Dona solution for injection 2 ml ampoule with solvent in 1 ml ampoules No. 6

Instructions for Dona injection solution 2 ml ampoule with solvent in 1 ml ampoules No. 6

Composition

active ingredient: 2 ml of solution (ampoule 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 injection;

solvent (ampoule B) contains

Excipients: diethanolamine, water for injection.

Dosage form

Solution for injection.

Main physicochemical properties: ampoule A made of brown transparent glass contains a colorless or light brown transparent liquid without suspended particles;

ampoule B (solvent) made of colorless transparent glass contains a colorless transparent liquid without suspended particles;

ampoule A+B (solution for injection) – a light brown transparent solution that does not contain suspended particles.

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory and antirheumatic drugs.

ATX code M01A X05.

Pharmacological properties

Pharmacodynamics.

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

Thus, the mechanism of action of glucosamine sulfate is to stimulate the synthesis of glycosaminoglycans and, accordingly, articular proteoglycans. In addition, glucosamine has an anti-inflammatory effect and inhibits the process of destruction of articular cartilage mainly due to the possible manifestations of its own metabolic properties, the ability to inhibit the activity of interleukin 1 (IL-1), which on the one hand affects the symptoms of osteoarthritis, and on the other hand potentially delays structural damage to the joints, as evidenced by data from long-term clinical studies.

According to initial in vitro and in vivo studies, exogenous administration of glucosamine sulfate stimulates proteoglycan biosynthesis, which is deficient in osteoarthritis, promotes the fixation of sulfur ions during the synthesis of glycosaminoglycans, and improves trophicity of articular cartilage.

Further studies have shown that glucosamine sulfate inhibits the synthesis of tissue-degrading substances such as superoxide radicals and the activity of lysosomal enzymes in addition to enzymes capable of destroying articular cartilage, such as collagenases and phospholipase A2. This action exerts a moderate anti-inflammatory effect, which is observed in in vivo animal models, including in some cases in experimental osteoarthritis, even without inhibition of cyclooxygenases, unlike non-steroidal anti-inflammatory drugs (NSAIDs).

More recent studies have shown that most of the above metabolic and anti-inflammatory effects may be related to the inhibition of intracellular signal transduction of IL-1, one of the cytokines involved in the pathogenesis of osteoarthritis, with subsequent inhibition of cytokine-induced gene transcription. Glucosamine sulfate, at plasma and synovial fluid concentrations reported in patients with osteoarthritis, can actually inhibit IL-1-induced gene expression of a series of pro-inflammatory enzymes in joint tissues, as well as pro-degenerative enzymes in cartilage, such as some metalloproteases, including aggrecanases. The potential influence of sulfur ions on the aforementioned pharmacodynamic properties of glucosamine is not fully understood.

All of the above properties have a beneficial effect on the degenerative processes in cartilage that underlie the pathogenesis of osteoarthritis, as well as on the clinical picture of the disease.

Short-term and medium-term studies have shown that the effectiveness of glucosamine sulfate on osteoarthritis symptoms is evident as early as 2–3 weeks after starting its use.

On the other hand, the efficacy of glucosamine sulfate treatment on symptoms, compared with conventional analgesics and nonsteroidal anti-inflammatory drugs, is optimal after a course of continuous use for 6 months or after a course of use for 3 months with an obvious aftereffect for 2 months after discontinuation.

Clinical trial results of daily continuous treatment over 3 years show a progressive increase in its effectiveness, with regard to symptoms and slowing of structural joint damage, as confirmed by X-ray.

Glucosamine sulfate has been shown to be well tolerated. No significant effects of glucosamine sulfate on the cardiovascular, respiratory, autonomic, or central nervous systems have been identified.

Pharmacokinetics.

In healthy volunteers, after multiple oral doses 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 1.5–4 h (median 3 h) after administration (tmax). At steady state, the AUC of plasma concentrations versus time was 14564 ± 4138 ng × h/ml. These parameters were obtained when the drug was administered in the fasting state, so it is not known whether food intake can significantly affect the absorption of the drug.

After oral administration, glucosamine is mainly distributed in the extravascular environment (including synovial fluid) after absorption, with a volume of distribution approximately 37 times greater than the total amount of water in the human body. Glucosamine is not protein bound.

The metabolic profile of glucosamine has not been studied because this drug, being a natural substance present in the human body, is used for the biosynthesis of some components of articular cartilage.

Only the terminal elimination half-life of glucosamine from human plasma has been determined from plasma glucosamine levels measured 48 hours after oral administration. The estimated value was approximately 15 hours.

Following oral administration of 14C-glucosamine, urinary excretion of radiolabeled elements in humans was 10 ± 9% of the administered dose, while faecal excretion was 11.3 ± 0.1%. Urinary excretion of unchanged glucosamine in humans following oral administration 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 breakdown products.

Glucosamine pharmacokinetics were linear after multiple dosing of 750–1500 mg once daily, whereas plasma glucosamine levels were lower than expected with increasing doses at 3000 mg. Steady-state glucosamine pharmacokinetics were not time-dependent, and showed no evidence of accumulation or reduced bioavailability compared to the pharmacokinetic profile observed after single administration.

The pharmacokinetics of glucosamine in men and women are similar, and no pharmacokinetic differences have been established between healthy volunteers and patients with osteoarthritis of the knee. In the latter, the mean plasma concentration 3 hours after the last dose of 1500 mg with repeated once-daily administration was 7.2 µM and was similar to that found in healthy volunteers, while the mean concentration in synovial fluid was only 25% lower and therefore also in the 10 µM range. The pharmacokinetics of glucosamine have not been studied in patients with renal or hepatic insufficiency, since, given the safety profile of the drug and due to the minor involvement of the kidneys in the elimination of glucosamine, no dose reduction is envisaged for these groups of patients.

The equilibrium concentrations of glucosamine in plasma and synovial fluid after multiple once-daily administration of 1500 mg are within 10 mM and, therefore, correspond to those for which pharmacological activity has been shown in studies in in vitro experimental models, confirming the mechanism of action and clinical effect of the drug.

Indication

Relief of symptoms in mild to moderate osteoarthritis of the knee.

Contraindication

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

Dona® should not be used in patients with shellfish allergies, as the active ingredient is derived from shellfish shells; such patients may be more likely to develop allergic reactions to glucosamine with possible exacerbation of 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, heart conduction diseases, atrioventricular block of the II-III degree, severe bradycardia, blood clotting disorders, Wolff-Parkinson-White syndrome, Adams-Stokes syndrome, history of seizures caused by the use of lidocaine, sick sinus syndrome, severe liver dysfunction, hypovolemia, myasthenia gravis, infections at the injection site, hypersensitivity to lidocaine and hypersensitivity to other amide-type anesthetics (since there is an increased risk of developing cross-hypersensitivity reactions).

Interaction with other medicinal products and other types of interactions

Mixing the contents of ampoules with other injectable drugs should be avoided.

In fact, the drug does not compete for absorption mechanisms; after absorption, it does not bind to plasma proteins, but is metabolized by incorporation as an endogenous substance into proteoglycans or is broken down without the participation of cytochrome system enzymes, as a result of which its interaction with other drugs is unlikely.

There is limited data on possible drug interactions with glucosamine, however, increases in INR (international normalized ratio) have been observed 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 increase the absorption and, consequently, the serum concentration of tetracyclines. However, the clinical significance of this interaction is likely to be limited.

The drug is compatible with nonsteroidal anti-inflammatory drugs and glucocorticosteroids.

The injectable form of the drug contains the excipient lidocaine. Cimetidine, peptidine, bupivacaine, propranolol, quinidine, disopyramide, amitriptyline, nortriptyline, chlorpromazine, imipramine increase the level of lidocaine in the blood serum, reducing its hepatic metabolism. Noradrenaline exhibits a synergistic effect when interacting with lidocaine.

MAO inhibitors should be used with caution, as they increase the risk of developing arterial hypotension and prolong the local anesthetic effect of the latter.

When used simultaneously with class IA antiarrhythmic drugs (including quinidine, procainamide, disopyramide), the QT interval is prolonged, and in very rare cases, AV block or ventricular fibrillation may develop.

The cardiotonic effect of cardiac glycosides is weakened.

When used simultaneously with sedatives, the sedative effects are enhanced.

Phenytoin enhances the cardiodepressive effect of lidocaine.

When used simultaneously with procainamide, delusions and hallucinations are possible.

Lidocaine may enhance the effect of drugs that cause neuromuscular blockade, since the latter reduce the conductivity of nerve impulses. Ethanol enhances the respiratory depressant effect of lidocaine.

Application features

The drug can only be administered by medical professionals.

In patients with a known risk factor for cardiovascular disease, monitoring of blood lipid levels is recommended, as hypercholesterolemia has been observed in several cases in patients receiving glucosamine.

It should be prescribed with caution to patients with glucose intolerance. At the beginning of treatment, it is advisable to monitor blood sugar levels in patients with diabetes.

There are known cases of exacerbation of asthma symptoms after starting glucosamine (symptoms of exacerbation disappeared after discontinuation of glucosamine). Therefore, the drug should be used with caution in the treatment of patients suffering from bronchial asthma, since such patients may be more prone to developing allergic reactions to glucosamine with possible exacerbation of symptoms of the disease. Special studies have not been conducted in patients with renal or hepatic insufficiency. However, the use of glucosamine in patients with severe hepatic or renal insufficiency should be monitored.

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

To avoid accidental intravasal administration of the drug, it is recommended to perform an aspiration test.

The safety of lidocaine anesthetics is questionable in patients prone to malignant hyperthermia, so their use should be avoided.

Before using lidocaine for heart diseases (hypokalemia reduces the effectiveness of lidocaine), it is necessary to normalize the level of potassium in the blood and monitor the ECG.

Serum creatine phosphokinase activity may increase after intramuscular injection of the drug, which may lead to an error in the diagnosis of acute myocardial infarction.

In case of sinus node dysfunction, prolongation of the P-Q interval, QRS widening, or in case of the occurrence or exacerbation of arrhythmia, the dose should be reduced or the drug should be discontinued.

Special caution should be exercised when using the drug in patients with circulatory failure, arterial hypotension, a history of arrhythmias, moderate hepatic and/or renal dysfunction. Given the presence of lidocaine in the composition, caution should also be exercised when prescribing to elderly patients, patients with epilepsy, with impaired cardiac conduction, and with respiratory failure.

Use during pregnancy or breastfeeding

There is no data on the use of the drug in pregnant or breastfeeding women, therefore the use of the drug is contraindicated in this category of patients.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the effect of the drug on the ability to drive and use other mechanisms have not been conducted. Dizziness, drowsiness, fatigue, cephalalgia or visual disturbances may develop during the use of glucosamine, so driving and operating other mechanisms should be avoided.

Method of administration and doses

For intramuscular use! The drug 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 prepared solution of the drug should be administered intramuscularly in 3 ml or 6 ml (solution A+B) 3 times a week for 4–6 weeks.

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

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

Glucosamine is not indicated for the treatment of acute pain.

Relief of symptoms (especially pain relief) is possible only after several weeks of treatment, and in some cases even after a longer time.

If no relief of symptoms occurs after 2–3 months of use, treatment should be reviewed.

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

Use in patients with renal and/or hepatic impairment. No studies on the kinetics of the drug 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 in such patients have not been established.

Overdose

No cases of overdose (accidental or intentional) have been reported. In case of overdose, the drug should be discontinued and, if necessary, symptomatic treatment should be carried out to restore water and electrolyte balance.

The injectable form of the drug contains the excipient lidocaine. The first symptoms of an overdose of lidocaine hydrochloride from the central nervous system may be numbness of the tongue and lips, excitement, euphoria, anxiety, tinnitus, dizziness, blurred vision, nystagmus, tremor, depression, drowsiness, loss of consciousness, up to coma, tonic-clonic convulsions. As is known from publications, symptoms of an overdose associated with lidocaine hydrochloride from the cardiovascular system and respiratory function may be a decrease in blood pressure, collapse, AV block and respiratory depression. It is necessary to monitor the patient's cardiovascular and respiratory function. A change in these parameters may indicate an overdose of the drug, so the patient should immediately be provided with oxygen access. All complications require symptomatic treatment.

Side effects

Criteria for assessing the frequency of adverse drug reactions:

On the part of the immune system: frequency unknown - allergic reactions (hypersensitivity);

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

Mental disorders: frequency unknown – insomnia;

from the nervous system: often - cephalalgia (headache), drowsiness, frequency unknown - dizziness;

On the part of the organs of vision: frequency unknown - visual impairment;

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

Vascular system: infrequently - redness;

from the digestive system: often - nausea, abdominal pain, indigestion, diarrhea, constipation, flatulence, heaviness in the stomach and pain, dyspepsia;

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

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

Hepatobiliary system: frequency unknown – jaundice;

general disorders and disorders at the injection site: often - fatigue, frequency unknown - edema, peripheral edema, injection site reaction;

Research results: frequency unknown – increased liver enzymes, increased blood glucose levels, increased blood pressure, fluctuations in INR (international normalized ratio).

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

The injectable form of the drug contains lidocaine. In exceptional cases, side effects characteristic of this component are possible:

from the digestive system: nausea, very rarely - vomiting;

from the nervous system: numbness of the tongue and lips, photophobia, diplopia, headache, confusion, muscle twitching, when used in high doses - tinnitus, excited state, anxiety, paresthesia, convulsions, loss of consciousness, coma, hyperacusis;

From the side of the organs of vision: visual impairment, conjunctivitis; when used in high doses - nystagmus;

Cardiovascular system: arterial hypotension, transverse heart block; frequency unknown - increased blood pressure; when used in high doses - arrhythmia, bradycardia, slowing of cardiac conduction, cardiac arrest, peripheral vasodilation, collapse, tachycardia, pain in the heart area;

Immune system disorders: immune system suppression, allergic reactions, including edema, skin reactions, itching; very rarely - urticaria, hypersensitivity reactions, including anaphylactoid reactions (including anaphylactic shock), generalized exfoliative dermatitis;

from the respiratory system: respiratory depression or respiratory arrest, shortness of breath;

others: feeling of heat, cold or numbness of the extremities, malignant hyperthermia; when used in high doses - rhinitis;

local reactions: tingling of the skin at the injection site, abscess, slight burning sensation (disappears with the development of the anesthetic effect within 1 minute), thrombophlebitis.

Expiration date

2 years.

The specified shelf life is valid if the packaging is intact and storage conditions are observed. Do not use the drug after the expiration date.

Storage conditions

Store out of the reach of children at a temperature not exceeding 25 °C.

Packaging

Ampoule A: made of brown transparent glass, contains 2 ml of active ingredient.

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

6 ampoules A and 6 ampoules B with solvent are packed in a PVC case and a cardboard box.

Vacation category

According to the recipe.

Producer

Biologichi Italia Laboratorios S.p.L.

Address

via Filippo Serpero, 2 - 20060 Masate (Milan), Italy.