DESCRIPTION

FLEXOST is indicated for the treatment and prevention of osteoarthritis. Its composition is formulated from natural products Glucosamine sulfate 220mg, chondroitin 220mg.

CLINICAL PHARMACOLOGY

Mechanism of Action

The benefit of Flexost in patients with osteoarthritis is the result of a number of effects including its anti-inflammatory activity, the stimulation of the synthesis of proteoglycans, ] and the decrease  in catabolic activity of chondrocytes inhibiting the synthesis of proteolytic enzymes and other substances that contribute to damage cartilage matrix and cause death of articular chondrocytes

Pharmacokinetics

Absorption

FLEXOST well absorbed from an oral dose, with about 90 percent gets absorbed in the small intestine, and from there it is transported via the portal circulation to the liver. Significant fraction of the ingested glucosamine is catabolized by the first/pass metabolism in the liver.   Free glucosamine is not detected in the serum after oral intake, and it is not know how much of the ingested dose is take up in the joints in humans. Some uptake in articular cartilage is seen in human studies.    After oral administration, glucosamine is rapidly absorbed so that some samples taken five and ten minutes after administration contained the highest observed concentrations as compared with the remaining samples (fig  1 ). The oral doses, however, were only 21% bioavailable.

The rate and extent of absorption of FLEXOST are not influenced by food; thus FLEXOST may be taken with or without food.

Distribution

The mean apparent volume of distribution following oral administration is approximately 52 L, indicating that FLEXOST is distributed into tissues. At therapeutic concentrations, 94% of FLEXOST in plasma is bound to proteins.  In which radioactivity rapidly appears in liver, kidneys and other tissues, including the articular cartilage.

Metabolism

FLEXOST is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations. 

After a single dose of 440 mg CGS traced with 14C-Gl, radioactivity appeared incorporated in plasma globulins with a lag time of 1.5 h and increasing with a rate of 0.24 h-1. The peak was reached at the 9th h after administration. The radioactivity then was eliminated with a t1/2 of 58 h. The absolute oral bioavailability evaluated on the AUCs of the globulin-incorporated radioactivity was 44%. The fecal excretion in 120 h was 11.3% of the administered dose showing that at least 88.7% of the administered dose was absorbed through the gastrointestinal tract.

Special Populations

Geriatrics:  In studies no difference has been experienced on geriatrics  then normal adult population. 

Pediatrics: FLEXOST has not been evaluated in individuals less than 16 years old.

Patients with Diabetes Mellitus:  In male patients with diabetes mellitus after a 420 mg FLEXOST dose,  While there have been concerns originating from in vitro studies and intravenous

administration to rodents that glucosamine might adversely affect glucose metabolism, careful studies in humans show no adverse effects on glucose homeostasis. Overall, 16 studies including 854 subjects for 37 weeks reported no adverse effects on glucose metabolism. Glucosamine

is well tolerated by humans for periods of up to three years. While the usual dose is 1500 mg/day in three doses, doses of up to 3200 mg/day were well tolerated. Healthy young subjects had no adverse effects from infusion of 9.7 g and only one of five developed a headache when 30.5 g was infused. This suggests that humans tolerate intake of at least 184 mg/kg/day of glucosamine daily. In 13 clinical trials reporting safety information there were no adverse effects of glucosamine on blood chemistries, hematologic parameters, urinalysis, occult blood in feces, or cardiovascular parameters. Symptoms or side effects were reported significantly less frequently with glucosamine than with placebo.  (See Case Studies) No dose adjustment is warranted

Elimination

Following a single dose of 440mg  FLEXOST in normal weight and obese subjects, fecal and urine excretion of the unabsorbed product was found to be the major route of elimination.

Glucosamine is rapidly eliminated so that for most samples, the plasma concentration falls below the detectable level of 0.63 g.mL-1 in 6 h, post-dose (fig 2).