MULTINGRIP BRONCHO

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MULTIGRIP BRONCHO

Composition:

Active substance: acetylcysteine;

One effervescent tablet contains 600 mg of acetylcysteine;

Excipients: sodium bicarbonate (E 500), citric acid (E 330), orange flavor (arabic gum (E 414), butylated hydroxyanisole (E 320), monohydrate of citric acid (E 330), maltodextrin), sucralose (E 955).

Pharmaceutical form. Effervescent tablets.

Main physicochemical characteristics: round-shaped tablets with flat surface, white in color with a yellowish tint.

Pharmacotherapeutic group. Mucolytic agents. Acetylcysteine. ATC code R05CB01.

Pharmacological Properties

Pharmacodynamics

N-acetyl-L-cysteine (NAC) exerts a pronounced mucolytic effect on mucous and mucopurulent secretions by depolymerizing mucoprotein complexes and nucleic acids, which increase the viscosity of the gelatinous and purulent components of sputum and other secretions. Additional properties include reduction of induced hyperplasia of mucocytes, increased surfactant production due to stimulation of type II pneumocytes, and stimulation of mucociliary apparatus activity, thereby promoting improved mucociliary clearance.

NAC also exerts a direct antioxidant effect due to the presence of a nucleophilic free thiol (SH) group, capable of directly interacting with electrophilic groups of reactive oxygen radicals. Particularly noteworthy is the fact that NAC prevents inactivation of α-1-antitrypsin—a protease inhibitor enzyme—by hypochlorous acid (HOCl), a potent oxidant produced by myeloperoxidase in activated phagocytes.

Moreover, the molecular structure of NAC allows it to readily penetrate cell membranes. Inside the cell, NAC is deacetylated to form L-cysteine, an essential amino acid for glutathione synthesis. In addition to being a glutathione precursor, NAC exerts an indirect antioxidant effect. Glutathione is a highly active tripeptide widely distributed in various animal tissues and is indispensable for maintaining cellular functional capacity and morphological integrity. It is, in fact, a key component of the most important intracellular defense mechanism against both exogenous and endogenous reactive oxygen species and certain cytotoxic substances, including paracetamol.

Paracetamol exerts cytotoxic effects by progressively depleting glutathione levels. NAC plays a crucial role in maintaining adequate glutathione levels, thereby enhancing cellular protection. As a result, NAC serves as a specific antidote in paracetamol poisoning.

In patients with chronic obstructive pulmonary disease (COPD), administration of 1200 mg of NAC daily for 6 weeks led to a significant increase in inspiratory volume and forced vital capacity (FVC), possibly due to reduced air trapping.

In patients with idiopathic pulmonary fibrosis (IPF), oral administration of acetylcysteine at 600 mg three times daily for one year, in combination with standard IPF therapy (prednisolone and azathioprine), helped preserve vital lung capacity (VLC) and diffusing capacity of the lungs measured by the single-breath carbon monoxide method.

When administered as inhalation therapy for one year, NAC contributed to a reduction in the progression rate of the disease in patients with IPF.

When used at very high doses (up to 3000 mg daily for 4 weeks) in patients with cystic fibrosis, NAC did not exhibit significant toxic effects.

The antioxidant efficacy of NAC is associated with a marked reduction in elastase activity in sputum, which is the most significant indicator of lung function in patients with cystic fibrosis. In addition, during treatment, a reduction in the number of neutrophils in the airways was observed, as well as a decrease in the number of neutrophils actively releasing elastase-rich granules.

Pharmacokinetics

Absorption

In humans, acetylcysteine is completely absorbed after oral administration. Due to metabolism in the intestinal wall and first-pass effect, the bioavailability of acetylcysteine after oral intake is very low (approximately 10%). No differences have been observed among various dosage forms. In patients with various respiratory and cardiovascular diseases, maximum plasma concentration of NAC is reached within 1–3 hours after administration and remains elevated for up to 24 hours.

Distribution

Acetylcysteine is distributed in the body both in unchanged form (20%) and as metabolites (active) (80%), with predominant distribution in the liver, kidneys, lungs, and bronchial secretions. The volume of distribution of NAC ranges from 0.33 to 0.47 L/kg. Plasma protein binding is approximately 50% at 4 hours after administration and decreases to 20% by 12 hours.

Metabolism

After oral administration, NAC is rapidly and extensively metabolized in the intestinal wall and liver. The resulting metabolite, cysteine, is considered active. Subsequently, both acetylcysteine and cysteine are metabolized via the same pathway.

Excretion

Approximately 30% of the administered dose is excreted by the kidneys. After oral administration, the elimination half-life (T_1/2) of NAC is 6.25 (4.59–10.6) hours.

Clinical Characteristics

Indications

Treatment of acute and chronic diseases of the bronchopulmonary system associated with increased mucus production.

Paracetamol overdose.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Peptic ulcer of the stomach and duodenum in the stage of exacerbation, hemoptysis, pulmonary hemorrhage.

Children under 12 years of age. This is not a contraindication for use in the treatment of paracetamol overdose.

Interaction with other medicinal products and other forms of interaction

Interaction studies have been conducted only in adults.

Concomitant use of acetylcysteine with antitussive agents may enhance mucus retention due to suppression of the cough reflex.

Activated charcoal reduces the effectiveness of acetylcysteine.

Information on inactivation of antibiotics by acetylcysteine has so far been obtained only from in vitro experiments with direct mixing of substances. If simultaneous administration of acetylcysteine and any oral preparations (including antibiotics) is necessary, they should be taken at an interval of at least 2 hours. This does not apply to loracarbef.

Significant arterial hypotension and dilation of the temporal artery have been observed when nitroglycerin and acetylcysteine are used concomitantly. If simultaneous use of nitroglycerin and acetylcysteine is required, patients should be monitored for arterial hypotension, which may be severe. Patients should be warned about the possibility of headache.

Concomitant use of acetylcysteine and carbamazepine may lead to subtherapeutic levels of carbamazepine.

Effect on laboratory tests

Acetylcysteine may interfere with colorimetric assays for salicylates and with the determination of ketone bodies in urine.

Special precautions for use

Patients with bronchial asthma should be under strict medical supervision during treatment due to the possible development of bronchospasm. If bronchospasm occurs, acetylcysteine therapy should be discontinued immediately.

The drug should be administered with caution to patients with a history of gastric or duodenal ulcer, especially when concomitantly taking other medicinal products that irritate the gastric mucosa.

Acetylcysteine should be administered with caution in patients with hepatic or renal impairment to avoid accumulation of nitrogen-containing substances in the body.

Acetylcysteine affects histamine metabolism; therefore, prolonged therapy should not be prescribed to patients with histamine intolerance, as it may lead to symptoms of intolerance (headache, vasomotor rhinitis, itching).

The use of acetylcysteine, particularly at the beginning of treatment, may cause liquefaction of bronchial secretions and increase their volume. If the patient is unable to effectively expectorate mucus, postural drainage and bronchoaspiration may be required.

A mild sulfur-like odor is not an indication of drug deterioration; it is characteristic of the active substance.

A single dose of the drug contains 115 mg of sodium in each effervescent tablet in the form of sodium bicarbonate, which corresponds to 5.75% of the WHO recommended maximum daily sodium intake of 2 g for adults. This should be taken into account by patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Pregnancy

Clinical data on the use of acetylcysteine in pregnant women are limited. Animal studies have not revealed any direct or indirect adverse effects on reproductive toxicity.

As a precautionary measure, the use of the medicinal product Multigrip Broncho, effervescent tablets, should be avoided during pregnancy.

Before using the drug during pregnancy, the potential risks should be weighed against the expected benefits.

Breastfeeding

There is no information available on the passage of acetylcysteine and/or its metabolites into breast milk. The risk to the infant cannot be excluded.

A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from the use of the medicinal product Multigrip Broncho, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data available on the effect of acetylcysteine on human fertility. Animal studies have not revealed any harmful effects on fertility in humans when the drug is used at recommended doses.

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

There are no data available on the effect of acetylcysteine on the ability to drive or operate machinery.

Method of Administration and Dosage

Adults and children aged 12 years and older

One effervescent 600 mg tablet should be dissolved in 1/3 glass of water and taken once daily.

The duration of treatment is determined individually by a physician, depending on the nature of the disease (acute or chronic).

Paracetamol overdose

Within the first 10 hours after ingestion of a toxic substance, administer the medicinal product Multigrip Broncho as soon as possible at a dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for 1–3 days.

The medicinal product Multigrip Broncho must be taken immediately after dissolution without delay.

No interactions with food have been reported; there are no recommendations regarding administration in relation to food intake.

Children

The product is indicated for children aged 12 years and older.

Overdose

There are no data on cases of overdose with oral formulations of acetylcysteine.

Adult volunteers have taken 11.2 g of acetylcysteine per day for three months without developing any serious adverse reactions.

Acetylcysteine administered at a dose of 500 mg/kg/day does not cause overdose.

Symptoms

Overdose may manifest with gastrointestinal symptoms such as nausea, vomiting, and diarrhea.

Treatment

There is no specific antidote in case of acetylcysteine poisoning; therapy is symptomatic.

Side effects

The most common adverse reactions associated with oral administration of acetylcysteine are gastrointestinal reactions. Hypersensitivity reactions, including anaphylactic shock, anaphylactic/anaphylactoid reactions, bronchospasm, angioneurotic edema, rash, and pruritus, have been observed less frequently.

The table below lists adverse reactions by system organ class and frequency of occurrence (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data)).

Within each group, adverse reactions are listed in order of decreasing severity.

In very rare cases, severe skin reactions such as Stevens-Johnson syndrome and Lyell's syndrome have been reported in connection with the use of acetylcysteine. In most cases, at least one other medicinal product may be more likely to be the cause of the mucocutaneous syndrome. Therefore, if any new changes appear on the skin or mucous membranes, a physician should be consulted immediately and administration of acetylcysteine should be discontinued without delay.

Cases of reduced platelet aggregation have been reported, but the clinical significance of this finding is not known.

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 and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Shelf life after first opening of the tube – 90 days.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture. Keep out of the reach and sight of children.

Packaging

10 tablets in a tube, 1 tube in a cardboard box.

Prescription status

Over-the-counter (without prescription).

Manufacturer

Alpex Pharma SA.

Manufacturer’s address and place of business

Via Cantonale, 6805 Medeglia-Vira, Switzerland.