Pankalor® forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANKALOR® FORTE (PANKALOR® FORTE)

Composition:

Active substance: acetylcysteine;

One effervescent tablet contains 600 mg of acetylcysteine;

Excipients: anhydrous citric acid, sodium bicarbonate, aspartame (E 951), flavoring agent Powdarome Lemon Premium.

Pharmaceutical form. Effervescent tablets.

Main physicochemical properties: white, round tablets with beveled edges, smooth on both sides, with a characteristic lemony odor, slightly sulfurous.

Pharmacotherapeutic group. Medicinal products used for cough and colds. Mucolytic agents. ATC code R05C B01.

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 vitreous and purulent components of sputum and other secretions. Additional properties include reduction of induced mucocyte hyperplasia, increased surfactant production due to stimulation of type II pneumocytes, and stimulation of mucociliary apparatus activity, thereby improving 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. Of particular interest is the fact that NAC prevents inactivation of α-1-antitrypsin—a protease inhibitor of elastase—by hypochlorous acid (HOCl), a strong oxidant produced by myeloperoxidase in activated phagocytes.

Moreover, the molecular structure of NAC enables it to easily penetrate cellular membranes. Inside the cell, NAC is deacetylated to form L-cysteine, an essential amino acid for glutathione synthesis. In addition, as a precursor of glutathione, NAC exhibits an indirect antioxidant effect. Glutathione is a highly active tripeptide widely distributed in animal tissues and essential 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 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 capacity (VC) 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), NAC did not exert significant toxic effects in patients with cystic fibrosis.

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 decrease in the number of neutrophils in the airways was observed, as well as a reduction in the number of activated neutrophils 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 administration 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 high for 24 hours.

Distribution.

Acetylcysteine is distributed in the body both in unchanged form (20%) and as metabolites (80%), predominantly accumulating 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% within 4 hours after administration and decreases to 20% within 12 hours.

Metabolism.

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

Excretion.

Approximately 30% of the 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 accompanied by increased production of viscous sputum.
• Paracetamol overdose.

Contraindications.

• Hypersensitivity to acetylcysteine or to any of the excipients.
• Active gastric or duodenal ulcer, hemoptysis, pulmonary hemorrhage.
• Phenylketonuria (see section "Special precautions").
• Children under 14 years of age. However, 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 adult patients.

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

If concomitant administration of acetylcysteine with oral antibiotics is necessary, a 2-hour interval should be maintained between the administration of these medicinal products. This does not apply to loracarbef.

Concomitant use of acetylcysteine and nitroglycerin may cause significant arterial hypotension and transiently increase arterial vasodilation. If concomitant use of nitroglycerin and acetylcysteine is required, patients should be monitored for signs of arterial hypotension and warned about the possible occurrence of headache.

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

Activated charcoal in high doses (as an antidote) may reduce the effectiveness of acetylcysteine.

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, treatment with acetylcysteine must be discontinued immediately.

The medicinal product should be used with caution in patients with a predisposition to gastrointestinal bleeding (e.g. esophageal varices, peptic ulcer), as oral administration of acetylcysteine may induce vomiting.

Caution is recommended when administering the drug to patients with a history of gastric or duodenal ulcer, particularly if they are concurrently 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.

Very rare cases of severe skin reactions, such as Stevens-Johnson syndrome and Lyell's syndrome, have been reported in association with acetylcysteine use. If new skin or mucosal lesions appear, treatment with acetylcysteine must be stopped immediately.

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

Administration 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, postural drainage and bronchoaspiration should be performed.

Excipients

The medicinal product contains aspartame, a phenylalanine derivative, which may be harmful to patients with phenylketonuria (see section "Contraindications").

This medicinal product contains 5.95 mmol (or 136.9 mg)/dose of sodium. Caution is advised when administering to 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 direct or indirect adverse effects on reproductive toxicity.

Use of the medicinal product Pankalor® Forte, effervescent tablets, should be avoided during pregnancy.

The potential risks and expected benefits should be carefully weighed before using the drug during pregnancy.

Breastfeeding

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

A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from use of Pankalor® Forte, taking into account the benefit of breastfeeding for the infant and the benefit of therapy for the woman.

Fertility

There are no data on the effect of acetylcysteine on human fertility. Animal studies have not revealed any harmful effect on fertility at recommended doses.

Effect on ability to drive vehicles or operate machinery

There is no evidence that acetylcysteine affects the ability to drive vehicles or operate machinery. However, patients should be informed that due to rare adverse effects such as somnolence or nausea, acetylcysteine may reduce their alertness and ability to drive or operate machinery.

Method of Administration and Dosage

The medicinal product is intended for oral administration.

Dissolve the effervescent tablet in half a glass of water and drink as quickly as possible. Administer before meals. A mild sulfurous odor is not a sign of product deterioration; it is characteristic of the active substance.

The medicinal product should not be taken for more than 4–5 days without consulting a physician. Additional fluid intake enhances the mucolytic effect of the medicinal product.

Treatment of acute and chronic bronchopulmonary diseases accompanied by increased sputum production.

Adults and children aged 14 years and older.

600 mg once daily, preferably in the morning.

Renal/hepatic impairment.

For patients with moderate to severe renal or hepatic insufficiency, dose adjustment is not required.

For patients with severe renal or hepatic dysfunction, the daily dose should be reduced or the dosing interval prolonged.

Paracetamol overdose.

Within the first 10 hours after ingestion of a toxic dose, administer Panclor® Forte at a dose of 140 mg/kg initially, followed by 70 mg/kg every 4 hours for 1–3 days.

Children.

Use in children aged 14 years and older.

Overdose.

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

Volunteers have taken 11.2 g of acetylcysteine per day for three months without developing any serious adverse effects.

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 for acetylcysteine poisoning; treatment is symptomatic.

Adverse reactions.

The most common adverse reactions associated with oral administration of acetylcysteine are gastrointestinal reactions.

The adverse reactions listed below are classified by system organ class and frequency of occurrence. The frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1 000), very rare (< 1/10000), and not known (cannot be estimated from the available data).

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

Immune system disorders: uncommon – hypersensitivity; rare – skin allergic reactions; very rare – anaphylactic/anaphylactoid reactions, anaphylactic shock.

Nervous system disorders: uncommon – headache; very rare – somnolence.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – tachycardia.

Vascular disorders: very rare – haemorrhages (bleeding).

Blood and lymphatic system disorders: frequency not known – anaemia, reduced platelet aggregation; however, the clinical significance of this is not established.

Respiratory, thoracic and mediastinal disorders: uncommon – rhinorrhoea; rare – cough, bronchospasm, dyspnoea, shortness of breath.

Gastrointestinal disorders: uncommon – stomatitis, abdominal pain, nausea, vomiting, diarrhoea; rare – dyspepsia; frequency not known – unpleasant odour of breath.

Skin and subcutaneous tissue disorders: uncommon – pruritus, urticaria, erythema, rash, angioedema (Quincke's oedema); very rare – Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome); frequency not known – eczema.

General disorders and administration site conditions: uncommon – hyperthermia; frequency not known – facial swelling.

Investigations – effects on laboratory and instrumental findings: uncommon – decreased blood pressure.

Cases of reduced platelet aggregation have been reported; however, the clinical significance of this is not established.

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 and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Incompatibilities.

When dissolving acetylcysteine, glassware should be used. Contact with metal and rubber surfaces should be avoided.

It is not recommended to dissolve acetylcysteine together with other medicinal products in the same glass.

Packaging.

2 tablets per blister, 10 blisters per cardboard pack.

Pharmaceutical category.

Over-the-counter (without prescription).

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and address of the place of business.

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.