Mirifuril

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIRAFURIL (MIROFURIL)

Composition:

Active substance: nitroxoline;

1 capsule contains 200 mg of nitroxoline;

Excipients: sucrose, corn starch, microcrystalline cellulose, magnesium stearate;

Capsule shell: titanium dioxide (E 171), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules, white in color, size 0, filled with yellow powder.

Pharmacotherapeutic group.

Antimicrobial agents used for the treatment of intestinal infections. Nitroxoline.

ATC Code A07AX03.

Pharmacological Properties

Pharmacodynamics

Nifuroxazide is an antimicrobial agent belonging to the nitrofuran derivative class. Its mechanism of action is not fully understood. The antimicrobial and antiparasitic properties of nifuroxazide are possibly due to the presence of an amino group. The local activity and lack of penetration into organs and body tissues determine the uniqueness of nifuroxazide compared to other nitrofuran derivatives, as this antidiarrheal agent lacks systemic effects. It is effective against Gram-positive and Gram-negative bacteria: Streptococcus pyogenes, Staphylococcus aureus, E. coli, Salmonellae, Shigellae.

Pharmacokinetics

After oral administration, the drug is partially absorbed (10–20%) from the gastrointestinal tract and extensively metabolized, with the main circulating components in the blood being metabolites. Biotransformation of nifuroxazide occurs in the intestine; approximately 20% of the administered dose is excreted unchanged. Nifuroxazide and its metabolites are excreted in feces. The rate of elimination depends on the amount of drug administered and gastrointestinal motility. Overall, elimination of nifuroxazide is slow, and it remains in the gastrointestinal tract for a prolonged period.

At therapeutic doses, nifuroxazide practically does not suppress normal intestinal microflora, does not induce the emergence of resistant microbial forms, and does not promote the development of cross-resistance to other antibacterial agents. Therapeutic effect is achieved within the first hours of treatment.

Preclinical Safety Data. Nifuroxazide demonstrates mutagenic potential.

The carcinogenic potential of nifuroxazide was evaluated in mice (50 animals of each sex per group) and rats (52 animals of each sex per group) that received nifuroxazide in their diet for 2 years at doses of 0, 200, 600, or 1800 mg/kg/day. Despite its mutagenic properties, carcinogenicity of nifuroxazide was not demonstrated in either mice or rats.

The doses administered to mice and rats (5400 mg/m² and 10800 mg/m², respectively) exceeded the maximum human dose of 1800 mg (493 mg/m² for a patient weighing 60 kg) by 11 and 22 times, respectively, when adjusted to body surface area.

Clinical characteristics.

Indications.

Acute infectious diarrhoea.

Contraindications.

• Hypersensitivity to nitroxoline, nitrofuran derivatives, or to any other component of the drug;
• fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency;
• pregnancy;
• children under 6 years of age (for this dosage form).

Interaction with other medicinal products and other forms of interaction.

Nitroxoline may be used in combination with drugs commonly used for the treatment of diarrhoea: rehydration solutions, antibiotics, chemotherapeutic agents, spasmolytics, and analgesics.

Concomitant use of nitroxoline with central nervous system (CNS) depressants and drugs that may cause dependence is not recommended.

Concomitant administration of other oral medicinal products should be avoided due to the strong adsorptive properties of nitroxoline.

Nitroxoline should not be used simultaneously with adsorbents, alcohol-containing drugs, or drugs that may cause disulfiram-like reactions.

Alcohol consumption is strictly prohibited during treatment with nitroxoline due to the risk of developing a disulfiram-like reaction, which may manifest as worsening diarrhoea, vomiting, abdominal pain, sensation of warmth in the face and upper body, hyperemia, tinnitus, dyspnoea, and tachycardia.

If other medicinal products (including over-the-counter drugs) are being taken, consult a physician before using Miriful.

Special precautions.

Nifuroxazide should not be used for more than 7 days. There are no indications for prolonged therapy. If diarrhea does not resolve within 3 days of starting treatment, further diagnostic evaluation is required to determine the underlying cause of symptoms. Antibiotic therapy may become necessary.

Treatment with nifuroxazide does not exclude the need for dietary management and rehydration. If diarrhea persists after 3 days of treatment, the dosage should be reassessed and a decision on rehydration therapy should be made. When needed, concomitant rehydration therapy should be administered according to the patient's age, clinical condition, and severity of diarrhea.

When oral or intravenous rehydration is indicated, the manufacturer's instructions for dilution and administration of the rehydration solutions must be strictly followed. If such rehydration is not required, fluid losses should be compensated by drinking large amounts of fluids containing salt and sugar (based on an average daily requirement of 2 liters of water).

Dietary recommendations during diarrhea should be observed: avoid fresh vegetables and fruits, spicy foods, frozen products, and beverages. Rice-based foods are recommended. The use of dairy products should be decided on a case-by-case basis.

If diarrhea is accompanied by clinical signs indicating severe disease (worsening general condition, fever, signs of intoxication), nifuroxazide should be administered together with antibacterial agents indicated for the treatment of intestinal infections, as the drug is only partially absorbed in the gastrointestinal tract and is extensively metabolized, with circulating metabolites being the main components in the bloodstream. The drug should not be used as monotherapy for intestinal infections complicated by sepsis.

Mirifuril contains sucrose, which should be taken into account when prescribing the drug to patients with diabetes mellitus. The drug should not be administered to patients with hereditary disorders of sucrose and fructose intolerance.

Alcohol consumption is strictly prohibited during treatment due to the risk of disulfiram-like reaction, which may manifest as worsening diarrhea, vomiting, abdominal pain, sensation of warmth in the face and upper body, hyperemia, tinnitus, dyspnea, and tachycardia.

If signs of hypersensitivity occur (dyspnea, rash, pruritus), the drug should be discontinued.

Patients with known intolerance to certain sugars should consult a physician before taking this medicinal product.

It should be noted that Mirifuril capsules contain sucrose (see section "Contraindications").

Content of bread units in single and daily doses of the drug:

Use during pregnancy or breastfeeding.

Pregnancy. The amount of data on the use of nifuroxazide in pregnant women is limited. Data from animal studies on reproductive toxicity are insufficient. Nifuroxazide exhibits mutagenic potential. The medicinal product is contraindicated during pregnancy and should not be used in women of childbearing potential who are not using effective contraception.

Breastfeeding. It is unknown whether nifuroxazide or its metabolites are excreted in breast milk. Due to the low bioavailability of nifuroxazide (gastrointestinal absorption of approximately 10–20% of the dose), its concentration in milk is likely to be low. However, an effect on the gastrointestinal microbiome of breastfed infants cannot be excluded. Because of the lack of clinical experience with nifuroxazide-containing medicinal products during breastfeeding, their use is not recommended.

Fertility. Based on animal studies, there is insufficient data available on the effect of nifuroxazide on fertility.

Ability to influence the speed of reactions while driving or operating machinery.

The medicinal product does not affect the ability to drive vehicles or operate machinery.

Dosage and Administration.

Take orally, regardless of food intake, swallowing the capsule with a glass of water. Use for the treatment of adults and children aged 6 years and older.

Maximum daily dose of nifuroxazide – 800 mg.

Children aged 6 to 18 years: 200 mg 3–4 times daily (intervals between doses 6–8 hours).

Adults: 200 mg 4 times daily (intervals between doses 6 hours).

Duration of treatment course is 5–7 days, but not more than 7 days. If no improvement occurs within the first 3 days of treatment, consult a physician. Use the medication strictly according to the instructions and at the specified dosage. Consult a physician before using the medicinal product.

Children.

Do not use in children under 6 years of age (for this dosage form).

For treatment of children under 6 years of age, prescribe Mirifuril as a suspension.

Overdose.

Specific information regarding symptoms of nifuroxazide overdose is not available.

One case of nifuroxazide overdose has been reported in a two-year-old child who received an unknown amount of the oral suspension. The child developed somnolence and diarrhea, which subsequently resolved. In case of suspected nifuroxazide overdose, careful observation of the patient is recommended, along with symptomatic and supportive treatment.

Adverse Reactions.

• Blood and lymphatic system disorders: One case of granulocytopenia has been reported.
• Immune system disorders: Allergic reactions, including anaphylactic shock, angioneurotic edema (Quincke's edema), urticaria, and pruritus. If an allergic reaction occurs, the drug must be discontinued.
• Gastrointestinal disorders: Individual cases of hypersensitivity to rifaximin manifest as abdominal pain, nausea, vomiting, and exacerbation of diarrhea. In cases of mild symptoms, no specific treatment or discontinuation of rifaximin is required, as symptoms resolve quickly. If the exacerbation is pronounced, administration of rifaximin should be discontinued. In the future, the patient must avoid taking rifaximin and other nitrofuran derivatives.
• Skin and subcutaneous tissue disorders: Skin reactions such as skin rash occur rarely.

One case of pustulosis in an elderly patient and one case of nodular pruritic rash associated with contact allergy to rifaximin have been reported.

If any adverse reactions occur, administration of the drug should be discontinued and medical advice must be sought immediately.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

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

Packaging.

5 capsules per blister; 2 or 3 blisters per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

ABC Farmaceutici S.p.A.

Manufacturer's address and location of operations.

Via Canton Moretti, 29 (Località San Bernardo), 10015 Ivrea (TO), Italy.