Crystalline glucosamine sulfate.
VIARTRIL-S 500: Each capsule contains Crystalline glucosamine sulfate 618 mg, equivalent to glucosamine sulfate 500 mg and 128 mg sodium chloride.
VIARTRIL-S (POWDER FOR ORAL SOLUTION): Each sachet contains Crystalline glucosamine sulfate 1884 mg, equivalent to glucosamine sulfate 1500 mg and 384 mg sodium chloride.
Excipients/Inactive Ingredients: Hard capsules 500 mg: magnesium stearate and talcum.
Powder for oral solution: aspartame, sorbitol, polyethylene glycol and citric acid.
Pharmacotherapeutic group: Other anti-inflammatory and anti-rheumatic agents, nonsteroidal anti-inflammatory drugs. ATC code: M01AX05.
Pharmacology: Pharmacodynamics: Mechanism of action: Glucosamine sulfate is the sulfate salt of the endogenous amino-monosaccharide glucosamine, a normal constituent and preferred substrate for the synthesis of glycosaminoglycans and proteoglycans in cartilage matrix and synovial fluid.
Early in vitro studies have shown that glucosamine sulfate stimulates the synthesis of glycosaminoglycans and thus of articular cartilage proteoglycans. However, glucosamine sulfate has been more recently shown to inhibit the interleukin-1 β (IL-1 β) intracellular signaling pathway via blockade of the intracellular activation and nuclear translocation of nuclear factor kappa B (NF-KB) in the cartilage chondrocytes and other relevant cells.
Pharmacodynamic effects: Early in vitro studies have demonstrated that glucosamine sulfate has anabolic and anticatabolic effects on cartilage metabolism; sulfate ions may contribute to the pharmacological effects exerted by glucosamine by controlling the rate of glycosaminoglycan and proteoglycan synthesis and inhibiting cartilage degrading enzymes.
More recent studies have postulated that glucosamine sulfate decreases IL-1 β mediated effects, thus inhibiting a cascade of events that lead to joint inflammation and cartilage damage, such as the synthesis of metalloproteases, cyclooxygenase-2 and extracellular matrix proteins that are absent in normal cartilage, the release of nitric oxide and of prostaglandin E2, the inhibition of chondrocyte proliferation and the induction of cell death. Differently from NSAIDs, glucosamine does not directly inhibit cyclooxygenase activities. Human chondrocyte cell models have shown that crystalline glucosamine sulfate inhibits IL-1-stimulated gene expression at glucosamine concentrations similar to or lower than those found in plasma and synovial fluid of knee osteoarthritis patients receiving the drug at the therapeutic dose of 1500 mg once daily. Animal models confirmed the potential of glucosamine sulfate at human equivalent doses in delaying the progression of the disease and alleviating its symptoms.
Clinical efficacy and tolerability: The safety and efficacy of glucosamine sulfate have been confirmed in clinical trials for treatment up to three years.
Short- and medium-term clinical studies have shown that the efficacy of glucosamine sulfate on osteoarthritis symptoms is evident already after 2-3 weeks from the beginning of administration. However, differently from NSAIDS, glucosamine sulfate has shown a duration of effect which ranges from 6 months to 3 years.
Clinical studies of daily continuous crystalline glucosamine sulfate treatment up to 3 years have shown a progressive improvement on the symptoms and a delay of the joint structural changes, as determined by plain radiography.
Glucosamine sulfate has demonstrated a good tolerability over both short-term and long-term treatment courses.
Pharmacokinetics: Absorption: After oral administration of 14C-labelled glucosamine, the radioactivity is rapidly and almost completely (about 90%) absorbed systemically in healthy volunteers. The absolute bioavailability of glucosamine in man after administration of oral glucosamine sulfate was 44%, due to first-pass effect of the liver. After oral administration of daily repeated doses of 1500 mg of glucosamine sulfate in healthy volunteers under fasting conditions, the maximum plasma concentrations at steady-state (Cmax,ss) averaged 1602±426 ng/ml between 1.5-4 h (median: 3 h; tmax). At steady-state, the AUC of the plasma concentrations vs. time curve was 14564±4138 ng.h/ml. It is unknown if meals significantly affect the drug oral bioavailability. The pharmacokinetics of glucosamine are linear after once daily repeated administrations in the dose interval 750-1500 mg with deviation from linearity at the dose of 3000 mg due to lower bioavailability. No gender differences were found in man with regard to the absorption and to the bioavailability of glucosamine. The pharmacokinetics of glucosamine was similar between healthy volunteers and patients with osteoarthritis of the knee.
Distribution: After oral absorption, glucosamine is significantly distributed in extra-vascular compartments including synovial fluid with an apparent distribution volume 37-fold higher than the total body water in humans. Glucosamine does not bind to plasma proteins. It is therefore highly unlikely that glucosamine might produce displacement drug interaction when co-administered with other drugs that are highly bound to plasma proteins.
Metabolism: The metabolic profile of glucosamine has not been studied because being an endogenous substance; it is used as a building block for the biosynthesis of articular cartilage components. Glucosamine is mainly metabolized through the hexosamine pathway and independently of the cytochrome enzyme system.
Crystalline glucosamine sulfate does not act as an inhibitor nor as an inducer of the human CYP450 isoenzymes including CYP 3A4, 1A2, 2E1, 2C9 and 2D6 even when tested at concentrations of glucosamine 300-fold higher than the peak plasma concentrations observed in man after therapeutic doses of crystalline glucosamine sulfate. No clinically relevant metabolic inhibition and/or induction interactions are expected between crystalline glucosamine sulfate and co-administered drugs that are substrates of the human CYP450 isoforms.
Excretion: In man, the terminal elimination half-life of glucosamine from plasma is estimated at 15 h. After oral administration of 14C-labelled glucosamine to humans, the urinary excretion of radioactivity was 10±9% of the administered dose while fecal excretion was 11.3±0.1%. The mean urinary excretion of unchanged glucosamine after oral administration in man was about 1% of the administered dose suggesting that the kidney and the liver do not significantly contribute to the elimination of glucosamine and/or of its metabolites and/or its degradation products.
Special population: Patients with renal or hepatic impairment: The pharmacokinetics of glucosamine were not investigated in patients with renal or hepatic insufficiency. Studies in renal impaired patient were considered irrelevant due to the limited contribution of the kidney to the elimination of glucosamine. Similarly, studies in subjects with hepatic impairment were not conducted given glucosamine metabolic fate as an endogenous substance. Therefore, for what described previously and in light of the good safety and tolerability profile of glucosamine, no dose adjustment is considered necessary in subjects with renal or hepatic insufficiency.
Children and adolescents: The pharmacokinetics of glucosamine was not investigated in children and adolescents.
Elderly patients: No specific pharmacokinetic studies were performed in elderly however in the clinical efficacy and safety studies mainly elderly patients were included. Dose adjustment is not required.
Toxicology: Preclinical safety data: The toxicity of crystalline glucosamine sulfate in animals was extremely low after single and repeated dosing studies. The maximum tested doses have shown no or minimal effects; these were reversible and there was no detectable target organ toxicity. The highest tested dose in animals corresponds to more than one hundred times the oral dose recommended for human use.
Crystalline glucosamine sulfate was not mutagenic in vitro and in vivo. Studies on carcinogenicity are not available.
In the rat, adverse effects on fertility, embryo/foetal development and postnatal development were not observed. In female rabbits, no teratogenic effects were reported for crystalline glucosamine sulfate.
Results from some in vitro and in vivo studies in animals, have shown that i.v. infusion of glucosamine in suprapharmacological concentrations reduces insulin secretion, probably via inhibition of glucokinase in the beta cells, and induces insulin resistance in peripheral tissues. The relevance in humans is inconclusive. Experimental studies in humans as well as clinical studies in healthy subjects and in individuals with diabetes, or with impaired glucose tolerance didn't show effects on fasting blood glucose levels, glucose metabolism, or insulin sensitivity.
Relieve symptoms of osteoarthritis.
Powder for oral solution: The content of one sachet, equivalent to 1500 mg of active ingredient, dissolved in a glass of water, is taken once daily, preferably at meals.
Hard capsules: 500 mg glucosamine sulfate.
One hard shell gelatin capsule, equivalent to 500 mg of glucosamine sulfate, is taken three times daily, preferably at meals.
Children and Adolescents: Efficacy and safety has not been established in children and adolescents, therefore glucosamine sulfate should not be used in children and adolescents below the age of 18.
Elderly: No specific studies have been performed in elderly, but according to clinical experience, dosage adjustment is not required when treating otherwise healthy, elderly patients.
Patients with impaired renal and/or liver function: In patients with impaired renal and/or liver function no dose recommendations can be given, since no studies have been performed (see also Precautions).
Glucosamine is not indicated for the treatment of acute painful symptoms. Relief of symptoms (especially pain relief) may not be experienced until after some weeks of treatment and in some cases even longer. If no relief of symptoms is experienced after 2-3 months, continued treatment with glucosamine should be re-evaluated.
No cases of accidental or intentional overdose are known. Based on acute and chronic toxicity studies in animals, symptoms of toxicity are not likely to occur at doses up to 200 times the therapeutic dose.
If overdose occurs treatment should be discontinued, symptomatic and standard supportive measures should be adopted as required e.g. act to restore the hydroelectrolytic balance.
Hypersensitivity to glucosamine or to any of the excipients listed in Description.
The product should not be given to patients who are allergic to shellfish as the active ingredient is obtained from shellfish.
Powder for oral solution: The powder for oral solution contains aspartame and is therefore contraindicated in patients with phenylketonuria.
The powder for oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this pharmaceutical form.
In asthmatic patients the product should be used with caution as these patients could be more susceptible to develop an allergic reaction to glucosamine with a possible exacerbation of their symptoms.
The sodium content of oral formulations (151 mg for the 1500 mg daily dose) should be taken into consideration by patients on a controlled sodium diet.
No special studies were performed in patients with renal or hepatic insufficiency. The toxicological and pharmacokinetic profile of the product does not indicate limitations for these patients. However, administration to patients with severe hepatic or renal insufficiency should be under medical supervision.
Caution is advised in treatment of patients with impaired glucose tolerance. Closer monitoring of blood sugar levels may be necessary in diabetics at the beginning of treatment.
The presence of other joint disease which would require alternative treatment should be excluded.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. No important effects on the CNS or motor system are known that might impair the ability to drive or use machines. However, caution is recommended if headache, somnolence, tiredness, dizziness or visual disturbances are experienced.
Use in Children: Glucosamine should not be used in children and adolescents under the age of 18 since safety and efficacy have not been established.
Pregnancy: There is no adequate data from the use of glucosamine in pregnant women. From animal studies only insufficient data are available. Glucosamine should not be used during pregnancy.
Breast Feeding: There is no data available on the excretion of glucosamine in human milk. The use of glucosamine during breastfeeding is therefore not recommended as there is no data on the safety of the newborn.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).
The following undesirable effects were observed whereas the frequency of undesirable effect is not known:
The most common adverse reactions associated with oral administration are nausea, abdominal pain, dyspepsia, flatulence, constipation and diarrhoea. The reported adverse reactions are usually mild and transitory.
In the following table, adverse reactions have been grouped on the basis of "Internationally agreed Order of Importance" System Organ Class (SOC) MedDRA Classification. In each SOC, undesirable effects were classified according to their occurrence frequency. In each frequency class the undesirable effects are reported according to a decreasing order of severity. (See table.)
Click on icon to see table/diagram/image
Cases of hypercholesterolaemia have been reported, but a causal link has not been demonstrated.
No specific drug interaction studies have been performed. However, the physicochemical and pharmacokinetic properties of glucosamine sulfate suggest a low potential for interactions. In addition glucosamine sulfate was found not to inhibit or to induce any of the major human CYP450 enzymes. In fact, the compound does not compete for absorption mechanisms and, after absorption, does not bind to plasma proteins, while its metabolic fate as an endogenous substance incorporated in proteoglycans or degraded independently of the cytochrome enzyme system, is unlikely to give rise to drug interactions. Due to the limited amount of information regarding drug interactions. Should be aware about the use with other drugs.
An increased effect of coumarinic anticoagulants during concomitant treatment with glucosamine sulfate has been reported. Therefore, a closer monitoring of the coagulation parameters may be considered in these patients when initiating or ending glucosamine therapy.
The oral administration of glucosamine sulfate can enhance the gastrointestinal absorption of tetracyclines but the clinical relevance of this interaction is probably limited.
Incompatibilities: Not applicable.
Store below 30°C.
Shelf-life: VIARTRIL-S 500: 3 years.
VIARTRIL-S (POWDER FOR ORAL SOLUTION): 3 years.
M01AX05 - glucosamine ; Belongs to the class of other non-steroidal antiinflammatory and antirheumatic products.
Cap 500 mg (hard gelatin, snap-fit, red-red (size 0), contains white powder, with the logo ROTTA printed in black ink on the body and head) x 90's, 500's. Powd for oral soln 1,500 mg (white) x 30's.