Donna

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DОNAâ (DONAâ)

Composition:

Active substance: 2 ml of solution (vial A) contains 502.5 mg of crystalline glucosamine sulfate, equivalent to 400 mg of glucosamine sulfate, and 102.5 mg of sodium chloride;

Excipients: lidocaine hydrochloride, water for injections;

solvent (vial B) contains

Excipients: diethanolamine, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: vial A made of brown transparent glass containing a clear liquid free from suspended particles;

vial B (solvent) made of colorless transparent glass containing a clear colorless liquid free from suspended particles;

vial A+B (injection solution) – clear solution free from suspended particles.

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

ATC code M01AX05.

Pharmacological Properties

Pharmacodynamics

The active substance, glucosamine sulfate, is a salt of glucosamine—an aminomonosaccharide naturally present in the human body under physiological conditions and used for the biosynthesis of glycosaminoglycans and proteoglycans of the articular cartilage matrix and synovial fluid.

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 degradation of articular cartilage 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 long-term clinical studies.

Initial in vitro and in vivo studies demonstrated 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 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 articular cartilage tissue, including collagenases and phospholipases A2. This action produces 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 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 suppression of cytokine-induced gene transcription. At plasma and synovial fluid concentrations observed in patients with osteoarthritis, glucosamine sulfate 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 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 apparent 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 is optimal after a continuous 6-month treatment course, or after a 3-month treatment course with a clear carry-over 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 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 first-pass liver metabolism. Absolute bioavailability in humans is unknown, but allometric calculations suggest it is similar to that observed in rats, i.e., between 20% and 30%.

In healthy volunteers, following 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 AUC (area under the plasma concentration-time curve) was 14564 ± 4138 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.

Following oral administration, 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 in humans. Protein binding of glucosamine has not been detected.

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

Only the terminal elimination half-life of glucosamine from human plasma has been established, 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-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 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. However, at a dose of 3000 mg, plasma glucosamine levels were lower than expected based on dose proportionality. Steady-state pharmacokinetics of glucosamine were time-independent and showed 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 observed between healthy volunteers and patients with knee osteoarthritis. In the latter group, the mean plasma concentration 3 hours after the last dose of 1500 mg administered once daily in repeated dosing was 7.2 µM, similar to that observed in healthy volunteers. 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, given the safety profile of the drug and the negligible 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 medicinal product.

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, tendency to bleeding.

Donna® should not be used in patients with allergy to shellfish, since the active ingredient is derived from shellfish shells; such patients may be more susceptible to developing allergic reactions to glucosamine, possibly 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, reduced left ventricular function, cardiac conduction disorders, second- to third-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 gravis, infection at the injection site, 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 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 can be assumed. Furthermore, 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, but 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 of medicinal products with glucosamine; however, an increase in INR (international normalized ratio) has been observed when oral vitamin K antagonists are used. 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 nonsteroidal anti-inflammatory drugs and glucocorticoids.

The injectable form of the drug 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 (MAO inhibitors) 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 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 is diminished.

When used concomitantly with sedatives, sedative effects are enhanced.

Phenytoin potentiates the cardiodepressant effect of lidocaine.

When used concomitantly with procainamide, delirium and hallucinations are possible.

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

Special precautions for use.

The administration of the drug should be performed only by healthcare professionals.

Glucosamine may alter glucose levels. In patients with impaired glucose tolerance, blood glucose levels should be monitored before initiating treatment and periodically during treatment, and insulin requirements adjusted if necessary (see section "Side effects").

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

Exacerbation of asthma symptoms after initiating glucosamine intake has been reported. Symptoms resolved upon discontinuation of glucosamine. Therefore, caution is advised when using the drug in patients with 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, glucosamine should be used with caution in patients with severe hepatic or renal insufficiency and should be monitored closely.

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

Serum creatine phosphokinase activity may increase after 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 development or worsening of arrhythmia, the dose should be reduced or the drug discontinued.

Particular caution is required 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 in 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.

Fertility. There are no data on the effect of the medicinal product on fertility. Therefore, women experiencing difficulties with conception or undergoing infertility evaluation should discontinue the drug.

Ability to affect reaction speed when driving or operating machinery. Studies on the effect of the drug on the ability to drive vehicles 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 product is not intended for intravenous administration.

Adult and elderly patients

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

The resulting drug solution should be administered intramuscularly at 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 solution preparation.

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 symptomatic improvement occurs within 2–3 months of treatment, the treatment regimen should be re-evaluated.

Use in elderly patients. No pharmacokinetic studies involving elderly patients have been conducted.

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

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

Overdose. Cases of overdose (accidental or intentional) have not been reported. In the event of overdose, discontinue the drug and, if necessary, initiate 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, excitement, euphoria, anxiety, tinnitus, dizziness, blurred vision, nystagmus, tremor, depression, drowsiness, loss of consciousness, up to coma, and tonic-clonic seizures. As reported in publications, 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 side effects: 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 (cephalalgia), 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, dyspepsia, diarrhea, constipation, flatulence, stomach heaviness and discomfort; frequency unknown – vomiting;

Skin and subcutaneous tissue disorders: uncommon – erythema, rash, pruritus; frequency unknown – hair loss, angioedema, 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 – swelling, peripheral edema, injection site reaction;

Investigations: frequency unknown – increased liver enzymes, increased blood glucose levels, increased blood pressure, fluctuations in INR (International Normalized Ratio).

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 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 unknown – sleep disturbances;

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

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

Respiratory system disorders: respiratory depression or respiratory arrest, dyspnea;

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

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

Reporting of adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 2 years.

The stated shelf life is valid provided the packaging remains intact and storage conditions are observed. Do not use the medicinal product after the expiry date.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

Incompatibilities. The medicinal product solution should not be mixed with other injectable solutions.

Packaging.

Ampoule A: brown transparent glass containing 2 ml of active substance.

Ampoule B: colorless transparent glass containing 1 ml of solvent.

6 ampoules A and 6 ampoules B with solvent are packaged in a PVC blister and cardboard box.

Prescription category. Prescription only.

Manufacturer. Biologici Italia Laboratoriz S.p.A.

Manufacturer's address and place of business.

Via Filippo Serpero, 2 - 20060 Masate (Milan), Italy