Artima

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARTIMA

Composition:

Ampoule A

Active ingredient: sodium chloride glucosamine sulfate;

1 ml of solution contains 251.25 mg of sodium chloride glucosamine sulfate, equivalent to 200 mg of glucosamine sulfate and 51.25 mg of sodium chloride;

Excipients: lidocaine hydrochloride, 1 M sulfuric acid solution, water for injections;

Ampoule B (solvent)

Excipients: diethanolamine, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: Ampoule A, made of colored transparent glass, contains a clear, colorless or light yellow to light brown liquid;

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

Ampoule A + B (injection solution): a colorless or light yellow to light brown clear 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 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 intrinsic 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 demonstrated that exogenous administration of glucosamine sulfate stimulates the biosynthesis of proteoglycans, which is impaired in osteoarthritis, promotes fixation of sulfur ions during glycosaminoglycan synthesis, and improves joint cartilage trophism.

Subsequent studies showed 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. This action results in a moderate anti-inflammatory effect observed in in vivo animal models, including certain cases of experimental osteoarthritis, even without inhibition of cyclooxygenase, unlike the mechanism of nonsteroidal anti-inflammatory drugs (NSAIDs).

More recent studies have shown that most of the above-mentioned 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 aforementioned 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 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 treatment 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 progressively increasing efficacy in terms of 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-labeled glucosamine, radioactively labeled components are rapidly and almost completely absorbed at the systemic level. In humans, approximately 90% of the radioactively labeled dose is absorbed. Absolute bioavailability of glucosamine in rats after oral administration of glucosamine sulfate was 26%, due to a 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 AUC (area under the plasma concentration-time curve) 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 detected.

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

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-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 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 its metabolites 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, showing no evidence of accumulation or reduced bioavailability compared to the pharmacokinetic profile observed after single-dose 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 group, the mean plasma concentration 3 hours after the last 1500 mg dose during 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 favorable safety profile of the drug 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 medicinal product.

Clinical characteristics.

Indications.

For relief of symptoms in mild to moderate knee osteoarthritis.

Contraindications.

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

The medicinal product Artima should not be used in patients with allergy to shellfish, as the active ingredient is derived from shellfish exoskeletons. Such patients are more prone to allergic reactions to glucosamine, potentially exacerbating disease symptoms.

The injectable form of the medicinal product 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, atrioventricular (AV) block of degree II–III, severe bradycardia, coagulation disorders, Wolff–Parkinson–White syndrome, Adams–Stokes syndrome, history of seizures induced by lidocaine, sinus node dysfunction syndrome, severe hepatic impairment, hypovolemia, myasthenia gravis, 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 Artima ampoules with other injectable medicinal products should be avoided.

Specific studies on drug interactions have not been conducted. However, based on the physicochemical and pharmacokinetic properties of glucosamine sulfate, a low potential for interactions can be assumed. 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, 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.

Data on possible interactions between medicinal products and glucosamine are limited; however, an increase in INR (international normalized ratio) 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 product is compatible with nonsteroidal anti-inflammatory drugs and glucocorticoids.

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

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.

Hallucinations and delirium may occur when lidocaine is used concomitantly with procainamide.

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

Special precautions.

The medicinal product should be administered only 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.

Exacerbation of asthma symptoms has been reported after initiating glucosamine therapy (symptoms resolved after discontinuation of glucosamine). Therefore, the product should be used cautiously in patients with bronchial asthma, as such patients are more prone 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 use in patients with severe hepatic or renal insufficiency 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 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 product, which may 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 product discontinued.

Particular caution should be exercised when administering the product to patients with circulatory insufficiency, arterial hypotension, history of arrhythmias, or moderate impairment of liver and/or kidney function. Due to the presence of lidocaine in the product, caution is also required when prescribing 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 medicinal product during pregnancy or breastfeeding; therefore, its use is contraindicated in these patient groups.

Ability to influence reaction rate while driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted. Dizziness, somnolence, fatigue, headache, or visual disturbances may occur during glucosamine use; 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 the contents of ampoule B (solvent, 1 ml) with the contents of ampoule A (drug solution, 2 ml) in a single syringe.

Administer the prepared drug solution intramuscularly at a dose of 3 ml or 6 ml (ampoule 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.

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

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

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

Children

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

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, agitation, euphoria, anxiety, tinnitus, dizziness, blurred vision, nystagmus, tremor, depression, drowsiness, loss of consciousness, up to coma, and tonic-clonic seizures. Symptoms of 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 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, 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, 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, injection site reaction;

Investigations: frequency not known — 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 medicinal product contains lidocaine. In exceptional cases, 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; when used in high doses — tinnitus, agitation, anxiety, paresthesia, seizures, loss of consciousness, coma, hyperacusis;

Eye disorders: visual disturbances, conjunctivitis; when used in high doses — nystagmus;

Psychiatric disorders: frequency not known — sleep disturbances;

Cardiovascular disorders: arterial hypotension, atrioventricular block; frequency not known — 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, pruritus; 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, mild burning sensation (disappears with development of anesthetic effect within 1 minute), thrombophlebitis.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy through 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 at a temperature of 2 °C to 8 °C.

Keep out of the reach and sight of children.

Packaging.

2 ml of solution in a vial made of colored transparent glass (vial A), in combination with 1 ml of solvent in a vial made of colorless transparent glass (vial B).

5 vials A and 5 vials B per pack; 5 vials A and 5 vials B in blisters, 1 blister with vials A and 1 blister with vials B per pack.

Prescription status. Prescription only.

Manufacturer.

LLC "BIOLIK PHARMA".

Manufacturer's address and location of business activity.

Legal entity address:

70 Pomirky Street, Kharkiv, Kharkiv region, 61070, Ukraine.

Address of business activity:

Pomirky-70, building without number, Kharkiv, Kharkiv region, 61070, Ukraine.