Pankalor® forte

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

Composition:

Active substance: acetylcysteine;

One sachet (3 g granules) contains 600 mg of acetylcysteine;

Excipients: sorbitol (E 420), aspartame (E 951), orange flavor.

Pharmaceutical form. Granules for oral solution.

Main physicochemical properties: white or almost white granules with a characteristic orange odor.

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 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. Of particular interest is the fact that NAC prevents the inactivation of α-1-antitrypsin—an enzyme that inhibits elastase—by hypochlorous acid (HOCl), a strong oxidant produced by myeloperoxidase in activated phagocytes.

Moreover, the molecular structure of NAC enables 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, as a precursor of glutathione, NAC exhibits an indirect antioxidant effect. Glutathione is a highly active tripeptide widely distributed in various 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 primary 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 significant improvements in inspiratory volume and forced vital lung 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 over 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 cause 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. Additionally, during treatment, a reduction was observed in the number of neutrophils in the respiratory tract, as well as 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 concentrations of acetylcysteine are reached within 1–3 hours after administration and remain 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 detection in the liver, kidneys, lungs, and bronchial secretions. The volume of distribution of acetylcysteine ranges from 0.33 to 0.47 L/kg. Plasma protein binding is approximately 50% four hours after administration and decreases to 20% after 12 hours.

Metabolism.

After oral administration, acetylcysteine 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 (T1/2) of acetylcysteine 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.
• Acute stage of gastric and duodenal peptic 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 were 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 administration of these medicinal products. This does not apply to loracarbef.

Concomitant use of acetylcysteine and nitroglycerin may cause significant arterial hypotension and transient increase in arterial vasodilation. If concomitant use of nitroglycerin and acetylcysteine is necessary, 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 efficacy 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, acetylcysteine therapy should 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, especially when concomitantly taking other medicinal products that irritate the gastric mucosa.

Acetylcysteine should be administered with caution to 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 the use of acetylcysteine. If new skin lesions or mucosal changes occur, treatment with acetylcysteine should be stopped immediately.

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, 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 sputum, postural drainage and bronchoaspiration should be performed.

Excipients.

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

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.

The use of the medicinal product Pankalor® Forte, granules for oral solution, 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 must be made whether to discontinue breastfeeding or to discontinue/abstain from using Pankalor® Forte, taking into account the benefits of breastfeeding for the infant and the therapeutic benefits for the mother.

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and method of administration

The medicinal product is intended for oral administration.

Dissolve the contents of the sachet in half a glass of water, stirring, and take as soon as possible. Administer before meals. A mild sulfurous odor is not an indication of product deterioration; it is characteristic of the active substance.

Do not take the medicinal product 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 disorders associated with increased mucus production.

Adults and children aged 14 years and older.

600 mg once daily, preferably in the morning.

Renal/hepatic impairment

Dose adjustment is not required in patients with mild to moderate renal or hepatic impairment.

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

Paracetamol overdose.

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

Children.

For 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 experiencing 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 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 < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data).

Within each group, adverse reactions are listed in order of decreasing 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, decreased platelet aggregation, although 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, angioneurotic oedema (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 test results: uncommon – decreased blood pressure.

Cases of decreased platelet aggregation have been reported, but the clinical significance of this is not established.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System 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 of children.

Incompatibilities.

When dissolving acetylcysteine, glassware should be used; avoid contact with metal and rubber surfaces.

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

Packaging.

3 g of granules in sachets. 10 or 30 sachets per cardboard pack.

Authorization category.

Over-the-counter (without prescription).

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Address of manufacturer and location of its operations.

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