrhea and increased intestinal acidity observed during active inflammatory bowel disease have only a minor effect on the delivery of mesalazine to the intestinal mucosa after oral administration. Urinary excretion of 20–25% of the daily dose is observed in individuals with accelerated intestinal transit. Similarly, a corresponding increase in fecal excretion is observed.

Systemic exposure after administration of Pentasa rectal suspension is significantly lower in patients with active ulcerative colitis compared to patients in remission.

Clinical characteristics.

Indications.

Ulcerative proctosigmoiditis and left-sided colitis.

Contraindications.

Hypersensitivity to mesalazine, salicylates, or to any of the excipients. Severe hepatic or renal impairment.

Interaction with other medicinal products and other forms of interactions.

Concomitant use with other known nephrotoxic agents, such as NSAIDs or azathioprine, may increase the risk of renal adverse reactions.

During combined treatment with Pentasa and azathioprine, 6-mercaptopurine, or thioguanine, a higher incidence of myelosuppressive effects has been observed in some studies, suggesting a possible interaction; however, the mechanism of interaction has not been fully established. Regular monitoring of leukocyte levels and adherence to an appropriate dosing regimen for thiopurines are recommended.

Evidence that mesalazine may reduce the anticoagulant effect of warfarin is weak.

Special precautions for use.

Patients with a history of hypersensitivity reactions to medicinal products containing sulfasalazine should be closely monitored by a physician at the beginning of treatment with Pentasa (risk of allergy to salicylates).

Severe skin adverse reactions

Severe skin adverse reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis, have been reported during treatment with mesalazine. If early signs or symptoms of severe skin adverse reactions occur, such as skin rash, mucosal lesions, or other signs of hypersensitivity, including acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, or severe headache, treatment must be discontinued immediately.

Caution should be exercised when administering the drug to patients with impaired liver function. Liver function parameters such as ALT and AST should be monitored before and during treatment at the physician’s discretion.

The drug is not recommended for use in patients with renal impairment. Renal function (serum and urine creatinine levels, urine sediment) should be monitored regularly, especially at the beginning of treatment. The urological status of the patient (test strips) should be determined before and during treatment at the physician’s discretion. Tests are recommended 2 weeks after initiation of treatment and then 2–3 times at 4-week intervals. If test results are within normal limits, periodic testing may be performed every three months. In case of appearance of additional symptoms, these tests should be performed immediately.

In patients who develop renal dysfunction during treatment, mesalazine-induced nephrotoxicity should be suspected. Concomitant use of other known nephrotoxic agents requires more frequent monitoring of renal function.

Cases of nephrolithiasis have been reported with mesalazine use, including stones composed of 100% mesalazine. Adequate fluid intake is recommended during treatment.

Patients with pulmonary diseases, particularly asthma, should be closely monitored throughout the treatment course (see section "Adverse reactions").

Mesalazine-induced hypersensitivity cardiac reactions (myo- and pericarditis) have been reported rarely.

Very rarely, serious blood dyscrasias associated with mesalazine use have been reported. Blood count with differential leukocyte count is recommended before and during treatment at the physician’s discretion. Concomitant treatment with mesalazine may increase the risk of blood dyscrasia in patients receiving azathioprine, 6-mercaptopurine, or thioguanine (see section "Interaction with other medicinal products and other forms of interaction"). Treatment should be discontinued if such adverse reactions are suspected or confirmed.

Any unused medicinal product and waste material must be disposed of in accordance with local requirements.

Pentasa rectal suspension may stain clothing and bed linen.

Use during pregnancy or breastfeeding.

Pentasa should be used during pregnancy and breastfeeding with caution and only when, in the physician’s opinion, the expected benefit to the pregnant woman outweighs the potential risk to the fetus. The underlying condition— inflammatory bowel disease (IBD)—may itself affect pregnancy outcomes.

There are no adequate data on the use of this medicinal product in pregnant women. However, results from a limited number of exposures during pregnancy suggest no adverse effect of mesalazine on pregnancy course or fetal/neonatal health. Currently, there are no other relevant epidemiological data available.

Pregnancy.

It is known that mesalazine crosses the placental barrier, and its concentrations in umbilical plasma are lower than those in maternal plasma. The metabolite acetyl-mesalazine has been found at equal concentrations in umbilical and maternal plasma. Animal studies with oral mesalazine administration did not indicate any direct or indirect harmful effects on pregnancy, embryonic and fetal development, parturition, or postnatal development. There are no adequate and well-controlled studies on the use of Pentasa in pregnant women. Limited data on mesalazine use do not indicate an increased overall frequency of congenital malformations in humans. Some data suggest an increased frequency of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active stages of inflammatory bowel diseases.

There have been reports of blood system disorders (pancytopenia, leukopenia, thrombocytopenia, anemia) in newborns whose mothers used Pentasa.

In one case, neonatal renal failure was reported after prolonged use of high doses of mesalazine (2–4 g orally) during pregnancy.

Breastfeeding period.

Mesalazine passes into breast milk. The concentration of mesalazine in breast milk is lower than in maternal blood, whereas its metabolite—acetyl-mesalazine—is present at similar or higher concentrations. There is limited experience with oral mesalazine use in breastfeeding women. Controlled studies on the use of Pentasa during breastfeeding have not been conducted. Hypersensitivity reactions such as diarrhea in the newborn cannot be excluded. If diarrhea develops in the infant, breastfeeding should be discontinued.

Fertility.

Data from animal studies on mesalazine use show no effect on male or female fertility.

Ability to affect reaction speed when driving or operating machinery.

Treatment with Pentasa does not affect the ability to drive vehicles or operate other machinery.

Method of Administration and Dosage

1 enema before bedtime.

Prior to administration of the enema, it is recommended to empty the bowel.

The enema is contained in an aluminum foil pouch.

1. Immediately before use, remove the bottle from the aluminum foil pouch and shake well.
2. To break the seal, rotate the nozzle one full turn (after turning, the nozzle should be in the same position as before rotation).
3. Place your hand into one of the polyethylene bags contained in the package.
4. Hold the container as shown in the illustration on the package.
5. To administer the enema, lie on the left side with the left leg straight and the right leg bent forward for balance. Gently insert the applicator tip into the rectum. Maintain steady, gentle pressure as the enema contents are expelled. The entire contents of the bottle should be administered within 30–40 seconds.
6. As soon as the bottle is empty, remove the nozzle while still squeezing the bottle.
7. The suspension should remain in the bowel. The patient should remain in the above-mentioned relaxed position for an additional 5–10 minutes or until the urge to defecate arises.
8. Wrap the polyethylene bag around the empty bottle. Dispose of it and wash your hands.

Geriatric Patients

Dosage adjustment in elderly patients is not required; however, caution is recommended when administering the drug, along with monitoring of renal function.

Information on use in patients with impaired renal and/or hepatic function is provided in the sections "Contraindications" and "Special Warnings and Precautions for Use".

Children. There is limited clinical data on the efficacy of treatment in children.

Overdose

A single intravenous dose of mesalazine at 920 mg/kg in rats and a single oral dose up to 5 g/kg in pigs was not lethal.

There is limited clinical experience with overdose of Pentasa, which does not indicate renal or hepatic toxicity.

Since Pentasa is an aminosalicylate, salicylate-like toxicity symptoms may occur, such as acid-base imbalance, hyperventilation, pulmonary edema, vomiting, dehydration, and hypoglycemia. Symptoms caused by salicylate overdose are well described in the medical literature.

There have been reports of patients taking 8 g of mesalazine daily for a month without any adverse effects.

Treatment of Overdose in Humans

As there is no specific antidote, treatment of overdose is supportive and symptomatic. Inpatient management includes careful monitoring of renal function.

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 sometimes occur.

Severe skin adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with mesalazine treatment (see section "Special Warnings and Precautions for Use").

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

The frequency of adverse effects is based on clinical trials and post-marketing reports and is defined as follows: common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders: very rare – blood count abnormalities (anemia, aplastic anemia, agranulocytosis, neutropenia, leukopenia (including granulocytopenia), pancytopenia, thrombocytopenia, and eosinophilia as part of an allergic reaction).

Immune system disorders: very rare – hypersensitivity reactions, including allergic exanthema and DRESS syndrome, drug fever.

Nervous system disorders: common – headache; rare – dizziness; very rare – peripheral neuropathy.

Cardiac disorders: rare – myocarditis* and pericarditis*.

Respiratory, thoracic and mediastinal disorders: very rare – allergic and fibrotic lung reactions (e.g., dyspnea, cough, bronchospasm, allergic alveolitis, pulmonary eosinophilia, interstitial lung disease, lung infiltrates, pneumonitis).

Gastrointestinal disorders: common – diarrhea, abdominal pain, nausea, vomiting; rare – increased amylase levels, acute pancreatitis*, flatulence; very rare – pancolitis.

Hepatobiliary disorders: very rare – elevated liver enzymes and cholestasis parameters (i.e., alkaline phosphatase, gamma-glutamyl transferase, and bilirubin), hepatotoxicity (including hepatitis*, cholestatic hepatitis, cirrhosis, liver failure).

Skin and subcutaneous tissue disorders: common – rash (including urticaria and erythematous rash); rare – photosensitivity**; very rare – reversible alopecia, allergic dermatitis, erythema multiforme; frequency not known – Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).

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

Renal and urinary disorders: very rare – renal dysfunction (including acute and chronic interstitial nephritis*, nephrotic syndrome, renal failure), discoloration of urine; frequency not known – nephrolithiasis***.

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

General disorders and administration site conditions: common – itching; uncommon – anal discomfort, irritation at the site of administration, tenesmus; very rare – fever.

* The mechanism of mesalazine-induced myocarditis and pericarditis, pancreatitis, nephritis, and hepatitis is unknown, but an allergic origin is possible. It should be noted that some of these conditions may also be associated with inflammatory bowel disease.

** Photosensitivity: more severe reactions have been observed in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.

*** See section "Special Warnings and Precautions for Use" for additional information.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at 15–25 °C in the original packaging. Keep out of reach of children.

Packaging. 100 mL of suspension in a bottle with a nozzle and internal valve; 1 bottle in an aluminum foil pouch; 5 or 7 bottles and 5 or 7 polyethylene pouches in a cardboard pack.

Prescription status. Prescription only.

Manufacturer. Ferring-Leciva, a.s., Czech Republic / Ferring-Leciva, a.s., Czech Republic.

Manufacturer's address and place of business.
K Rybniku 475, Jesenice u Prahy, 252 42, Czech Republic / K Rybniku 475, Jesenice u Prahy, 252 42, Czech Republic.