Document: OSAFLEX 1178 mg powder for oral solution, sachet ENG SmPC change

• OSAFLEX powder for oral solution, sachet SmPC
• OSAFLEX 1178 mg powder for oral solution, sachet ENG SmPC

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Osaflex 1178 mg powder for oral solution, sachet.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet contains: 1884 mg mixture of glucosamine hydrochloride and anhydrous sodium sulphate, corresponding to 1500 mg glucosamine sulphate or 1178 mg glucosamine.

Excipients with known effect:

Each sachet contains 2.5 mg aspartame (E951), 151 mg sodium and 2,028 mg sorbitol (E420).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral solution, sachet.

White, crystalline powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

One sachet daily. The powder should be dissolved in a glass of water (250ml) and drunk.

Glucosamine is not indicated for the treatment of acute painful symptoms. Relief of symptoms (especially pain relief) may not be experienced until after several 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.

Osaflex should be taken at meals.

Additional information on special populations

Children and adolescents

Osaflex is not recommended for use in children and adolescents below the age of 18, due to lack of data on safety and efficacy.

Elderly

No specific studies have been performed in the elderly, but according to clinical experience dosage adjustment is not required when treating otherwise healthy, elderly patients.

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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Osaflex must not be given to patients who are allergic to shellfish as the active substance is obtained from shellfish.

4.4 Special warnings and precautions for use

A doctor must be consulted to rule out the presence of joint diseases for which other treatment should be considered.

In patients with impaired glucose tolerance, monitoring of the blood glucose levels and, where relevant, insulin requirements is recommended before start of treatment and periodically during treatment.

In patients with a known risk factor for cardiovascular disease, monitoring of the blood lipid levels is recommended, since hypercholesterolemia has been observed in a few cases in patients treated with glucosamine.

A report on exacerbated asthma symptoms triggered after initiation of glucosamine therapy has been described (symptoms resolved after withdrawal of glucosamine). Asthmatic patients starting on glucosamine should therefore be aware of potential worsening of symptoms.

Osaflex contains aspartame, a source of phenylalanine, which may be harmful for people with phenylketonuria.

Osaflex contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

One sachet contains 6,6 mmol (151 mg) sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

No specific drug interaction studies have been performed. However, the physico-chemical 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 degradated independently of the cytochrome system, is unlikely to give rise to drug interactions.

Increased effect of coumarin anticoagulants (e.g. warfarin) during concomitant treatment with glucosamine has been reported. Patients treated with coumarin anticoagulants should therefore be monitored closely when initiating or ending glucosamine therapy.

Concurrent treatment with glucosamine may increase the absorption and serum concentration of tetracyclines, but the clinical relevance of this interaction is probably limited.

Non-steroidal anti-inflammatory drugs (NSAIDs) can be administered together with glucosamine sulfate.

Due to limited documentation on potential drug interactions with glucosamine, one should generally be aware of altered response or concentration of concurrently used medicinal products.

4.6 Fertility, pregnancy and lactation

Fertility

In the rat, no adverse effects on fertility have been observed.

Pregnancy
Studies in animals did not show reproductive toxicity. There is no adequate data from the use of glucosamine in pregnant women. Osaflex should therefore not be used during pregnancy.

Breast Feeding

There is no data available on the excretion of glucosamine in human milk. Osaflex should therefore not be used during breastfeeding.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Glucosamine is not expected to have any effects on the ability to drive and use machines. If dizziness or drowsiness is experienced, car driving and the operating of machinery are not recommended.

4.8 Undesirable effects

The most common adverse reactions associated with treatment with glucosamine are nausea, abdominal pain, indigestion, constipation, and diarrhoea. In addition, headache, tiredness, rash, itching, and flushing have been reported. The reported adverse reactions are usually mild and transitory.

System Organ Class	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)	Not known (cannot be estimated from the available data)
Immune system disorders				Allergic reactions (Hypersensitivity)
Metabolism and nutrition disordesr				Diabetes inadequate control
Nervous system disorders	Headache Tiredness Somnolence			Dizziness
Respiratory, thoracic and mediastinal disorders				Asthma/ Asthma aggravated
Gastrointestinal disorders	Nausea Abdominal pain Indigestion Diarrhoea Constipation Flatulence			Vomiting
Skin and subcutaneous tissue disorders		Erythema Rash Itching Flushing		Angioedema Urticaria
General Disorders and Administration Site Conditions				Oedema, peripheral oedema
Hepatobiliary disorders				Hepatic enzyme increased and jaundice
Investigations				International normalized ratio fluctuation

Sporadic, spontaneous cases of hypercholesterolemia have been reported, but causality has not been established.

Reporting of suspected adverse events

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Signs and symptoms of accidental or intentional overdose with glucosamine might include headache, dizziness, disorientation, arthralgia, nausea, vomiting, diarrhoea or constipation. In case of overdose, treatment with glucosamine should be discontinued and standard supportive measures should be adopted as required.

One case of overdose has been reported in a 12-year old female who took orally 28 g of glucosamine hydrochloride. She developed arthralgia, vomiting and disorientation. The patient fully recovered.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other anti-inflammatory and anti-rheumatic agents, non-steroidal anti-inflammatory drugs.

ATC code: M01AX05

Mechanism of action:

Glucosamine is an endogenous substance. Exogenous administration of glucosamine to animals may increase the proteoglycan synthesis in cartilage and thereby inhibit the degradation of the cartilage. Long term studies indicate that glucosamine may have a positive effect on the metabolism of the cartilage.

However, the mechanism of action of glucosamine in humans is unknown. Clinical studies have shown that pain relief is expected to occur after some weeks of treatment with glucosamine.

Clinical efficacy and tolerability:

Glucosamine sulfate has demonstrated a good tolerability over both short-term and long-term treatment courses.

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

The distribution volume is approximately 5 litres. Glucosamine does not bind 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 pharmacokinetic of glucosamine was not investigated in patients with renal or hepatic insufficiency (See section 4.2).

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.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development. Carcinogenicity studies are not available.

Results from some in vitroand in vivostudies 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Aspartame (E951)

Sorbitol (E420)

Citric acid anhydrous

Macrogol 4000

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

One sachet made of a three-layered material comprising paper, aluminium and polyethylene.

Pack-sizes of 30 and 90 sachets. Not all pack-sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

To be completed nationally

8 MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2009-07-16

10 DATE OF REVISION OF THE TEXT

2016-10-26