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FLAVOCOXID

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Flavocoxid is considered to be a medical food product. It contains a blend of Free-B-Ring flavonoids and flavan from phytochemical food source materials.

Specific Substances

    1) Flavonoids
    2) Free-B-Ring Flavonoids
    3) Flavan
    1.2.1) MOLECULAR FORMULA
    1) Baicalin (the primary Free B-Ring flavonoid): C21-H18-O11 (Prod Info Limbrel(TM), 2004)
    2) Catechin (the primary flavan): C15-H14-O6 (Prod Info Limbrel(TM), 2004)

Available Forms Sources

    A) FORMS
    1) LIMBREL(R): Flavocoxid 250 mg and 500 mg capsules (Prod Info LIMBREL(R) oral capsules, 2015).
    2) LIMBREL250(R): Flavocoxid 250 mg with 50 mg of citrated zinc bisglycinate (10 mg elemental zinc) capsules (Prod Info LIMBREL250(R) oral capsules, 2015).
    3) LIMBREL500(R): Flavocoxid 500 mg with 50 mg of citrated zinc bisglycinate (10 mg elemental zinc) capsules (Prod Info LIMBREL500(R) oral capsules, 2015).
    B) SOURCES
    1) Flavocoxid contains a blend of Free-B-Ring flavonoids and flavan from phytochemical food source materials. These materials are Generally Recognized As Safe (GRAS) by experts in the field (Prod Info LIMBREL(R) oral capsules, 2015).
    C) USES
    1) Flavocoxid is considered to be an ethical medical food product. It is used for the clinical dietary management of osteoarthritis, including associated inflammation (Prod Info LIMBREL(R) oral capsules, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Flavocoxid (LIMBREL(R)) is considered to be an ethical medical food product. It is used for the clinical dietary management of osteoarthritis, including associated inflammation. Flavocoxid contains a blend of Free-B-Ring flavonoids and flavan from phytochemical food source materials. These materials are Generally Recognized As Safe (GRAS) by experts in the field. LIMBREL250(R) and LIMBREL500(R) contain flavocoxid 250 mg or 500 mg with 50 mg of citrated zinc bisglycinate (10 mg elemental zinc) capsules. Refer to ZINC COMPOUND monograph for toxicity from zinc.
    B) PHARMACOLOGY: Flavocoxid, a specially formulated medical food product, maintains and restores the balance of fatty acids by dampening metabolism of amino acids (AA) as well as blocking the metabolism of AA by the 5- lipooxygenase enzymes. It also has a strong antioxidant activity through limitation of the oxidative conversion of AA by reactive oxygen species to other damaging fatty acid products.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON: Nausea, diarrhea, and flatulence. OTHER EFFECTS: Increased varicose veins, hypertension, edema, psoriasis, elevated liver enzymes, jaundice, eosinophilia, and hypersensitivity pneumonitis. Concurrent use of flavocoxid and NSAIDS or COX-2 inhibitors can cause gastrointestinal bleeding, ulceration and perforation.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. In animal studies, the administration of up to 20 times the recommended human use (500 mg/day to 1000 mg/day) did not produce adverse events.
    0.2.20) REPRODUCTIVE
    A) The manufacturer does not recommend the use of flavocoxid in pregnant or lactating women.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes in symptomatic patients.
    C) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    D) Monitor serum electrolytes in patients with severe diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Severe toxicity is unlikely. Treatment is symptomatic and supportive.
    B) DECONTAMINATION
    1) Gastrointestinal decontamination is generally not necessary. Consider activated charcoal only after very large ingestions or if coingestants with significant toxicity are involved.
    C) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress. Hypersensitivity pneumonitis has rarely been reported with flavocoxid use. Symptoms included fever, cough, hypoxemia, and diffuse pulmonary infiltrates.
    D) ANTIDOTE
    1) None.
    E) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    F) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    G) PHARMACOKINETICS
    1) Metabolism of flavocoxid is by glucuronidation and sulfation, with little hepatic metabolism by cytochrome P450 isoenzymes (CYP).

Range Of Toxicity

    A) TOXICITY: Overdose data is limited. In animal studies, the administration of up to 20 times the recommended human dose (500 mg/day) did not produce adverse events.
    B) THERAPEUTIC DOSE: One 250 mg or one 500 mg capsule every 12 hours; total daily dose 500 mg to 1000 mg.

Clinical Effects

Summary Of Exposure

    A) USES: Flavocoxid (LIMBREL(R)) is considered to be an ethical medical food product. It is used for the clinical dietary management of osteoarthritis, including associated inflammation. Flavocoxid contains a blend of Free-B-Ring flavonoids and flavan from phytochemical food source materials. These materials are Generally Recognized As Safe (GRAS) by experts in the field. LIMBREL250(R) and LIMBREL500(R) contain flavocoxid 250 mg or 500 mg with 50 mg of citrated zinc bisglycinate (10 mg elemental zinc) capsules. Refer to ZINC COMPOUND monograph for toxicity from zinc.
    B) PHARMACOLOGY: Flavocoxid, a specially formulated medical food product, maintains and restores the balance of fatty acids by dampening metabolism of amino acids (AA) as well as blocking the metabolism of AA by the 5- lipooxygenase enzymes. It also has a strong antioxidant activity through limitation of the oxidative conversion of AA by reactive oxygen species to other damaging fatty acid products.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON: Nausea, diarrhea, and flatulence. OTHER EFFECTS: Increased varicose veins, hypertension, edema, psoriasis, elevated liver enzymes, jaundice, eosinophilia, and hypersensitivity pneumonitis. Concurrent use of flavocoxid and NSAIDS or COX-2 inhibitors can cause gastrointestinal bleeding, ulceration and perforation.
    E) WITH POISONING/EXPOSURE
    1) Overdose data is limited. In animal studies, the administration of up to 20 times the recommended human use (500 mg/day to 1000 mg/day) did not produce adverse events.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) VENOUS VARICES
    1) WITH THERAPEUTIC USE
    a) Increased varicose veins has been reported in patients (2% or greater) taking flavocoxid 125 mg BID in clinical trials (Prod Info Limbrel(TM), 2004).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported in patients (2% or greater) taking flavocoxid 125 mg BID in clinical trials (Prod Info Limbrel(TM), 2004).
    C) EDEMA
    1) WITH THERAPEUTIC USE
    a) Fluid accumulation in the knee has been reported in patients (2% or greater) taking flavocoxid 125 mg BID in clinical trials (Prod Info Limbrel(TM), 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea is one of the most common adverse effects of flavocoxid (Prod Info LIMBREL(R) oral capsules, 2015).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea is one of the most common adverse effects of flavocoxid (Prod Info LIMBREL(R) oral capsules, 2015).
    C) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) Flatulence is one of the most common adverse effects of flavocoxid (Prod Info LIMBREL(R) oral capsules, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) In controlled clinical trials, borderline elevations of liver enzymes (1.2 to 3 times the upper limit of normal) were observed in less than 10% of patients. In less than 20% of patients, increased ALT and AST (greater than 3 to 5 times upper limit of normal) was observed. Severe liver injuries, including jaundice or eosinophilia, were also observed. In all of these cases, adverse effects resolved within 2 to 4 weeks (Prod Info LIMBREL(R) oral capsules, 2015).
    b) During postmarketing surveillance through March 2011, 21 patients developed elevated liver enzymes, including 4 patients with jaundice (Prod Info LIMBREL(R) oral capsules, 2015).
    c) During the Drug-Induced Liver Injury Network (DILIN) prospective study, a total of 877 patients with suspected drug-induced liver injury were enrolled between 2004 and 2010. Four patients were identified as having liver injury associated with flavocoxid use. All 4 patients (women aged 57 to 68 years) were administered flavocoxid 250 to 500 mg twice daily for treatment of arthritis or musculoskeletal pain. Within 3 months of flavocoxid administration, patients developed jaundice (n=3), abdominal pain (n=3), pruritus (n=3), fever (n=2), and rash (n=1). Their initial serum bilirubin levels ranged from 1.9 to 11.9 mg/dL, ALT levels were elevated (range 741 to 1375 international units/L) and moderate increases in alkaline phosphatase (range 286 to 530 units/L). Tests for acute and chronic viral hepatitis and imaging studies for biliary obstruction were all negative. There was no evidence of prolongation of the prothrombin time or signs/symptoms of hepatic failure. Liver injury began to resolve within a few days of flavocoxid discontinuation and serum enzyme levels returned to normal ranges within 3 months of onset. Causality was very likely due to flavocoxid in 3 patients and possible in 1 patient, who was also exposed to pregabalin, duloxetine, and tizanidine. There was no evidence of chronic or ongoing liver injury following readministration of flavocoxid in these patients (Chalasani et al, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) PSORIASIS
    1) WITH THERAPEUTIC USE
    a) Psoriasis has been reported in patients (2% or greater) taking flavocoxid 250 mg BID in clinical trials (Prod Info Limbrel(TM), 2004).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity pneumonitis has rarely been reported with flavocoxid use. Symptoms included fever, cough, hypoxemia, and diffuse pulmonary infiltrates (Prod Info LIMBREL(R) oral capsules, 2015).
    b) During postmarketing surveillance through March 2011, 10 patients developed hypersensitivity pneumonitis (Prod Info LIMBREL(R) oral capsules, 2015).

Reproductive

    3.20.1) SUMMARY
    A) The manufacturer does not recommend the use of flavocoxid in pregnant or lactating women.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) The manufacturer does not recommend the use of flavocoxid in pregnant women (Prod Info Limbrel(TM), 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) The manufacturer does not recommend the use of flavocoxid in lactating women (Prod Info Limbrel(TM), 2004).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes in symptomatic patients.
    C) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    D) Monitor serum electrolytes in patients with severe diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and liver enzymes in symptomatic patients.
    C) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    D) Monitor serum electrolytes in patients with severe diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Severe toxicity is not expected after overdose of flavocoxid. Gastrointestinal decontamination is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Severe toxicity is not expected after overdose of flavocoxid. Gastrointestinal decontamination is generally not necessary. Consider activated charcoal only after very large ingestions or if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF TOXICITY
    a) Severe toxicity is unlikely. Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and liver enzymes in symptomatic patients.
    3) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    4) Monitor serum electrolytes in patients with severe diarrhea.

Range Of Toxicity

Summary

    A) TOXICITY: Overdose data is limited. In animal studies, the administration of up to 20 times the recommended human dose (500 mg/day) did not produce adverse events.
    B) THERAPEUTIC DOSE: One 250 mg or one 500 mg capsule every 12 hours; total daily dose 500 mg to 1000 mg.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended dose is one 250 mg capsule every 12 hours for 500 mg total daily dose; higher doses such as 250 mg three times daily (750 mg total daily dose) may be used under a physician's supervision. Food should not be taken one hour before or one hour after the use of flavocoxid (Prod Info Limbrel(TM), 2004).
    7.2.2) PEDIATRIC
    A) The manufacturer does not recommend the use of flavocoxid in children under the age of 18 years (Prod Info Limbrel(TM), 2004).

Maximum Tolerated Exposure

    A) ANIMAL STUDIES
    1) Overdose data is limited. In animal studies, the administration of up to 20 times the recommended human dose (500 mg/day to 1000 mg/day) did not produce adverse events (Prod Info Limbrel(TM), 2004).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Flavocoxid contains a blend of Free-B-Ring flavonoids and flavans from phytochemical food source materials. These materials are Generally Recognized As Safe (GRAS) by experts in the field (Prod Info Limbrel(TM), 2004).
    B) FLAVONOID - Baicalin, the primary Free-B-Ring flavonoid (5,6,7-trihydroxyflavone, 7-O-beta-D-glucuronopyranoside) is derived from the source Scutellaria baicalensis (Prod Info Limbrel(TM), 2004).
    C) FLAVAN - Catechin, the primary flavan (3,3',4',5,7-pentahydroxyflavan (2R,3S form)), and its stereo-isomer, epicatechin (3,3',4',5,7-pentahydroxyflavan (2R,3R form)) are derived from the source Acacia catechu (Prod Info Limbrel(TM), 2004).
    D) In animal and human studies, flavocoxid has been found to possess anti-inflammatory and analgesic properties. The following mechanism of actions have been suggested (Prod Info Limbrel(TM), 2004):
    1) Inhibition of prostaglandin synthesis, via the inhibition of cyclo-oxygenase (COX) (not highly selective for the COX-2 pathway).
    2) Inhibition of inflammatory pathway of arachidonic acid metabolism known as the 5-lipoxygenase (5-LO or 5-LOX) pathway. This inhibition reduces the production of leukotriene-B4 (LTB4), an agent that fosters white blood cell chemotaxis and the subsequent release of reactive oxygen species and pro-inflammatory cytokines.
    3) Acts through an antioxidant mechanism by reduction of ROS including hydroxyl radical, superoxide anion radical and hydrogen peroxide. ROS may play a key role in the degradation of cartilage in osteoarthritis.
    4) Reduces the pro-inflammatory cytokines interleukin-1-beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in in vitro models.

Physicochemical

Physical Characteristics

    A) Flacovoxid is a yellow to light brown powder. It is partially soluble in water and glycerol, soluble in ethanol, methanol, and acetonitrile (Prod Info Limbrel(TM), 2004).

Molecular Weight

    1) Baicalin (the primary Free B-Ring flavonoid): 446.37 (Prod Info Limbrel(TM), 2004)
    2) Catechin (the primary flavan): 290.27 (Prod Info Limbrel(TM), 2004)

References

General Bibliography

    1) Chalasani N, Vuppalanchi R, Navarro V, et al: Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis: a case series. Ann Intern Med 2012; 156(12):857-860.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    4) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    5) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    6) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    7) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    8) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    9) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    10) Product Information: LIMBREL(R) oral capsules, flavocoxid oral capsules. Primus Pharmaceuticals, Inc. (per manufacturer), Scottsdale, AZ, 2015.
    11) Product Information: LIMBREL250(R) oral capsules, flavocoxid citrated zinc bisglycinate oral capsules. Primus Pharmaceuticals, Inc. (per manufacturer), Scottsdale, AZ, 2015.
    12) Product Information: LIMBREL500(R) oral capsules, flavocoxid citrated zinc bisglycinate oral capsules. Primus Pharmaceuticals, Inc. (per manufacturer), Scottsdale, AZ, 2015.
    13) Product Information: Limbrel(TM), flavocoxid capsules. Primus Pharmaceuticals, Scottsdale, AZ, 2004.
    14) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.