Jev

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

Composition:

Active substances: glucosamine, sodium chloride;

1 ml of injection solution (ampoule A) contains 251.25 mg of glucosamine sulfate sodium chloride, equivalent to 200 mg of glucosamine sulfate and 51.25 mg of sodium chloride;

Excipients:

ampoule A: lidocaine hydrochloride, hydrochloric acid diluted or concentrated, water for injections;

ampoule B (solvent): diethanolamine, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties:

ampoule A – clear, colorless or slightly yellowish-brown solution;

ampoule B (solvent) – clear, colorless solution;

ampoule A+B (injection solution) – clear, colorless or slightly yellowish-brown solution.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Other non-steroidal anti-inflammatory and antirheumatic agents. Glucosamine. 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 ground substance of articular cartilage.

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

Initial in vitro and in vivo studies have shown 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 the trophism of articular cartilage.

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

More recent studies have shown 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 inhibition 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 affect degenerative processes in cartilage, which underlie 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 nonsteroidal anti-inflammatory drugs (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 respect to symptoms 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-labeled 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 after 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 14564 ± 4138 ng·h/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 primarily distributed 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 drug, being a naturally occurring substance in the human body, is used in the biosynthesis of certain components of articular 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 after oral administration. The calculated value was approximately 15 hours.

After oral administration of 14C-labeled 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%. Renal excretion of unchanged glucosamine in humans after oral administration was 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 dosing at 750–1500 mg once daily, the pharmacokinetics of glucosamine were linear. However, at a dose of 3000 mg, plasma glucosamine levels were lower than expected based on dose escalation. Steady-state pharmacokinetics of glucosamine did not depend on time and showed no evidence of accumulation or reduced bioavailability compared to the pharmacokinetic profile observed after single administration.

Pharmacokinetics of glucosamine in men and women are similar. No differences in pharmacokinetics have been observed between healthy volunteers and patients with knee osteoarthritis. In the latter, the mean plasma concentration 3 hours after the last 1500 mg dose in 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 adjustment 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 drug.

Clinical characteristics.

Indications.

Relief of symptoms in mild to moderate knee osteoarthritis.

Contraindications.

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

The medication DZHAYV® should not be administered to patients with allergy to shellfish, as the active ingredient is derived from shellfish exoskeletons; such patients may be more prone to developing allergic reactions to glucosamine, potentially exacerbating disease symptoms.

The formulation contains the excipient lidocaine, which has the following contraindications: cardiogenic shock; severe arterial hypotension; acute heart failure; severe forms of chronic heart failure; reduced 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 dysfunction syndrome; severe hepatic impairment; hypovolemia; myasthenia; infections at the injection site; hypersensitivity to lidocaine; and increased sensitivity to other amide-type local anesthetics (due to an increased risk of cross-reactivity hypersensitivity reactions).

Interaction with other medicinal products and other forms of interaction.

Mixing the contents of the medication’s ampoules with other injectable drugs 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 can be assumed. Furthermore, it has been established that glucosamine sulfate does not inhibit or induce the activity of major human CYP450 enzymes.

The medicinal product does not effectively 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 potential interactions between medicinal products and glucosamine; however, an increase in INR (International Normalized Ratio) has been observed when oral vitamin K antagonists are used concomitantly. Therefore, patients receiving oral vitamin K antagonists should be closely monitored when initiating or discontinuing glucosamine therapy. Concomitant treatment with glucosamine may enhance the absorption and, consequently, the serum concentration of tetracyclines. However, the clinical significance of this interaction is likely limited.

The medicinal product is compatible with NSAIDs and glucocorticoids.

The formulation contains the excipient lidocaine. Cimetidine, pethidine, bupivacaine, propranolol, quinidine, disopyramide, amitriptyline, nortriptyline, chlorpromazine, and imipramine increase lidocaine serum 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 may increase the risk of arterial hypotension and prolong the local anesthetic effect.

When used concomitantly with class IA antiarrhythmic agents (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 may be diminished.

When used concomitantly with sedatives, sedative effects are enhanced.

Phenytoin enhances the cardiodepressant effect of lidocaine.

Concomitant use with procainamide may lead to delirium and hallucinations.

Lidocaine may potentiate the effects of agents causing neuromuscular blockade, as the latter reduce nerve impulse conduction. Ethanol enhances the respiratory depressant effect of lidocaine.

Special precautions for use

Administration of the medicinal product should only be performed by healthcare professionals.

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

The product should be prescribed with caution to patients with glucose intolerance. At the beginning of treatment, blood glucose levels should be monitored in patients with diabetes mellitus.

Exacerbations of asthma symptoms have been reported following the initiation of glucosamine therapy (symptoms resolved after discontinuation of glucosamine). Therefore, the product should be used with caution in patients suffering from bronchial asthma, as such patients may be more susceptible to allergic reactions to glucosamine, potentially leading to worsening of disease symptoms. Specific studies in patients with renal or hepatic impairment have not been conducted. However, use of glucosamine in patients with severe hepatic or renal impairment should be monitored.

One dose of the medicinal product contains 40.3 mg of sodium. This should be taken into account when prescribing 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 conditions (hypokalemia reduces lidocaine efficacy), serum potassium levels should be normalized and ECG monitoring should be performed.

Serum creatine phosphokinase activity may increase after intramuscular injection of the medicinal product, which may lead to misdiagnosis of acute myocardial infarction.

In case of sinus node dysfunction, prolonged P-Q interval, QRS complex widening, or occurrence or exacerbation of arrhythmia, the dose should be reduced or the medicinal product discontinued.

Particular caution should be exercised when administering the medicinal product to patients with circulatory insufficiency, arterial hypotension, history of arrhythmias, or moderate hepatic and/or renal dysfunction. Due to the presence of lidocaine in the formulation, caution is also required when prescribing the product to elderly patients, patients with epilepsy, cardiac conduction disorders, or respiratory insufficiency.

Use during pregnancy or breastfeeding

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

Ability to affect driving and use of machines

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. During glucosamine use, dizziness, somnolence, fatigue, headache, or visual disturbances may occur; therefore, driving and operating machinery should be avoided.

Dosage and Administration

For intramuscular use only!

The medicinal product is not intended for intravenous administration.

Adult and elderly patients

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

The resulting injectable solution (Solution A+B) should be administered intramuscularly at 3 ml or 6 ml 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.

The medicinal product may be combined with oral forms of glucosamine.

Glucosamine is not indicated for the treatment of acute pain syndrome.

Symptom 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 after 2–3 months of use, the treatment should be re-evaluated.

Use in elderly patients

No pharmacokinetic studies of glucosamine have been conducted in elderly patients.

Use in patients with renal and/or hepatic impairment

No pharmacokinetic studies of glucosamine have been conducted in this population (see section "Special precautions for use").

Children

Do not use in children and adolescents, as the safety and efficacy of glucosamine in these patient groups have not been established.

Overdose

No cases of overdose (accidental or intentional) have been reported. In the event of overdose, discontinue the medicinal product and, if necessary, administer symptomatic treatment aimed at restoring fluid and electrolyte balance.

The medicinal product contains the excipient lidocaine. The initial signs of lidocaine hydrochloride overdose affecting the central nervous system may include numbness of the tongue and lips, restlessness, euphoria, anxiety, tinnitus, dizziness, blurred vision, nystagmus, tremor, depression, drowsiness, loss of consciousness, up to coma, and tonic-clonic seizures. According to published reports, 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 should be monitored. Changes in these parameters may indicate overdose; therefore, immediate oxygen supply should be provided. All complications require symptomatic treatment.

Adverse reactions.

Criteria for assessing the frequency of adverse drug reactions: very common (> 1/10), common (from > 1/100 to < 1/10), uncommon (from > 1/1000 to < 1/100), rare (from > 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

Immune system disorders: frequency not known – allergic reactions (hypersensitivity).

Metabolism and nutrition disorders: frequency not known – negative impact on blood glucose monitoring, hyperglycemia in patients with impaired glucose tolerance.

Psychiatric disorders: frequency not known – insomnia.

Nervous system disorders: common – headache (cephalalgia), drowsiness; frequency not known – dizziness.

Eye disorders: frequency not known – visual disturbances.

Cardiac disorders: frequency not known – cardiac arrhythmia, e.g. tachycardia.

Vascular disorders: uncommon – flushing.

Gastrointestinal disorders: common – nausea, abdominal pain, dyspepsia, diarrhea, constipation, flatulence, epigastric fullness and discomfort, dyspepsia.

Skin and subcutaneous tissue disorders: uncommon – erythema, rash, pruritus; frequency not known – hair loss, angioedema, urticaria.

Respiratory, thoracic and mediastinal disorders: frequency not known – asthma, exacerbation of asthma.

Hepatobiliary disorders: frequency not known – jaundice.

General disorders and administration site conditions: common – fatigue; frequency not known – swelling, peripheral edema, injection site reaction.

Investigations: frequency not known – increased liver enzymes, increased blood glucose levels, increased blood pressure, fluctuations in INR values.

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

The medicinal product contains lidocaine. The following adverse reactions characteristic of this component may occur in exceptional cases.

Gastrointestinal disorders: nausea; very rare – vomiting.

Nervous system disorders: numbness of lips and tongue, photophobia, diplopia, headache, confusion, muscle twitching; at high doses – tinnitus, agitation, anxiety, paresthesia, seizures, loss of consciousness, coma, hyperacusis.

Eye disorders: visual disturbances, conjunctivitis; at high doses – nystagmus.

Psychiatric disorders: frequency not known – sleep disturbances.

Cardiovascular disorders: arterial hypotension, atrioventricular block; frequency not known – increased blood pressure; at 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, pruritus; very rare – urticaria, hypersensitivity reactions including anaphylactoid reactions (e.g. anaphylactic shock), generalized exfoliative dermatitis.

Respiratory, thoracic and mediastinal disorders: respiratory depression or respiratory arrest, dyspnea.

Other: sensation of heat, cold or numbness in extremities, malignant hyperthermia; at high doses – rhinitis.

General disorders and administration site conditions: skin tingling at injection site, abscess, sensation of mild burning (disappears with the onset of anesthetic effect within 1 minute), thrombophlebitis.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

2 ml in ampoules, 5 ampoules (ampoule A) in a blister pack, supplied with 1 ml solvent in ampoules, 5 ampoules (ampoule B) in a blister pack, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

TOV NVF "MIKROKHEM"

(responsible for batch release, excluding batch control/testing)

JSC "Halychfarm"

(responsible for manufacturing and batch control/testing, excluding batch release)

Manufacturer's address and location of its business activities.

Ukraine, 01013, Kyiv, Budynsturiy str., 5

Ukraine, 79024, Lviv, Opryshkovska str., 6/8

INSTRUCTIONS

for medical use of the medicinal product

DZHAV®

(DJAIV)

Composition:

Active substances: glucosamine, sodium chloride;

1 ml of injection solution (Ampoule A) contains 251.25 mg of glucosamine sulfate sodium chloride, equivalent to 200 mg of glucosamine sulfate and 51.25 mg of sodium chloride;

Excipients:

Ampoule A: lidocaine hydrochloride, hydrochloric acid diluted or concentrated, water for injections;

Ampoule B (solvent): diethanolamine, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties:

Ampoule A – clear, colorless or light yellowish-brown solution;

Ampoule B (solvent) – clear, colorless solution;

Ampoule A+B (injection solution) – clear, colorless or light yellowish-brown solution.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic agents. Other non-steroidal anti-inflammatory and antirheumatic agents. Glucosamine. 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 joint 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 potential metabolic properties and ability to suppress the activity of interleukin-1 (IL-1), thereby influencing both the symptoms of osteoarthritis and potentially delaying structural joint damage, as evidenced by 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 insufficient in osteoarthritis, promotes fixation of sulfate ions during glycosaminoglycan synthesis, and improves joint cartilage trophism.

Subsequent studies have shown that glucosamine sulfate inhibits the synthesis of tissue-destructive 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. Glucosamine sulfate also has 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, resulting in subsequent suppression of cytokine-induced gene transcription. At plasma and synovial fluid concentrations observed in patients with osteoarthritis, glucosamine sulfate can actually 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 affect 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 the symptoms of osteoarthritis becomes apparent within 2–3 weeks after the start of treatment.

On the other hand, the therapeutic efficacy of glucosamine sulfate in symptom relief, compared to conventional analgesics and nonsteroidal anti-inflammatory drugs, is optimal after a continuous 6-month treatment course, or after a 3-month treatment course with a clear post-treatment effect lasting for 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 symptoms and slowing of structural joint damage, as confirmed radiographically.

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-labeled glucosamine, radioactively labeled components are rapidly and almost completely absorbed systemically. In humans, approximately 90% of the radioactively labeled 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 14564 ± 4138 ng·h/mL. These parameters were obtained when the drug was administered on an empty stomach; therefore, it is unknown whether food intake may significantly affect drug absorption.

After oral administration and absorption, glucosamine is primarily distributed 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 detected.

The metabolic profile of glucosamine has not been studied, as this drug, being a naturally occurring substance in the human body, is used for 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 after oral administration. The calculated value was approximately 15 hours.

After oral administration of 14C-labeled 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 low on average (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. However, 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.

The pharmacokinetics of glucosamine in men and women are similar. No differences in pharmacokinetics 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, following 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 adjustment 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 and thus correspond to concentrations at which pharmacological activity has been demonstrated in in vitro experimental models, confirming the mechanism of action and clinical efficacy of the drug.

Clinical characteristics.

Indications.

Relief of symptoms in mild to moderate knee osteoarthritis.

Contraindications.

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

The medication DJAYV® should not be administered to patients with allergy to shellfish, as the active ingredient is derived from shellfish exoskeletons; such patients may be more prone to allergic reactions to glucosamine, potentially exacerbating disease symptoms.

The formulation 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; second–third degree atrioventricular block; severe bradycardia; coagulation disorders; Wolff–Parkinson–White syndrome; Adams–Stokes syndrome; history of seizures induced by lidocaine; sinoatrial node dysfunction syndrome; severe hepatic impairment; hypovolemia; myasthenia; local infection at the injection site; hypersensitivity to lidocaine; and increased sensitivity to other amide-type local anesthetics (due to an increased risk of cross-reactivity in hypersensitivity reactions).

Interaction with other medicinal products and other forms of interaction.

Mixing the contents of the medication vials with other injectable drugs 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. Furthermore, glucosamine sulfate has been shown not to inhibit or induce the activity of major human CYP450 enzymes.

The drug essentially 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.

Limited data exist on potential interactions between medicinal products and glucosamine; however, an increased INR (International Normalized Ratio) has been observed during concomitant use with oral vitamin K antagonists. Therefore, patients receiving oral vitamin K antagonists should be closely monitored when initiating or discontinuing glucosamine therapy. Concomitant treatment with glucosamine may enhance the absorption and thus increase serum concentrations of tetracyclines. However, the clinical significance of this interaction is likely limited.

The medication is compatible with NSAIDs and glucocorticosteroids.

The formulation contains the excipient lidocaine. Cimetidine, pethidine, bupivacaine, propranolol, quinidine, disopyramide, amitriptyline, nortriptyline, chlorpromazine, and 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 may increase the risk of arterial hypotension and prolong the local anesthetic effect of lidocaine.

Concomitant use with Class IA antiarrhythmic agents (including quinidine, procainamide, disopyramide) may prolong the QT interval; in very rare cases, AV block or ventricular fibrillation may occur.

The cardiotonic effect of cardiac glycosides may be diminished.

When used concomitantly with sedatives, sedative effects are enhanced.

Phenytoin enhances the cardiodepressant effect of lidocaine.

Concomitant use with procainamide may lead to delirium and hallucinations.

Lidocaine may potentiate the effects of agents causing neuromuscular blockade, as the latter reduce nerve impulse conduction. Ethanol enhances the respiratory depressant effect of lidocaine.

Special precautions for use

Administration of the medicinal product should only be performed by healthcare professionals.

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

The product should be administered with caution in patients with glucose intolerance. At the beginning of treatment, blood glucose monitoring is advisable in patients with diabetes mellitus.

There have been reported cases of asthma symptom exacerbation following the initiation of glucosamine therapy (symptoms resolved after discontinuation of glucosamine). Therefore, the drug should be used with caution in patients suffering from bronchial asthma, as such patients may be more susceptible to allergic reactions to glucosamine, potentially leading to worsening of disease symptoms. Specific studies in patients with renal or hepatic impairment have not been conducted. However, use of glucosamine in patients with severe hepatic or renal impairment should be monitored.

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

Prior to administering lidocaine in patients with heart disease (hypokalemia reduces lidocaine efficacy), serum potassium levels should be normalized and ECG monitoring should be performed.

Serum creatine phosphokinase activity may increase following intramuscular injection of the drug, which could lead to misdiagnosis of acute myocardial infarction.

In case of sinus node dysfunction, prolonged P-Q interval, widened QRS complex, or occurrence or worsening of arrhythmia, 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 arrhythmias, or moderate hepatic and/or renal dysfunction. 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 available on the use of the drug in pregnant women or women who are breastfeeding; therefore, use of the medicinal product in these patient groups is contraindicated.

Ability to influence reaction rate while driving or operating machinery

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. During glucosamine use, dizziness, somnolence, fatigue, headache, or visual disturbances may occur; therefore, driving vehicles and operating machinery should be avoided.

Method of Administration and Dosage

For intramuscular use only!

The medicinal product is not intended for intravenous administration.

Adult and elderly patients

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

The prepared injection solution (solution A+B) should be administered intramuscularly at 3 ml or 6 ml 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 and tolerability of the medicinal product.

The medicinal product may be combined with oral forms of glucosamine.

Glucosamine is not indicated for the treatment of acute pain syndrome.

Symptom relief (particularly reduction of pain) may occur only after several weeks of treatment, and in some cases — even after a longer period.

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

Use in elderly patients

No pharmacokinetic studies of glucosamine have been conducted in elderly patients.

Use in patients with renal and/or hepatic impairment

No pharmacokinetic studies of glucosamine have been conducted in this population (see section "Special precautions for use").

Children

Do not use in children and adolescents, as the safety and efficacy of glucosamine in these patient groups have not been established.

Overdose

No cases of overdose (accidental or intentional) have been reported. In case of overdose, discontinue the medicinal product and, if necessary, administer symptomatic treatment aimed at restoring fluid and electrolyte balance.

The medicinal product contains the excipient lidocaine. The first signs of lidocaine hydrochloride overdose affecting the central nervous system may include numbness of the tongue and lips, agitation, euphoria, anxiety, tinnitus, dizziness, blurred vision, nystagmus, tremor, depression, drowsiness, loss of consciousness, up to coma, and tonic-clonic seizures. According to published reports, 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 should 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: very common (> 1/10), common (from > 1/100 to < 1/10), uncommon (from > 1/1000 to < 1/100), rare (from > 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Immune system disorders: frequency not known – allergic reactions (hypersensitivity).

Metabolism and nutrition disorders: frequency not known – negative impact on blood glucose monitoring, hyperglycemia in patients with impaired glucose tolerance.

Psychiatric disorders: frequency not known – insomnia.

Nervous system disorders: common – headache (cephalalgia), drowsiness; frequency not known – dizziness.

Eye disorders: frequency not known – visual disturbances.

Cardiac disorders: frequency not known – 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, pruritus; frequency not known – hair loss, angioneurotic edema, urticaria.

Respiratory, thoracic and mediastinal disorders: frequency not known – asthma, exacerbation of asthma.

Hepatobiliary disorders: frequency not known – jaundice.

General disorders and administration site conditions: common – fatigue; frequency not known – edema, peripheral edema, reaction at injection site.

Investigations: frequency not known – increased liver enzymes, increased blood glucose levels, increased blood pressure, fluctuations in INR values.

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

The medicinal product contains lidocaine. In exceptional cases, the following adverse reactions characteristic of this component may occur:

Gastrointestinal disorders: nausea; very rare – vomiting.

Nervous system disorders: numbness of the tongue and lips, photophobia, diplopia, headache, confusion, muscle twitching; at high doses – tinnitus, agitation, anxiety, paresthesia, seizures, loss of consciousness, coma, hyperacusis.

Eye disorders: visual disturbances, conjunctivitis; at high doses – nystagmus.

Psychiatric disorders: frequency not known – sleep disturbances.

Cardiovascular disorders: arterial hypotension, atrioventricular block; frequency not known – increased blood pressure; at 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, pruritus; very rare – urticaria, hypersensitivity reactions including anaphylactoid reactions (e.g. anaphylactic shock), generalized exfoliative dermatitis.

Respiratory, thoracic and mediastinal disorders: respiratory depression or respiratory arrest, dyspnea.

Other: sensation of heat, cold or numbness in extremities, malignant hyperthermia; at high doses – rhinitis.

General disorders and administration site conditions: skin tingling at injection site, abscess, mild burning sensation (disappears as anesthetic effect develops within 1 minute), thrombophlebitis.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

2 ml in vials, 5 vials (vial A) in a blister pack, supplied with 1 ml solvent in vials, 5 vials (vial B) in a blister pack, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM LLC (Production unit (all stages of manufacturing process))

Manufacturer's address and place of business.

24-v Promyslova St., Severodonetsk, Luhansk Oblast, 93400, Ukraine