Thiogamma I.V.

Clear, yellowish to greenish-yellow colored, sterile aqueous solution for infusion, with approx. 50 ml fill volume.
One vial (50 ml) contains 600 mg thioctic acid (alpha-lipoic acid) [in the form of 1167.70 mg meglumine salt].
Excipients/Inactive Ingredients: Meglumine, macrogol 300, water for injection.

Pharmacotherapeutic group: Other medicines for the alimentary tract and metabolism. ATC Code: A16AX01.
Pharmacology: Pharmacodynamics: Thioctic acid, along with its major metabolite dihydro-lipoic acid (DHLA), is a potent antioxidant that is capable of scavenging oxygen free radicals, redox interaction with other antioxidants, and inhibition of lipid peroxidation. Thioctic acid is characterized by high reactivity to free radicals; it is capable of regenerating vitamins C and E, as well as glutathione.
Four main molecular mechanisms have been implicated in glucose-mediated microvascular damage (retinopathy, nephropathy, neuropathy). All seem to reflect a single hyperglycemia-induced initial process of overproduction of superoxide anion by the mitochondrial electron-transport chain. Thus, oxidative stress represents the primary cause of hyperglycaemia-induced microvascular complications, which provides the rationale for the treatment of diabetic neuropathy by antioxidants such as alpha-lipoic acid.
Experimental diabetic neuropathy is characterized by impaired nerve conduction velocity, reduced nerve blood flow, and a variety of metabolic abnormalities in peripheral nerve that have been ascribed to hyperglycemia, abnormal fatty acid metabolism, ischaemic hypoxia, and/or oxidative stress. Alpha-lipoic acid improves nerve blood flow, reduces oxidative stress, and also ameliorates nerve conduction, intraepidermal nerve fiber density, and nocifensive behavior in experimental diabetic neuropathy.
This means that alpha-lipoic acid also improves the criteria for establishing the presence of somatic diabetic neuropathy in rodent models. These criteria parallel those used to diagnose diabetic neuropathy in patients. In general, the experimental evidence supports the concept that the observed favorable effects of Thioctic acid have clinical relevance.
Pharmacokinetics: Biotransformation: Thioctic acid is subject to a first-pass effect in the liver.
There is considerable interindividual variation in the systemic availability of thioctic acid. By oxidation of the side chain and conjugation, alpha-lipoic acid is biotransformed and eliminated predominantly via the kidneys.
Elimination: The plasma half-life of thioctic acid in humans is approximately 25 minutes, while total plasma clearance is 10-15 ml/min/kg. At the end of a 30 minute infusion of 600 mg, the plasma levels are approximately 20 μg/ml. The use of radioactive markers in animal experiments (rats, dogs) has shown that the excretion path is mainly renal, at 80-90 % in the form of metabolites. Also, in humans there are only small quantities of intact substance excreted in the urine. Biotransformation occurs mainly by oxidative side chain shortening (β oxidation) and/or S-methylation of the corresponding thiols.
Thioctic acid reacts in vitro with metal ion complexes (e.g. with cisplatin). Thioctic acid forms difficult-to-dissolve complex compounds with sugar molecules.
Toxicology: Preclinical safety data: Acute toxicity: Acute toxicity in test animals is rare. The lethal intravenous dose in rats is about 400 mg/kg body weight, the lethal oral dose in dogs 400-500 mg/kg body weight. In dogs after administration of high doses vomiting, drooling and sedation were observed. In end-stage, tonic-clonic seizures occur.
Chronic toxicity: There are no data for chronic animal toxicity studies.
Mutagenicity and carcinogenicity: Studies of mutagenic potential did not provide evidence of gene or chromosomal mutations.
There was no evidence of a tumorigenic potential of thioctic acid when it was orally administrated to rats in a carcinogenicity study. Co-administration of thioctic acid and cancerogenic N-nitroso-dimethylamine (NDEA) does not increase its tumour-promoting effect.
Reproduction toxicity: Thioctic acid has no influence on fertility and early development of the embryo in rats, up to a maximum tested oral dose of 68.1 mg/kg body weight. No malformation producing properties were found after intravenous infusion in rabbits up to the maternal toxic dose range.

Sensory disturbances in cases of diabetic polyneuropathy.

Posology: Adults: In the case of severe (very pronounced) symptoms of diabetic polyneuropathy in adults, the intravenous administration of one daily dose of 600 mg thioctic acid is recommended (equivalent to one ampoule of Thioctic acid 600 mg/50 ml, solution for infusion).
Peadiatric population: Thioctic acid 600 mg/50 ml, solution for infusion should not be used in children, as there is no clinical experience in this age group.
Hepatic impairment: Experience is limited in patients with hepatic impairment. Therefore, Thioctic acid 600 mg/50 ml, solution for infusion should be used with caution in these patients.
Method and Duration of administration: In adults, an initial treatment phase of 2-4 weeks for once daily. Parenteral administration (intravenous infusion) is recommended. After completion of the infusion therapy, daily use of 600 mg thioctic acid film-coated tablets is recommended.
Adults should receive a slow intravenous infusion with the contents being administered over at least 30 minutes. The infusion is done directly from the bottle using a standard infusion set and the provided light-protected suspension bag. The active substance is photosensitive and the infusion bottle should be removed from the carton box only shortly before administration. The minimum infusion time of 30 minutes must be ensured.
The product may be diluted with physiologic saline solution (0.9% Sodium chloride solution) only.

Symptoms: In case of overdose, nausea, vomiting and headache may occur. After accidental or suicidal ingestion of oral doses of 10-40 g of thioctic acid in combination with alcohol, severe intoxication has been reported, in some cases with fatal outcome. Initially, clinical intoxication can present as psychomotor agitation or clouding of consciousness. Later, typical symptoms such as generalized seizures and lactic acidosis may develop. In addition, hypoglycemia, shock, rhabdomyolysis, hemolysis, disseminated intravascular coagulation (DIC), bone marrow depression, and multiple organ dysfunction were described after the use of high doses of thioctic acid.
Therapy: At the slightest suspicion of an intoxication, immediate hospitalisation is required and the treating institution's standard procedures for cases of poisoning should be initiated.
Treatment of generalized seizures, lactic acidosis and other life-threatening consequences of intoxication must follow the principles of modern intensive care and must be based on the symptoms. Currently, there is no evidence that haemodialysis, haemoperfusion or filtration methods for forced elimination of thioctic acid are appropriate for mitigating the symptoms of intoxication.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Hypersensitivity reactions including anaphylactic shock reactions have been reported in conjunction with parenteral administration of Thioctic acid 600 mg/50 ml, solution for infusion (see Adverse Reactions). Therefore, patients must be strictly monitored. In case of early symptoms (e.g. pruritus, nausea, malaise, etc.) therapy must be immediately suspended and other therapeutic measures started, if required (see Incompatibilities under Cautions for Usage).
In single cases, in decompensated or poorly controlled diabetic patients in poor general condition, severe anaphylactic reactions may occur in association with the use of Thioctic acid 600 mg/50 ml, solution for infusion.
Cases of Insulin Autoimmune Syndrome (IAS) have been reported during treatment with alpha-lipoic acid (thioctic acid). Patients with human leukocyte antigen genotypes such as HLA-DRB1*04:06 and HLA-DRB1*04:03 alleles are more susceptible to develop IAS when treated with alpha-lipoic acid. HLA-DRB1*04:03 allele (susceptibility to IAS odds ratio: 1.6) is especially found in Caucasians, with a higher prevalence in southern than in northern Europe; and HLA-DRB1*04:06 allele (susceptibility to IAS odds ratio: 56.6) is especially found in Japanese and Korean patients.
Insulin Autoimmune Syndrome (IAS) should be considered in the differential diagnosis of spontaneous hypoglycaemia in patients using alpha-lipoic acid (see Adverse Reactions).
Effects on ability to drive and use machines: Thioctic acid 600 mg/50 ml, solution for infusion has no or negligible influence on the ability to drive and use machines.

In accordance with the general principles of pharmacotherapy, medicines should be used during pregnancy and lactation only after careful consideration of the benefit/risk ratio. Animal studies are insufficient with respect to reproductive toxicity.
Pregnancy: Animal studies have not demonstrated teratogenic effects associated with thioctic acid. However, fetal risk in human cannot be ruled out. The available evidence is inconclusive or is inadequate for determining fetal risk of the product when used in pregnant women or women of childbearing potential. There are no adequate studies in humans. It is not known whether thioctic acid crosses the placenta and if it is responsible for any fetal adverse effects.
Breastfeeding: It is unknown whether thioctic acid is excreted in human breast milk. Breastfeeding women should start treatment with thioctic acid only after careful determination of the indication by a physician even though the reproductive toxicological studies have not resulted in any evidence regarding the effect on fertility, early embryonal development and showed no embryotoxic properties.
The effects on the nursing infant from exposure to the drug in breast milk are unknown. The use of thioctic acid while breast feeding is not recommended.
Fertility: It is unknown whether thioctic acid has an effect on fertility.

In the assessment of side effects the following frequency categories are used: 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 from the available data).
Blood and lymphatic system disorders: Very rare: Thrombopathy.
Immune system disorders: Frequency unknown: Insulin autoimmune syndrome (see Precautions).
Allergic skin reactions (urticaria, itching, eczema, skin rash), systemic allergic reactions (including anaphylactic shock).
Metabolism and nutrition disorders: Frequency unknown: As a result of the improved utilisation of glucose, blood sugar levels may fall. In such cases, hypoglycaemia-like symptoms such as dizziness, sweating, headaches and impaired vision have been observed.
Nervous system disorders: Very rare: Changes and/or disturbances to the sense of taste.
Convulsion.
Eye disorders: Very rare: Double vision.
Skin and subcutaneous tissue disorders: Very rare: Purpura.
General disorders and administration site conditions: Very rare: Infusion site reactions.
Frequency unknown: After rapid intravenous infusion, symptoms such as pressure in the head and respiratory distress may occur, although these subside spontaneously.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Concomitant administration of cisplatin with Thioctic acid 600 mg/50 ml, solution for infusion leads to loss of efficacy of cisplatin.
The blood-sugar lowering effect of insulin or oral anti-diabetics may be reinforced.
Close monitoring of blood sugar levels is indicated during thioctic acid therapy, particularly during the initial phase. In individual cases, to avoid hypoglycaemia, it is necessary to reduce the insulin dose or the dose of the oral anti-diabetics.
Regular intake of alcohol represents a significant risk factor for the development and progression of neuropathic pathologies and thus can impair the success of treatment with Thioctic acid 600 mg/50 ml, solution for infusion. Patients with diabetic polyneuropathy are recommended to avoid the consumption of alcohol. This also applies to therapy-free intervals.

Incompatibilities: Thioctic acid reacts in vitro with metal ion complexes (e.g. with cisplatin) and with sugar molecules (e.g. levulose solutions); it forms low solubility complex.
Furthermore, Thioctic acid 600 mg/50 ml, solution for infusion is incompatible with glucose solution, Ringer solution and with solutions that are known to react with sulfhydryl-groups or disulfide bridges.
Thioctic acid 600 mg/50 ml, solution for infusion product can be diluted with physiological saline solution (0.9% sodium chloride solution) when administered as an infusion.
Special precautions for disposal and other handling: Thioctic acid 600 mg/50 ml, solution for infusion product can be diluted with physiological saline solution (0.9% sodium chloride solution) when administered as an infusion.

Do not store above 30°C.
Keep in the original package in order to protect from light. The infusion solution should be used immediately after opening, it should be protected from light and kept in the provided light protection bag.
Shelf life: 2 years.

Drugs for Neuropathic Pain

A16AX01 - thioctic acid ; Belongs to the class of various alimentary tract and metabolism products.

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