Glucosat

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Glucosat

Composition:

Active substance: sodium chloride glucosamine sulfate;

2 ml of solution (ampoule A) contains 502.5 mg of sodium chloride glucosamine sulfate, equivalent to 400 mg of glucosamine sulfate and 102.5 mg of sodium chloride;

Excipients: lidocaine hydrochloride, water for injections;

solvent (ampoule B) contains:

Excipients: diethanolamine, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: ampoule A made of brown transparent glass contains a colorless or light-yellow clear liquid;

ampoule B (solvent) made of colorless transparent glass contains a colorless clear liquid;

ampoule A + B (solution for injection) – a clear colorless or light-yellow solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01AX05.

Pharmacological properties.

Pharmacodynamics.

The active substance, glucosamine sulfate, is a salt of the aminomonosaccharide glucosamine, which under physiological conditions is naturally present in the human body and is used together with sulfates for the biosynthesis of hyaluronic acid in synovial fluid and glycosaminoglycans of the cartilage matrix.

Thus, the mechanism of action of glucosamine sulfate involves stimulation of glycosaminoglycan synthesis and, consequently, of joint proteoglycans. In addition, glucosamine exerts anti-inflammatory effects and inhibits the process of joint cartilage degradation, primarily due to its intrinsic metabolic properties and ability to suppress the activity of interleukin-1 (IL-1). This affects both the symptoms of osteoarthritis and potentially delays structural joint damage, as evidenced by data from long-term clinical studies.

Initial in vitro and in vivo studies indicate that exogenous administration of glucosamine sulfate stimulates the biosynthesis of proteoglycans, which is impaired in osteoarthritis, promotes fixation of sulfate ions during glycosaminoglycan synthesis, and improves cartilage nutrition.

Subsequent studies have shown that glucosamine sulfate inhibits the synthesis of tissue-damaging substances such as superoxide radicals, as well as the activity of lysosomal enzymes and other enzymes capable of degrading joint cartilage tissue, including collagenases and phospholipases A2. This action results in a moderate anti-inflammatory effect observed in animal models in vivo, including in some cases of experimental osteoarthritis, even without inhibition of cyclooxygenase, unlike nonsteroidal anti-inflammatory drugs (NSAIDs).

More recent research has demonstrated that most of the aforementioned metabolic and anti-inflammatory effects may be related to the inhibition of intracellular signal transduction induced by IL-1, one of the cytokines involved in the pathogenesis of osteoarthritis, leading to subsequent suppression of cytokine-induced gene transcription. Glucosamine sulfate, at plasma and synovial fluid concentrations observed in patients with osteoarthritis, can effectively inhibit IL-1-induced gene expression of a series of pro-inflammatory enzymes in joint tissues, as well as degenerative enzymes in cartilage, such as certain metalloproteinases, including aggrecanases. The potential influence of sulfate ions on these pharmacodynamic properties of glucosamine has not yet been fully elucidated.

All the above-mentioned properties favorably influence the degenerative processes in cartilage underlying the pathogenesis of osteoarthritis, as well as the clinical presentation of the disease.
Short-term and medium-term studies have shown that the efficacy of glucosamine sulfate on osteoarthritis symptoms becomes evident within 2–3 weeks after initiation of treatment.

On the other hand, the therapeutic efficacy of glucosamine sulfate compared to conventional analgesics and NSAIDs is optimal after a continuous 6-month treatment course, or after a 3-month course with a clear post-treatment effect lasting up to 2 months after discontinuation.

Results from clinical studies of daily continuous treatment over 3 years indicate a progressive increase in efficacy with regard to both symptom relief and slowing of structural joint damage, as confirmed by radiographic evaluation.

Glucosamine sulfate has demonstrated good tolerability. No significant effects of glucosamine sulfate on the cardiovascular, respiratory, autonomic, or central nervous systems have been observed.

Pharmacokinetics.
Studies conducted in humans and animals have shown that after oral administration of 14C-glucosamine, radioactively labeled components are rapidly and almost completely absorbed systemically. In humans, approximately 90% of the radiolabeled dose is absorbed. Absolute bioavailability of glucosamine in rats following oral administration of glucosamine sulfate was 26%, due to the first-pass liver effect. Absolute bioavailability in humans is unknown, but according to allometric calculations, it is similar to that observed in rats, i.e., between 20% and 30%.

In healthy volunteers, after repeated oral administration of glucosamine sulfate at a dose of 1500 mg per day, the maximum steady-state plasma concentration (Cmax, ss) was 1602 ± 425 ng/mL (8.9 µM). This concentration was reached within 1.5–4 hours (median – 3 hours) after administration (tmax). At steady state, the area under the plasma concentration-time curve (AUC) was 14,564 ± 4,138 ng × hour/mL. These parameters were obtained when the drug was administered on an empty stomach; therefore, it is unknown whether food intake significantly affects drug absorption.

After oral administration and absorption, glucosamine is distributed primarily into the extravascular space (including synovial fluid), with a volume of distribution approximately 37 times higher than the total body water content. Protein binding of glucosamine has not been observed.

The metabolic profile of glucosamine has not been studied, as this medicinal substance, being a naturally occurring compound present in the human body, is utilized in the biosynthesis of certain components of joint cartilage.

Only the terminal elimination half-life of glucosamine from human plasma has been determined, based on measurements of plasma glucosamine levels over 48 hours following oral administration. The calculated value was approximately 15 hours.

After oral administration of 14C-glucosamine, urinary excretion of radioactively labeled components in humans accounted for 10 ± 9% of the administered dose, while fecal excretion was 11.3 ± 0.1%. The level of unchanged glucosamine excreted in urine after oral administration in humans was on average low (approximately 1% of the administered dose). These results indicate that the kidneys do not play a significant role in the elimination of glucosamine and/or its metabolites and/or degradation products.
With repeated administration at doses of 750–1500 mg once daily, the pharmacokinetics of glucosamine were linear, whereas at a dose of 3000 mg, plasma glucosamine levels were lower than expected based on dose escalation. Steady-state pharmacokinetics of glucosamine were time-independent, showing no evidence of accumulation or reduced bioavailability compared to the pharmacokinetic profile observed after single-dose administration. Pharmacokinetics of glucosamine are similar in men and women, and no differences have been established between healthy volunteers and patients with knee osteoarthritis. In the latter group, the mean plasma concentration 3 hours after the last 1500 mg dose with repeated once-daily administration was 7.2 µM, similar to that observed in healthy volunteers, while the mean concentration in synovial fluid was only 25% lower and thus also within the 10 µM range. Pharmacokinetics of glucosamine have not been studied in patients with renal or hepatic impairment; however, due to the drug’s safety profile and the minor role of the kidneys in glucosamine elimination, dose reduction in these patient groups is not required.

Steady-state concentrations of glucosamine in plasma and synovial fluid after repeated once-daily administration of 1500 mg are within the range of 10 µM, corresponding to concentrations at which pharmacological activity has been demonstrated in in vitro experimental models, thereby confirming the mechanism of action and clinical efficacy of the medicinal product.

Clinical characteristics.

Indications.

Symptomatic relief in mild to moderate knee osteoarthritis.

Contraindications.

Individual hypersensitivity to the active substance or to any of the excipients, predisposition to bleeding.

Glucosat should not be administered to patients with allergy to shellfish, as the active ingredient is derived from shellfish shells. Such patients may be more prone to allergic reactions to glucosamine, potentially exacerbating disease symptoms.

The injectable form of the drug contains the excipient lidocaine, which has the following contraindications: cardiogenic shock, severe arterial hypotension, acute heart failure, severe forms of chronic heart failure, impaired left ventricular function, cardiac conduction disorders, II–III degree atrioventricular block, severe bradycardia, coagulation disorders, Wolff–Parkinson–White syndrome, Adams–Stokes syndrome, history of seizures induced by lidocaine, sinoatrial node weakness syndrome, severe hepatic dysfunction, hypovolemia, myasthenia, injection site infections, hypersensitivity to lidocaine, and increased sensitivity to other amide-type local anesthetics (due to an increased risk of cross-sensitivity reactions).

Interaction with other medicinal products and other forms of interaction.

Mixing the contents of the drug's ampoules with other injectable medicinal products should be avoided.
Specific studies on drug interactions have not been conducted. However, considering the physicochemical and pharmacokinetic properties of glucosamine sulfate, a low potential for interactions is expected. Moreover, it has been established that glucosamine sulfate does not inhibit or induce the activity of major human CYP450 enzymes.

The drug does not compete for absorption mechanisms; after absorption, it does not bind to plasma proteins and is metabolized either by incorporation as an endogenous substance into proteoglycans or by degradation without involvement of the cytochrome enzyme system, making interactions with other medicinal products unlikely.

There are limited data on possible interactions between medicinal products and glucosamine. However, an increase in the international normalized ratio (INR) has been observed when glucosamine is used concomitantly with oral vitamin K antagonists. Therefore, patients receiving oral vitamin K antagonists should be closely monitored when starting or discontinuing glucosamine therapy. Concomitant treatment with glucosamine may enhance the absorption and thus the serum concentration of tetracyclines. However, the clinical significance of this interaction is likely limited.

The drug is compatible with NSAIDs and glucocorticoids.

The injectable form of the drug contains the excipient lidocaine. Cimetidine, meperidine, bupivacaine, propranolol, quinidine, disopyramide, amitriptyline, nortriptyline, chlorpromazine, imipramine increase serum lidocaine levels by reducing its hepatic metabolism. Norepinephrine exhibits a synergistic effect when interacting with lidocaine.

Monoamine oxidase inhibitors (MAOIs) should be used with caution, as they increase the risk of arterial hypotension and prolong the local anesthetic effect of lidocaine. When used concomitantly with class IA antiarrhythmics (including quinidine, procainamide, disopyramide), QT interval prolongation may occur; in very rare cases, AV block or ventricular fibrillation may develop.

The cardiotonic effect of cardiac glycosides is reduced.

When used concomitantly with sedatives, the sedative effect is enhanced.

Phenytoin enhances the cardiodepressant effect of lidocaine.

Concomitant use with procainamide may cause delirium and hallucinations.

Lidocaine may enhance the effect of drugs causing blockade of neuromuscular transmission, as the latter reduce nerve impulse conduction. Ethanol enhances the respiratory depressant effect of lidocaine.

Special precautions for use.

The drug should be administered only by healthcare professionals.

Lipid blood levels should be monitored in patients with known risk factors for cardiovascular diseases, as hypercholesterolemia has been observed in several cases of patients receiving glucosamine.

The medicinal product should be prescribed with caution to patients with glucose intolerance. At the beginning of treatment, monitoring of blood glucose levels is advisable in patients with diabetes mellitus. There have been reported cases of asthma exacerbation after initiating glucosamine intake (symptoms resolved after discontinuation of glucosamine). Therefore, the drug should be used cautiously in patients with bronchial asthma, as such patients may be more susceptible to allergic reactions to glucosamine, potentially leading to exacerbation of disease symptoms. Specific studies in patients with renal or hepatic impairment have not been conducted. However, glucosamine use in patients with severe liver or kidney dysfunction should be monitored.

One dose of the medicinal product contains 40.3 mg of sodium. This should be taken into account when prescribing the drug to patients on a strict low-sodium diet.

To avoid accidental intravascular injection, an aspiration test is recommended.

The safety of lidocaine-type anesthetics is questionable in patients predisposed to malignant hyperthermia; therefore, such use should be avoided.

Before administering lidocaine in cardiac disorders (hypokalemia reduces lidocaine efficacy), potassium levels in blood should be normalized and ECG monitoring should be performed. Serum creatine phosphokinase activity may increase after intramuscular injection of the drug, which could lead to misdiagnosis of acute myocardial infarction.

If sinus node dysfunction, prolonged P-Q interval, widened QRS complex, or development or worsening of arrhythmia occurs, the dose should be reduced or the drug discontinued.

Particular caution should be exercised when administering the drug to patients with circulatory insufficiency, arterial hypotension, history of arrhythmia, or moderate impairment of liver and/or kidney function. Due to the presence of lidocaine in the formulation, caution is also required when prescribing the drug to elderly patients, patients with epilepsy, conduction disorders of the heart, or respiratory insufficiency.

Use during pregnancy or breastfeeding.

There are no data on the use of the drug in pregnant women or women who are breastfeeding; therefore, the drug is contraindicated in these patient groups.

Ability to affect reaction speed when driving or operating machinery. Studies on the effect of the drug on the ability to drive or operate machinery have not been conducted. Dizziness, drowsiness, fatigue, headache, or visual disturbances may occur during glucosamine use; therefore, driving and operating machinery should be avoided.

Method of Administration and Dosage

For intramuscular use only. The medication is not intended for intravenous administration.

Adult and elderly patients

Before use, mix solution B (1 ml solvent) with solution A (2 ml drug solution) in one syringe.

The prepared drug solution should be administered intramuscularly as 3 ml or 6 ml (solution A+B) three times a week for 4–6 weeks.

The presence of a yellowish tint in the solution in ampoule A does not affect the efficacy or tolerability of the medicinal product.

Injections of the drug may be combined with oral administration of the drug in powder form for preparing a solution.

Glucosamine is not indicated for the treatment of acute pain syndrome. Symptomatic relief (particularly reduction in pain) may only occur after several weeks of treatment, and in some cases even after a longer period.

If no symptom relief occurs within 2–3 months of use, the treatment should be re-evaluated.

Use in elderly patients. No studies on the pharmacokinetics of the drug involving elderly patients have been conducted.

Use in patients with renal and/or hepatic impairment. No pharmacokinetic studies have been conducted in this patient population (see section "Special Instructions").

Children

Do not use in children and adolescents, as the safety and efficacy of the drug in these patients have not been established.

Overdose

Cases of overdose (accidental or intentional) have not been reported. In case of overdose, discontinue the drug and, if necessary, administer symptomatic treatment aimed at restoring water-electrolyte balance.

The injectable form of the drug contains the excipient lidocaine. Initial symptoms of lidocaine hydrochloride overdose affecting the central nervous system may include numbness of the tongue and lips, nervousness, euphoria, anxiety, tinnitus, dizziness, blurred vision, nystagmus, tremor, depression, drowsiness, lethargy, loss of consciousness, up to coma, and tonic-clonic seizures. According to published data, symptoms related to lidocaine hydrochloride overdose affecting the cardiovascular system and respiratory function may include decreased arterial pressure, collapse, AV block, and respiratory depression. Cardiovascular and respiratory functions of the patient must be monitored. Changes in these parameters may indicate drug overdose; therefore, immediate oxygen supply should be provided. All complications require symptomatic treatment.

Adverse reactions.

Criteria for assessing the frequency of adverse drug reactions:

Immune system disorders: frequency unknown – allergic reactions (hypersensitivity);

Metabolism and nutrition disorders: frequency unknown – negative impact on blood sugar monitoring, hyperglycemia in patients with impaired glucose tolerance;

Psychiatric disorders: frequency unknown – insomnia;

Nervous system disorders: common – headache, drowsiness; frequency unknown – dizziness;

Eye disorders: frequency unknown – visual disturbances;

Cardiac disorders: frequency unknown – cardiac arrhythmia, e.g. tachycardia;

Vascular disorders: uncommon – flushing;

Gastrointestinal disorders: common – nausea, abdominal pain, indigestion, diarrhea, constipation, flatulence, stomach discomfort and pain, dyspepsia;

Skin and subcutaneous tissue disorders: uncommon – erythema, rash, itching; frequency unknown – hair loss, angioneurotic edema, urticaria;

Respiratory, thoracic and mediastinal disorders: frequency unknown – asthma, exacerbation of asthma;

Hepatobiliary disorders: frequency unknown – jaundice;

General disorders and administration site conditions: common – fatigue; frequency unknown – edema, peripheral edema, injection site reaction;

Investigations: frequency unknown – increased liver enzymes, increased blood glucose, increased blood pressure, INR fluctuations.

Isolated spontaneous cases of hypercholesterolemia have been reported; however, a causal relationship has not been established.

The injectable form of the drug contains lidocaine. In exceptional cases, adverse reactions characteristic of this component may occur:

Gastrointestinal disorders: nausea, very rare – vomiting;

Nervous system disorders: numbness of lips and tongue, photophobia, diplopia, headache, confusion, muscle twitching; when used in high doses – tinnitus, excited state, anxiety, paresthesia, seizures, loss of consciousness, coma, hyperacusis;

Eye disorders: visual disturbances, conjunctivitis; when used in high doses – nystagmus;
Psychiatric disorders: frequency unknown – sleep disturbances;

Cardiovascular disorders: arterial hypotension, atrioventricular block; frequency unknown – increased blood pressure; when used in high doses – arrhythmia, bradycardia, slowed cardiac conduction, cardiac arrest, peripheral vasodilation, collapse, tachycardia, chest pain;

Immune system disorders: immune system suppression, allergic reactions including swelling, skin reactions, itching; very rare – urticaria, hypersensitivity reactions including anaphylactoid reactions (e.g. anaphylactic shock), generalized exfoliative dermatitis;

Respiratory disorders: respiratory depression or respiratory arrest, dyspnea;
Other: sensation of heat, cold or numbness in extremities, malignant hyperthermia; when used in high doses – rhinitis;

Local reactions: skin tingling at injection site, abscess, sensation of mild burning (disappears as anesthetic effect develops within 1 minute), thrombophlebitis.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date.

Storage conditions. Store in original packaging protected from light at a temperature of 2 to 8 °C. Keep out of reach of children.

Packaging.

Vial A made of transparent brown glass contains 2 ml of the medicinal product.

Vial B made of colorless transparent glass contains 1 ml of solvent.

5 vials A in a blister; 5 vials B in a blister. One blister with vials A and one blister with vials B in a cardboard box.

1 vial A and 1 vial B in a blister. One blister in a cardboard box.

6 vials A in a blister; 6 vials B in a blister. One blister with vials A and one blister with vials B in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "FZ "STADA", Ukraine.

Manufacturer's address and location of its business activity.

37, Kyivska St., Bila Tserkva, Kyiv region, 09100, Ukraine.