Pankalor

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

Composition:

Active substance: acetylcysteine;

1 sachet (1 g of granules) contains 200 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. Mucolytics. 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 that increase the viscosity of the vitreous 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 species. Of particular interest is the fact that NAC prevents inactivation of α-1-antitrypsin—an enzyme that inhibits elastase—by hypochlorous acid (HOCl), a potent oxidant produced by myeloperoxidase in activated phagocytes.

Moreover, the molecular structure of NAC allows 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 exerts 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 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 lung vital capacity (VC) and diffusing capacity of the lungs for carbon monoxide measured by the single-breath method.

When used as inhaled therapy over one year, NAC contributed to slowing disease progression in patients with IPF.

When administered at very high doses (up to 3000 mg daily for 4 weeks) in patients with cystic fibrosis, NAC did not produce 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 was observed in the number of neutrophils in the airways, as well as 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 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 acetylcysteine 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 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% at 4 hours after administration and decreases to 20% by 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 (T_1/2) of acetylcysteine is 6.25 (4.59–10.6) hours.

Clinical characteristics.

Indications.

• Treatment of acute and chronic diseases of the bronchopulmonary system associated with increased production of viscous sputum.
• Paracetamol overdose.

Contraindications.

• Hypersensitivity to acetylcysteine or any of the excipients.
• Active gastric or duodenal ulcer, hemoptysis, pulmonary hemorrhage.
• Phenylketonuria (see section "Special precautions").
• Children under 2 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, an interval of 2 hours 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 result in 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, as bronchospasm may occur. If bronchospasm develops, treatment with acetylcysteine must be discontinued immediately.

Mucolytic agents may cause bronchial obstruction in children under 2 years of age. Due to physiological characteristics of the respiratory system in this age group, the ability to clear respiratory secretions is limited. Therefore, mucolytic agents should not be used in children under 2 years of age (see section "Contraindications").

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 cause vomiting.

Patients with a history of gastric or duodenal ulcer should use the drug cautiously, 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.

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 or mucous membrane lesions appear, treatment with acetylcysteine must be discontinued 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, 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 sputum, 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").

Use during pregnancy or breastfeeding

Pregnancy

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

The use of the medicinal product Pankalor®, granules for oral solution, should be avoided during pregnancy.

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

Breastfeeding

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

A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from using Pankalor® taking into account the benefit of breastfeeding for the child 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 shown any harmful effect on fertility in humans when the drug is used at recommended doses.

Ability to influence reaction speed when driving or operating machinery

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

Method of Administration and Dosage

The medicinal product is intended for oral administration.

Dissolve the contents of the sachet in half a glass of water with stirring and take as quickly as possible. Administer before meals.

Do not use 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 diseases of the bronchopulmonary system accompanied by increased sputum production.

Adults and children aged 14 years and older.

200 mg 2 or 3 times daily.

Children aged 6–14 years.

200 mg twice daily.

Children aged 2–6 years.

100 mg (half of the resulting solution after dissolving one sachet) 2\u20133 times daily.

Renal/hepatic impairment.

Dose adjustment is not required for patients with mild to moderate renal or hepatic insufficiency.

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

Paracetamol overdose.

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

Children.

To be used in children aged 2 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 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.

Side effects.

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

The side effects listed below are classified by system organ class and frequency of occurrence. The frequency categories of adverse reactions are defined as follows: 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 available data).

Within each category, side effects are listed in descending 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 – drowsiness.

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, 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, 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: uncommon – decreased blood pressure.

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. 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 Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Keep out of the 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 in the same glass with other medicinal products.

Packaging.

1 g granules in sachets. 10 or 30 sachets in a cardboard pack.

Pharmaceutical category.

Over-the-counter (without prescription).

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and place of business.

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