Droglican®

Droglican®

Symptomatic treatment of osteoarthritis of the knee in patients with moderate to severe pain

This drug (with this brand and datasheet) is registered in Spain, but is also approved in other countries. For more information please contact us.

Droglican®

DROGLICAN is indicated for the symptomatic treatment of osteoarthritis of the knee in patients with moderate to severe pain in which treatment combined with chondroitin sulfate and glucosamine is indicated.

Pharmaco-therapeutic group: Other specific anti-rheumatic agents, code ATC M01CX.

DROGLICAN is composed of chondroitin sulfate, a polysaccharide of the glycosaminoglycans group (in the form of glucosamine hydrochloride), a natural amino monosaccharide.

Chondroitin sulfate is one of the main elements that form cartilage and combines with a central protein, forming proteoglycan, which gives cartilage its mechanical and elastic properties. The therapeutic activity of chondroitin sulfate in patients with osteoarthritis is due to several factors: anti-inflammatory activity [measured by the interleukin inhibition-1â (IL-1â), metaloprotease-3 (MMP-3) and prostaglandin E2 (PGE2)]; stimulation of the synthesis of proteoglicans and hyaluronic acid; inhibition of the cartilage's proteolytic enzymes (including collagenase, elastase, proteoglycanase, phospholipase A2, N-acetylglucosaminidase, etc.) and inhibition of the nuclear translocation of the nuclear factor kappa B (NF-êB) involved in certain chronic inflammatory processes.

Glucosamine is an endogenous substance and a normal constituent of the polysaccharide chain of the cartilage matrix and of the glycosaminoglycans of the synovial liquid. In vitro and in vivo studies have demonstrated that glucosamine stimulates the physiological synthesis of glycosaminoglicans and proteoglycans by means of chondrocytes and of hyaluronic acid by means of sinoviocytes. Subsequent studies have shown that glucosamine can inhibit the synthesis of certain substances like superoxide radicals and the activity of the lysosomal enzymes and of the joint cartilage destroying enzymes such as collagenase and phospholipase A2.

It has been observed that chondroitin sulfate and glycosamine hydrochloride promote the formation of new cartilage in vitro by means of stimulation of the synthesis of collagen and proteoglycans; an effect that presents synergy when both are used in combination.

Clinical efficacy and safety:

Several studies have evaluated the effect of chondroitin sulfate and glucosamine in combination with positive results on osteoarthritis symptoms. Below we set out the results of the biggest clinical trial conducted with both drugs separately and in combination. A randomized, double-blind, multi-center trial on a total of 1583 patients with osteoarthritis of the knee, (NIH, USA; N Engl J Med 354;8;2006) studied the effect of 5 treatments (500 mg glucosamine 3 times a day; 400 mg chondroitin sulfate 3 times a day; 200 mg celecoxib a day; 500 mg glucosamine + 400 mg chondroitin sulfate 3 times a day; placebo) on pain reduction over 6 months. The results showed that glucosamine (64.0%), chondroitin sulfate (65.4%) or the combination of both (66.6%), did not cause a significant reduction of pain compared to the placebo (60%) in the entire population of the study. The researchers stated that this lack of response could be due to the fact that most of the patients had mild pain (therefore little ability to discern the improvement in the pain) and due to a much higher response to the placebo (60%) than that expected (35%). However, the analysis on the group of patients with moderate to severe pain, suggests that combined treatment with chondroitin sulfate + glucosamine significantly reduces pain compared to the placebo (79.2% vs. 54.3%, p=0.002) in patients suffering from osteoarthritis of the knee. In this same clinical trial a significant reduction in the swelling was observed, accompanied or otherwise by joint effusion (synovitis), in the group treated with chondroitin sulfate, compared to placebo (p= 0.01).

Similarly, the following secondary evaluation parameters also improved in a statistically significant way (treatment of the combination compared to the placebo) in the group of patients with moderate to severe pain: the pain and function subscales of the WOMAC (Western Ontario and McMaster Universities) index; the overall score of the WOMAC index; the 50% reduction of the WOMAC index; the OMERACT-OARSI response criteria (group of response criteria established for clinical trials on ostearthritis by the International Ostearthritis Research Society).

QUALITATIVE AND QUANTITIVE COMPOSITION

Each capsule contains 200 mg of chondroitin sulfate and 250 mg of glucosamine hydrochloride. To consult the complete list of excipients, see the List of excipients section.

PHARMACEUTICAL FORM

Hard capsule: The capsule is hard gelatin of a Turquoise color.

CLINICAL DATA 
Therapeutic Indications of DROGLICAN hard capsules 200 mg/250 mg

DROGLICAN is indicated for the symptomatic treatment of osteoarthritis of the knee in patients with moderate to severe pain in which treatment combined with chondroitin sulfate and glucosamine is indicated.

Dosage and administration of DROGLICA hard capsules 200 mg/250 mg

Adults (including the elderly):

The recommended dose is 2 capsules 3 times a day (1,200 mg/day of chondroitin sulfate and 1,500 mg/day of glucosamine hydrochloride) to be administered for a period of at least 6 months.

Pediatric population:

DROGLICAN is not recommended for use in children and adolescents under 18 years of age, due to the absence of data on its safety and efficacy.

Kidney and/or liver insufficiency:

No recommendations can be given in patients with kidney or liver insufficiency as no studies have been conducted.

The capsules can be taken before, during or after meals. It is recommended for patients who normally have gastric intolerance to medicines in general to take it after the meal.

The capsules must be taken without chewing and with a sufficient quantity of liquid.

Contraindications of DROGLICAN hard capsules 200 mg/250 mg

Hypersensitivity to the active principle or any of the excipients.

DROGLICAN must not be administered to patients allergic to seafood as one of the main active principles (glucosamine) is obtained from seafood.

Warnings and Precautions for DROGLICAN hard capsules 200 mg/250 mg

In patients with glucose intolerance it is recommended to monitor glucose levels and, where appropriate, the insulin requirements before starting the treatment and regularly during it.

Heart and/or kidney insufficiency:

On very rare occasions (<1/10,000) some kind of edema and/or water retention has been described in patients treated with chondroitin sulfate. This phenomenon can be attributed to the chondroitin sulfate's osmotic effect.

Interactions with other medicines of DROGLICAN hard capsules 200 mg/250 mg

No studies have been conducted on interaction between glucosamine and chondroitin.

However, in rats and at doses much higher than those recommended, 50 mg/kg/day (equivalent to 4,000 mg in humans /day), it was observed that a slight platelet antiaggregate activity may exist, which should be taken into account in the case of use concurrently with platelet antiaggregates (aspirin, dipiridamol, clopidrogel, ditazol, triflusal and ticlopidine). In the entire clinical and pharmacovigilance investigation on chondroitin sulfate carried out at the recommended dose, no effects whatsoever were detected at platelet level.

There is limited data on possible interactions of medicines with glucosamine, but increases in the INR parameter with coumarin anticoagulants (warfarin and acenocoumarol) have been described. Patients treated with coumarin anticoagulants must therefore be closely monitored at the start and at the end of treatment.

Glucosamine can increase the absorption and serum concentrations of tetracyclines and reduce the absorption of penicillins and chloranphenicol.

Warnings and Precautions for DROGLICAN hard capsules 200 mg/250 mg

Pregnancy

Sufficient data does not exist on use of chondroitin sulfate and glucosamine in pregnant women. Studies on animals are insufficient to determine reactions in pregnancy and/or on embryonic, fetal or post-natal development. Therefore, DROGLICAN must not be used during pregnancy.

Breast-feeding

There is no information available on the excretion of chondroitin sulfate and glucosamine in breast milk. Therefore, and due to the lack of safety information for the new-born infant, use of CONDROSAN during the breast-feeding period is not recommended.

Effects on driving ability of DROGLICAN hard capsules 200 mg/250 mg

No studies have been conducted on the effects on driving ability and using machinery. If you feel faint or sleepy, it is not recommended to drive vehicles or operate machinery.

Pharmacokinetic properties of DROGLICAN hard capsules 200 mg/250 mg

Frequent (≥1/100 to <1/10); Infrequent (≥1/1,000, <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10.000); Unknown (cannot be estimated on the basis of the data available).

In the GAIT (Glucosamine/Chondroitin Arthritis Intervention Trial), a double-blind, multi-center trial controlled with placebo and active group, in which 317 patients were treated with the chondroitin sulfate and glucosamine hydrochloride combination, most of the adverse reactions experienced were of a mild and transitory nature.

Next we list, classified by organs and systems, the adverse reactions experienced in at least 2 patients of the study in the group treated with the chondroitin sulfate and glucosamine hydrochloride combination, considered to possibly be related to the treatment. The adverse reactions are listed in descending order of severity within each frequency interval.

Additional explorations

Rare: Increased hepatic enzymes, abnormal urine analysis

Infections and infestations

Rare: Infection of the upper respiratory tract, infection of the urine tract

Nervous system disorders

Frequent: Rare Cefalea: Dysgeusia

Gastrointestinal disorders

Frequent: Diarrhea, nausea, dyspepsia, flatulence. Rare: Gastro-oesofagal reflux, pain in the upper abdomen, constipation, abdominal discomfort, abdominal distension

General disorders and alterations in the place of administration

Rare: Fatigue

Muscular-skeletal disorders and conjunctive tissue disorders

Rare: Muscle cramp, pain in an extremity

Below we list, classified by organs and systems, the adverse reactions described in the chondroitin sulfate technical sheet.

Immunological system disorders

Very rare: Hypersensitivity

Gastrointestinal disorders

Rare: Nausea, gastrointestinal disorder

General disorders and alterations in the place of administration

Very rare: Edema, liquid retention

Below we list, classified by organs and systems, the adverse reactions described in the chondroitin sulfate technical sheet.

Skin and subcutaneous tissue disorders

Infrequent: Rash, itching, flushing

Unknown: Angioedema, urticaria

Nervous system disorders

Frequent: Cefalea, fatigue

Unknown: Fainting

Gastrointestinal disorders

Frequent: Nausea, abdominal pain, dyspepsia, diarrhea, constipation

Unknown: Vomiting

General disorders and alterations in the place of administration

Unknown: Edema, peripheral edema

Overdose of DROGLICAN hard capsules 200 mg/250 mg

No overdose studies have been conducted

The signs and symptoms produced by an accidental or intentional overdose of glucosamine can include headache, vertigo, disorientation, arthralgia, nausea, vomiting and diarrhea.

In clinical studies, one out of five healthy young persons experienced headache following infusion of up to 30 g of glucosamine. A case of overdose was also reported in a 12-year-old girl who ingested 28 g of glucosamine hydrochloride. The symptoms that appeared were arthralgia, vomiting and disorientation. The patient recovered completely.

In the event of an overdose, the treatment must be suspended and the necessary support measures adopted.

Going by the acute and chronic toxicity results, toxic symptoms are not to be expected, even after a high dose.

PHARMACOLOGICAL PROPERTIES 
Pharmacokinetic properties of DROGLICAN hard capsules 200 mg/250 mg

Pharmaco-therapeutic group: Other specific anti-rheumatic agents, code ATC M01CX.

DROGLICAN is composed of chondroitin sulfate, a polysaccharide of the glycosaminoglycans group (in the form of glucosamine hydrochloride), a natural amino monosaccharide.

Chondroitin sulfate is one of the main elements that form cartilage and combines with a central protein, forming proteoglycan, which gives cartilage its mechanical and elastic properties. The therapeutic activity of chondroitin sulfate in patients with osteoarthritis is due to several factors: anti-inflammatory activity [measured by the interleukin inhibition-1â (IL-1â), metaloprotease-3 (MMP-3) and prostaglandin E2 (PGE2)]; stimulation of the synthesis of proteoglicans and hyaluronic acid; inhibition of the cartilage's proteolytic enzymes (including collagenase, elastase, proteoglycanase, phospholipase A2, N-acetylglucosaminidase, etc.) and inhibition of the nuclear translocation of the nuclear factor kappa B (NF-êB) involved in certain chronic inflammatory processes.

Glucosamine is an endogenous substance and a normal constituent of the polysaccharide chain of the cartilage matrix and of the glycosaminoglycans of the synovial liquid. In vitro and in vivo studies have demonstrated that glucosamine stimulates the physiological synthesis of glycosaminoglicans and proteoglycans by means of chondrocytes and of hyaluronic acid by means of sinoviocytes. Subsequent studies have shown that glucosamine can inhibit the synthesis of certain substances like superoxide radicals and the activity of the lysosomal enzymes and of the joint cartilage destroying enzymes such as collagenase and phospholipase A2.

It has been observed that chondroitin sulfate and glycosamine hydrochloride promote the formation of new cartilage in vitro by means of stimulation of the synthesis of collagen and proteoglycans; an effect that presents synergy when both are used in combination.

Clinical efficacy and safety:

Several studies have evaluated the effect of chondroitin sulfate and glucosamine in combination with positive results on osteoarthritis symptoms. Below we set out the results of the biggest clinical trial conducted with both drugs separately and in combination. A randomized, double-blind, multi-center trial on a total of 1583 patients with osteoarthritis of the knee, (NIH, USA; N Engl J Med 354;8;2006) studied the effect of 5 treatments (500 mg glucosamine 3 times a day; 400 mg chondroitin sulfate 3 times a day; 200 mg celecoxib a day; 500 mg glucosamine + 400 mg chondroitin sulfate 3 times a day; placebo) on pain reduction over 6 months. The results showed that glucosamine (64.0%), chondroitin sulfate (65.4%) or the combination of both (66.6%), did not cause a significant reduction of pain compared to the placebo (60%) in the entire population of the study. The researchers stated that this lack of response could be due to the fact that most of the patients had mild pain (therefore little ability to discern the improvement in the pain) and due to a much higher response to the placebo (60%) than that expected (35%). However, the analysis on the group of patients with moderate to severe pain, suggests that combined treatment with chondroitin sulfate + glucosamine significantly reduces pain compared to the placebo (79.2% vs. 54.3%, p=0.002) in patients suffering from osteoarthritis of the knee. In this same clinical trial a significant reduction in the swelling was observed, accompanied or otherwise by joint effusion (synovitis), in the group treated with chondroitin sulfate, compared to placebo (p= 0.01).

Similarly, the following secondary evaluation parameters also improved in a statistically significant way (treatment of the combination compared to the placebo) in the group of patients with moderate to severe pain: the pain and function subscales of the WOMAC (Western Ontario and McMaster Universities) index; the overall score of the WOMAC index; the 50% reduction of the WOMAC index; the OMERACT-OARSI response criteria (group of response criteria established for clinical trials on ostearthritis by the International Ostearthritis Research Society).

Pharmacokinetic properties of DROGLICAN hard capsules 200 mg/250 mg

Combination:

No pharmacokinetic studies have been conducted on the combination.

Chondroitin sulfate:

Several studies signal that chondroitin sulfate's bioavailability oscillates between 15 and 24% of the dose administered orally. Of the absorbed fraction of chondroitin sulfate, 10% is in the form of chondroitin sulfate and 90% in the form of depolymerized derivatives of less molecular weight, which suggests it is subject to a first step effect. After oral administration of chondroitin sulfate, the maximum concentration of chondroitin sulfate in blood is reached in 4 hours.

In blood, 85% of the concentration of chondroitin sulfate and of the depolymerized derivatives is fixed in different plasma proteins. The distribution volume of chondroitin sulfate is relatively small, approximately 0.3 l/kg. In man, chondroitin sulfate presents an affinity with joint tissue. In rats, as well as joint tissue, chondroitin sulfate also presents an affinity with the wall of the small intestine, liver, brain and kidneys.

At least 90% of the dose of chondroitin sulfate is metabolized primarily by lysosomal sulfatase, to then be depolymerized by hyaloronidase, â-glucuronidase and â-N-acetilhexosaminidase. The liver, kidneys and other organs participate in the depolymerization of chondroitin sulfate. No interactions with other medicines have been described at metabolization level. Chondroitin sulfate is not metabolized by cytochrome P450 enzymes.

The systemic lightening of chondroitin sulfate is 30.5 ml/min or 0.43 ml/min/kg. The average lifetime oscillates between 5 and 15 hours depending on the experimental protocol. The most important route by which chondroitin sulfate and the depolymerized derivatives are eliminated is the kidney.

The kinetics of chondroitin sulfate is first order up to single doses of 3,000 mg. Multiple doses of 800 mg in patients with osteoarthritis does not alter the kinetics order of chondroitin sulfate.

Glucosamine:

Two glucosamine salts, sulfate and hydrochloride are used for therapeutic purposes and are considered a prodrug: both salts completely dissolve in the stomach where they are converted into glucosamine free base for its absorption in the small intestine.

The pharmacokinetics of 14C-glucosamine was studied in healthy volunteer men, with a single dose administered intravenously, intramuscularly or orally. After oral administration, free glucosamine was not detectable in plasma. The radioactivity incorporated in the plasma proteins followed pharmacokinetic steps similar to those obtained after i.v. or i.m. administration, but the plasma concentrations were less than those obtained after parenteral administration, probably due to a first pass hepatic effect.

After oral administration, approximately 90% of the glucosamine sulfate administered is absorbed in the gastrointestinal tract.

There is no information on the rest of the pharmacokinetic parameters in humans but they have been widely studied in rats and dogs, using uniformly marked  14C-glucosamine.

The free 14C-glucosamine quickly disappears from the plasma and concurrently the radioactivity appears incorporated in the plasma globules, in the liver and in the kidney and also in the joint tissue where it is found in higher concentrations than in the blood.

Glucosamine is excreted in the urine in the 48 hours following oral administration, in the proportion of approximately 5% of the administered dose. The main quantity of glucosamine administered orally is metabolized in the tissues and is eliminated as COin exhaled air.

Repeated daily administration of the marked 14C-glucosamine sulfate shows that the stationary state in blood is reached during the third day of administration and that it does not accumulate after this period.

Pre-clinical data on the safety of DROGLICAN hard capsules 200 mg/250 mg

The data from the non-clinical studies conducted with chondroitin sulfate and glucosamine do not show special risks for human beings according to the following studies available:

• For chondroitin sulfate according to conventional pharmacological studies on safety, toxicity at repeated dose, mutagenicity, genotoxicity and toxicity for reproduction.

• For glugosamine according to conventional pharmacological studies on safety, toxicity at repeated dose and genotoxicity.

The results obtained in in vitro studies in animals, have demonstrated that glucosamine reduces insulin secretion and increases resistance to insulin, probably due to glucokinase inhibition in the beta cells. The clinical relevance of this fact is unknown.

PHARMACEUTICAL DATA 
List of excipients of DROGLICAN hard capsules 200 mg/250 mg

Per capsule: magnesium stearate. Composition of the capsule: gelatin, titanium dioxide, carmin indigo (E132).

Incompatibilities of DROGLICAN hard capsules 200 mg/250 mg

Not applicable.

Validity period of DROGLICAN hard capsules 200 mg/250 mg

3 years. 

Special storage precautions for DROGLICAN hard capsules 200 mg/250 mg

Do not keep at temperatures above 30ºC. Keep in the original package to protect it from humidity.

Nature and content of the DROGLICAN hard capsules 200 mg/250 mg container

Aluminum and plastic blisters (PVC/PVDC) packaged in cardboard boxes.

Containers of 90 capsules.

Special precautions for disposal and other handling of DROGLICAN hard capsules 200 mg/250 mg

The elimination of the medicine not used and of all the materials that have been in contact with it will be done in accordance with local regulations.

MARKETING AUTHORISATION HOLDER

BIOIBÉRICA S.A.

Ctra. Nacional II, Km. 680,6

08389 Palafolls

Barcelona – Spain

Telephone: 93 490 49 08

AUTHORISATION/RENEWAL DATE

September 2009

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Joint Health

E-mail address:
humanhealth@bioiberica.com
Telephone number:
+34 93 490 49 08
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+34 93 490 97 11