Berlition® 600 capsules

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BERLITHION® 600 CAPSULES

Composition:

Active substance: thioctic acid;

1 soft capsule contains 600 mg of thioctic acid;

Excipients: solid fat, medium-chain triglycerides;

capsule shell: non-crystallizing sorbitol solution, 70% (E 420); glycerol (85%); gelatin; titanium dioxide (E 171); carmine lake (E 120).

Pharmaceutical form. Soft capsules.

Main physicochemical properties: elongated soft gelatin capsule of pink color, containing a yellow paste-like mass.

Pharmacotherapeutic group.

Other agents affecting the digestive system and metabolic processes.

ATC code A16AX01.

Pharmacological properties.

Pharmacodynamics.

Thioctic acid is a vitamin-like substance produced in the body and functions as a coenzyme in the oxidative decarboxylation of α-keto acids. Hyperglycemia caused by diabetes mellitus leads to glucose deposition on matrix proteins of blood vessels and the formation of so-called advanced glycation end-products (AGEs). This process results in reduced endoneurial blood flow and endoneurial hypoxia/ischemia, associated with increased production of free oxygen radicals that damage peripheral nerves. A depletion of the antioxidant glutathione in peripheral nerves has also been observed.

In studies on rats, thioctic acid influenced the biochemical process induced by streptozotocin-caused diabetes, reducing the formation of advanced glycation end-products, improving endoneurial blood flow, increasing the physiological levels of the antioxidant glutathione acting within the nerve affected by diabetes, and exerting antioxidant effects against free oxygen radicals. These effects indicate the ability of thioctic acid to improve peripheral nerve function. This applies particularly to sensory disturbances in diabetic polyneuropathy, which may manifest as dysesthesias and paresthesias, such as burning sensations, pain, numbness, or tingling.

In 1995, a multicenter, placebo-controlled study was conducted on the efficacy of thioctic acid in the symptomatic treatment of diabetic polyneuropathy, which provided evidence of the favorable effect of thioctic acid on symptoms such as burning sensations, paresthesias, numbness, and pain.

Pharmacokinetics.

After oral administration, thioctic acid is rapidly absorbed. Due to significant presystemic metabolism, the absolute bioavailability (compared to intravenous administration) of orally administered thioctic acid is approximately 20%. Because of rapid distribution into tissues, the half-life of thioctic acid in plasma is approximately 25 minutes. The relative bioavailability of thioctic acid from oral solid dosage forms is over 60% relative to the oral solution. Maximum plasma concentration—approximately 4 μg/mL—was measured about 30 minutes after oral administration of 600 mg of thioctic acid. In animal experiments (rats, dogs) using radiolabeling, renal excretion (80–90%) was found to be predominant, specifically in the form of metabolites. In humans, only a small amount of unchanged substance is excreted in urine. Biotransformation occurs mainly through oxidation of the side chain (β-oxidation) and/or via S-methylation of the corresponding thiols.

Thioctic acid interacts in vitro with ionic metal complexes (e.g., cisplatin). Thioctic acid forms poorly soluble complex compounds with sugar molecules.

Clinical characteristics.

Indications.

Paresthesia in diabetic polyneuropathy.

Contraindications.

Hypersensitivity to thioctic acid or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

The efficacy of cisplatin is reduced when treated simultaneously with the medicinal product Berlition® 600 capsules.

Thioctic acid is a metal chelator and therefore, according to basic principles of pharmacotherapy, should not be administered simultaneously with metal compounds (e.g., dietary supplements containing iron or magnesium, or dairy products, as they contain calcium). If the total daily dose of Berlition® 600 capsules is taken 30 minutes before breakfast, dietary supplements containing iron and magnesium may be taken during the day or in the evening.

Possible enhancement of the glucose-lowering effect of insulin or oral antidiabetic agents; therefore, especially during the initial stage of treatment with thioctic acid, careful monitoring of blood glucose levels is recommended. To avoid symptoms of hypoglycemia, in some cases it may be necessary to reduce the dose of insulin or oral antidiabetic agent.

Regular consumption of alcoholic beverages is a significant risk factor for the development and progression of the clinical picture of neuropathy and thus may also interfere with the effectiveness of treatment with Berlition® 600 capsules. Therefore, patients with diabetic polyneuropathy are strongly advised to abstain from alcohol consumption. This also applies to periods when therapy is not being administered.

Special precautions for use

The main factor in effective treatment of diabetic polyneuropathy is optimal control of the patient's blood glucose levels. At the beginning of treatment for polyneuropathy, transient intensification of paresthesia with a sensation of tingling or "pins and needles" may occur due to regenerative processes. When using thioctic acid in patients with diabetes mellitus, frequent monitoring of blood glucose levels is required. In some cases, it may be necessary to reduce the doses of antidiabetic medications to prevent the development of hypoglycemia.

Berlition® 600 capsules contain sorbitol and therefore should not be used in patients with the rare hereditary condition fructose intolerance.

There has been one reported case of autoimmune insulin syndrome (AIS) during treatment with thioctic acid. Patients with certain HLA (human leukocyte antigen) genotypes, such as HLA-DRB1*04:06 and HLA-DRB1*04:03 alleles, are more susceptible to developing AIS during treatment with thioctic acid. The HLA-DRB1*04:03 allele (relative risk ratio for AIS susceptibility – 1.6) is predominantly found among individuals of European descent, with higher prevalence in Southern Europe than in Northern Europe. The HLA-DRB1*04:06 allele (relative risk ratio for AIS susceptibility – 56.6) is mainly prevalent among patients in Japan and Korea. The possibility of developing AIS should be considered in patients receiving thioctic acid when establishing a differential diagnosis of spontaneous hypoglycemia (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Fertility

Toxicological studies on reproductive function have not shown any evidence of effects on fertility.

Pregnancy

Berlition® 600 capsules should be used during pregnancy only after careful assessment of the benefit-risk ratio.

Lactation

There are no data on the passage of thioctic acid or its metabolites into breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue therapy with Berlition® 600 capsules, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Ability to influence reaction rate when driving or operating machinery

During treatment, caution is advised when driving vehicles, operating machinery, or engaging in other potentially hazardous activities requiring increased attention and rapid psychomotor reactions, due to the possible occurrence of adverse reactions such as hypoglycemia, dizziness, and visual disturbances.

Method of Administration and Dosage

Adults

Dosage

The recommended dose is 1 capsule of Berlition® 600 capsules (equivalent to 600 mg of thioctic acid) taken once daily approximately 30 minutes before the first meal. In cases of severe paraesthesia, treatment may be initiated with intravenous infusion therapy using thioctic acid.

Method of Administration

Berlition® 600 capsules should be taken on an empty stomach, swallowed whole with sufficient fluid. Concomitant food intake may impair absorption; therefore, it is particularly important for patients with prolonged gastric emptying time to take the medication 30 minutes before breakfast. Since diabetic polyneuropathy is a chronic condition, long-term therapy may be required. Optimal glycemic control is the cornerstone of treatment for diabetic polyneuropathy.

Children

Berlition® 600 capsules are not intended for use in children and adolescents due to lack of clinical experience.

Overdose

In cases of overdose, nausea, vomiting, and headache may occur. Following accidental ingestion or suicide attempts involving oral administration of thioctic acid in doses ranging from 10 g to 40 g in combination with alcohol, severe intoxications have been observed, in some cases resulting in death. The initial clinical presentation of intoxication may include psychomotor agitation or impaired consciousness, typically followed by generalized seizures and the development of lactic acidosis. Other reported consequences of high-dose thioctic acid intoxication include hypoglycemia, shock, rhabdomyolysis, hemolysis, disseminated intravascular coagulation syndrome, bone marrow suppression, and multi-organ failure.

Treatment. Immediate hospitalization is indicated even upon suspicion of severe intoxication with Berlition® 600 capsules (e.g., ingestion of more than 10 capsules of 600 mg in adults or doses exceeding 50 mg/kg body weight in children), along with measures in accordance with general principles of poisoning management (e.g., induction of emesis, gastric lavage, activated charcoal administration, etc.). Treatment of life-threatening complications such as generalized seizures and lactic acidosis should follow modern intensive care principles and be conducted symptomatically. Currently, there is no confirmed benefit of hemodialysis, hemoperfusion, or filtration techniques for enhanced elimination of thioctic acid.

Adverse reactions.

The following classification was used to assess the frequency of adverse events:

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;

not known: cannot be estimated based on available data.

Immune system disorders.

Very rare: allergic reactions, including skin rash, urticaria (urticarial rash), pruritus, dyspnea.

Not known: autoimmune insulin syndrome (see section "Special precautions"), eczema.

Metabolism and nutrition disorders.

Very rare: hypoglycemia.

Nervous system disorders.

Common: dizziness.

Very rare: dysgeusia, headache, hyperhidrosis.

Eye disorders.

Very rare: visual disturbances.

Gastrointestinal disorders.

Common: nausea.

Very rare: vomiting, gastrointestinal pain, diarrhea.

General disorders.

Very rare: decreased blood glucose levels associated with improved glucose utilization. Symptoms resembling hypoglycemia: dizziness, sweating, headache, and visual disturbances.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 capsules in a blister; 3 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

BERLIN-CHEMI AG.

Manufacturer's address and place of business.

Glienicker Weg 125, 12489 Berlin, Germany.