Nifuroxazide alkaloid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NIFUROXAZIDE ALKALOID®

Composition:
Active substance: nifuroxazide;
1 capsule contains nifuroxazide 100 mg or 200 mg;
Excipients: microcrystalline cellulose, maize starch, povidone, anhydrous colloidal silicon dioxide, sodium lauryl sulfate, magnesium stearate;
Capsule shell composition: titanium dioxide (E 171), quinoline yellow (E 104), yellow FCF (E 110), gelatin.

Dosage form: Hard capsules.

Main physicochemical properties:
Capsules 100 mg: hard gelatin capsules, size №2, opaque, yellow in color. The capsule content is bright yellow powder.
Capsules 200 mg: hard gelatin capsules, size №1, opaque, yellow in color. The capsule content is bright yellow powder.

Pharmacotherapeutic group:
Antidiarrheal agents, drugs used in the treatment of infectious and inflammatory intestinal diseases. Antimicrobial agents for the treatment of intestinal infections. Nifuroxazide.
ATC code: A07AX03.

Pharmacological properties

Pharmacodynamics:
Nifuroxazide is a derivative of 5-nitrofuran and acts exclusively within the intestinal lumen. The mechanism of action of nifuroxazide is not fully understood. The antimicrobial and antiparasitic properties of nifuroxazide and other nitrofuran derivatives are attributed to the NO2 group, which is particularly effective in treating intestinal infections. The drug is especially effective against Gram-positive bacteria: Streptococcus pyogenes, Staphylococcus pyogenes, and Gram-negative bacteria: Escherichia coli, Salmonella, and Shigella.

Pharmacokinetics:
After oral administration, the medicinal product is partially absorbed (10–20%) from the gastrointestinal tract and is significantly metabolized. The majority of the active substance circulates in the blood as metabolites. It is excreted from the body predominantly in feces.

Preclinical safety data:
Nifuroxazide demonstrates a potential mutagenic effect. The carcinogenic effect of nifuroxazide was evaluated in mice (50 of each sex per group) and rats (52 of each sex per group), which received nifuroxazide in food for 2 years at doses of 0, 200, 600, or 1800 mg/kg/day. Despite mutagenic properties, carcinogenicity of nifuroxazide was not demonstrated in either mice or rats. Studies with nifuroxazide were conducted over two years in mice and rats at doses of 5400 mg/m² and 10800 mg/m², respectively, based on body surface area conversion, which exceeded the maximum human dose of 1800 mg (493 mg/m² for a 60 kg patient) by 11 to 22 times.

Clinical characteristics

Indications:
Acute infectious diarrhea.

Contraindications:
Hypersensitivity to nitrofuran derivatives or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction:
Nifuroxazide can be used in combination with drugs commonly used for the treatment of diarrhea: rehydration solutions, antibiotics, chemotherapeutic agents, spasmolytics, and analgesics.
The use of nifuroxazide with central nervous system (CNS) depressants and drugs that may cause dependence is not recommended.
Simultaneous intake of other oral medicinal products should be avoided due to the strong adsorption properties of nifuroxazide.
Nifuroxazide should not be used simultaneously with adsorbents, alcohol-containing preparations, or drugs that may cause disulfiram-like reactions.
Alcohol consumption is strictly prohibited during nifuroxazide therapy due to the risk of developing a disulfiram-like reaction, which may manifest as worsening diarrhea, vomiting, abdominal pain, facial flushing, hyperemia, tinnitus, dyspnea, tachycardia.

Special precautions for use:
If diarrhea does not resolve after 3 days of treatment initiation, further diagnostic evaluation is required to determine the cause of symptoms. Antibiotic therapy may become necessary.
Alcohol consumption is contraindicated during nifuroxazide therapy due to the risk of disulfiram-like reactions.
During nifuroxazide treatment, rehydration therapy (oral or intravenous) should be administered according to the patient's condition and severity of diarrhea. If rehydration is not required, fluid losses should be compensated by consuming large amounts of fluids containing salt and sugar (approximately 2 liters of water per day).
Dietary recommendations during diarrhea should be followed: avoid fresh vegetables and fruits, leafy greens, spicy foods, frozen foods and drinks. Preference should be given to rice and grilled meat. The use of dairy products should be decided on a case-by-case basis.
Nifuroxazide Alkaloid should not be prescribed as monotherapy for intestinal infections complicated by sepsis.
The medicinal product contains the dye "Yellow FCF" (E 110), which may cause allergic reactions.
In case of hypersensitivity reactions (dyspnea, facial swelling, swelling of lips, tongue, skin rash, pruritus), nifuroxazide should be discontinued immediately.

Use during pregnancy or breastfeeding:

Pregnancy:
Data on the use of nifuroxazide in pregnant women are limited. Reproductive toxicity data from animal studies are insufficient. Nifuroxazide exhibits mutagenic potential. Therefore, nifuroxazide is not recommended during pregnancy and should not be prescribed to women of reproductive age who are not using effective contraception.

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

Fertility:
There is insufficient information from animal studies regarding the effect of nifuroxazide on fertility.

Effect on the ability to drive or operate machinery:
No effect.

Method of administration and dosage:
For oral use.

Adults and children aged 12 years and older:
Adults: 200 mg (or 2 capsules of 100 mg) four times daily.
Children (aged 12 years and older): 200 mg (or 2 capsules of 100 mg) 3–4 times daily (600–800 mg of nifuroxazide per day).
Treatment duration: not more than 7 days. If necessary, treatment may be prolonged depending on the patient's clinical condition.

Children:
For children under 12 years of age, Nifuroxazide Alkaloid in the form of oral suspension is recommended.

Overdose:
Symptoms of overdose have not been described. In case of suspected overdose, the patient should be closely monitored and supportive and symptomatic treatment should be administered.

Adverse reactions:
In patients hypersensitive to nitrofuran derivatives, granulocytopenia may occur; allergic reactions, usually of the skin type (rash, pruritus, urticaria, pustular eruptions). In isolated cases, as with other nitrofuran derivatives, dyspnea, severe hypersensitivity reactions including angioedema and anaphylactic shock may occur.
In case of severe adverse reactions, the drug must be discontinued and symptomatic therapy initiated. The patient should avoid nifuroxazide and other nitrofuran derivatives in the future.

Immune system disorders:
Possible allergic reactions, including angioedema, urticaria, pruritus, skin rash, anaphylactic shock. The occurrence of an allergic reaction requires discontinuation of the drug.

Gastrointestinal disorders:
Individual cases of hypersensitivity to nifuroxazide may manifest as abdominal pain, nausea, vomiting, and worsening of diarrhea. If symptom intensity is mild, no specific therapy or discontinuation of nifuroxazide is required, as symptoms resolve quickly. If exacerbation is pronounced, nifuroxazide should be discontinued.

Reporting suspected adverse reactions after medicinal product registration is of great importance. This allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: http://aisf.dec.gov.ua/.

Shelf life: 5 years.
Do not use after the expiry date stated on the packaging.

Storage conditions:
Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging:
100 mg capsules: 10 capsules in a blister made of aluminum foil and PVC film; 1 blister (10 capsules), 2 blisters (20 capsules), or 3 blisters (30 capsules) in a cardboard box.
200 mg capsules: 10 capsules in a blister made of aluminum foil and PVC film; 1 blister (10 capsules) or 2 blisters (20 capsules) in a cardboard box.

Prescription status: Prescription only.

Manufacturer:
ALKALOID AD Skopje.
ALKALOID AD Skopje.

Manufacturer's address and place of business:
Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.