Pankalor

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

Composition:

Active ingredient: acetylcysteine;

1 effervescent tablet contains 200 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 bevelled edges, smooth on both sides, with a characteristic lemon odor, slightly reminiscent of sulfur.

Pharmacotherapeutic group. Agents used for cough and common cold. 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 that increase the viscosity of the viscid 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 oxidative 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 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 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 oxidative radicals, both exogenous and endogenous, and against 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 is the 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), administration of oral acetylcysteine 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 reducing 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 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 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, after oral administration, acetylcysteine is completely absorbed. 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 (active) (80%), with predominant presence 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 about 50% four hours after administration and decreases to 20% after 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.

Elimination.

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.

• 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.
• Acute stage of gastric and duodenal peptic 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 have been conducted only in adults.

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

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

Concomitant use of acetylcysteine and nitroglycerin may cause significant arterial hypotension and transient 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 effectiveness of acetylcysteine.

Effect on laboratory test results.

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 should 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.

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 or mucous membrane lesions appear, treatment with acetylcysteine should 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, 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 mucus, postural drainage and bronchoaspiration should be performed.

Excipients. The medicinal product contains aspartame, a phenylalanine derivative, which is dangerous for patients with phenylketonuria (see section "Contraindications").

This medicinal product contains 5.95 mmol (or 136.9 mg) of sodium per dose. 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 function.

It is recommended to avoid using the medicinal product Pankalor®, effervescent tablets, 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. Risk to the infant cannot be excluded.

A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from using the medicinal product Pankalor®, 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 at the 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 due to rare adverse effects such as somnolence or nausea, acetylcysteine may reduce their ability to drive or operate machinery.

Method of Administration and Dosage

The medicinal product is intended for oral administration.

Dissolve the effervescent tablet in 1/2 glass of water and drink as quickly as possible. Administer before meals. A mild sulfurous odor is not an indication 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.

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 2 times daily.

Children aged 2–6 years.

100 mg (half of the resulting solution after dissolving one effervescent tablet) 2–3 times daily.

Patients with impaired renal/hepatic function.

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

For 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 a toxic dose, Pankalor® should be administered as soon as possible 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 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; therapy 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 organ systems 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), frequency 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 — 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, but 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 from the mouth.

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 test results: uncommon — decreased blood pressure.

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product has been authorised is of great importance. 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 any suspected adverse reactions and lack of efficacy of the medicinal product via 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 reach and sight 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.

2 tablets in a blister, 10 blisters in a cardboard pack.

Category of supply.

Over-the-counter.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of operations.

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