Flavocoxid (Limbrel)
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Flavocoxid (Limbrel)

LIMBREL™
(flavocoxid™) Capsules by Oral Administration. Dispensed by prescription. (U.S. patents 7,108,868 and 7,192,611; other patents pending.)

A specially formulated medical food product, consisting primarily of a proprietary blend of flavonoid (polyphenol) ingredients, for the clinical dietary management of the metabolic processes of osteoarthritis (OA). Must be administered under physician supervision.

DRUG DESCRIPTION

OSTEOARTHRITIS (OA)

OA as a Metabolic Deficiency Disease

Metabolic processes are important in the progression of OA. After initial damage to the joint due to trauma, overuse, or genetic factors, a cascade of inflammation, triggered by the release of cytokines (e.g., TNFα, IL-β, IL-6), begins the development of OA. These cytokines up-regulate the expression of COX-2 (cyclooxygenase-2) and 5-LOX (5-lipoxygenase) enzymes, which metabolize fatty acids in the joint. This process is both enzymatic as well as oxidative, and occurs at a cellular level where the essential fatty acid, arachidonic acid (AA), is converted into various inflammatory products. With age, elevated levels of AA accumulate both from the diet and increased conversion of phospholipids produced by further damage to cells in the joint. Therefore, OA is sustained by imbalanced AA metabolism. Managing AA metabolism benefits OA patients by decreasing the damaging, metabolic inflammatory processes in the joint to improve functional mobility, reduce stiffness, and decrease joint discomfort.

When joint damage occurs, phospholipids released from damaged cell membranes are converted to AA. Enzymatic breakdown of AA then generates fatty acid metabolites that are involved in platelet aggregation, maintenance of stomach mucosa, organ function, proper blood flow, urine production, blood pressure, viral immunity, bone turnover and tissue repair. AA is metabolized via the COX (COX-1 & COX-2) and LOX (5-LOX) pathways to thromboxanes, prostaglandins, prostacyclins, and leukotrienes. Balanced AA metabolism by COX-1 and COX-2 is essential to sustain proper levels of critical regulators for renal and cardiovascular function maintained by thromboxanes (vasoconstrictors) and prostacyclins (vasodilators). An imbalance of these metabolites can result in high blood pressure, peripheral edema and, in severe cases, myocardial infarction. AA, metabolized by 5-LOX, produces leukotrienes (particularly LTB4), that are strong chemoattractant molecules responsible for the migration of white blood cells (WBCs) to the site of injury. WBCs attracted to the joint by leukotrienes release histamines, produce reactive oxygen species (ROS) and cytokines, triggering additional inflammatory processes not treated by traditional non-steroidal anti-inflammatory drugs (NSAIDs) or selective COX-2 inhibitors. Inhibition of either or both COX-1 and COX-2 has been shown to shunt AA metabolism down the 5-LOX pathway, thereby potentially increasing, rather than reducing, inflammation in cartilage. In addition, AA is converted via an oxidative mechanism mediated by reactive oxygen species (ROS) to the oxidized lipids F2-isoprostanes, malondialdehyde, and 4-hydroxynonenal that directly degrade cartilage and induce production of other inflammatory proteins.

Primary Ingredients

LIMBREL (flavocoxid) consists of a proprietary blend of two types of flavonoids, Free-B-Ring flavonoids and flavans, from Scutellaria baicalensis and Acacia catechu, respectively. These ingredients in LIMBREL (flavocoxid) are Generally Recognized As Safe (GRAS). For an ingredient to be recognized as GRAS, it requires technical demonstration of non-toxicity and safety, general recognition of safety through widespread usage, and agreement of that safety by experts in the field. Many ingredients have been determined by the U.S. Food and Drug Administration (FDA) to be GRAS, and are listed as such by regulation, in Volume 21 Code of Federal Regulations (CFR) Sections 182, 184, and 186. Other ingredients may achieve “self-affirmed” GRAS status via a panel of experts in the pertinent field who co-author a GRAS Report. Finally, the FDA has specifically permitted a few ingredients as safe medical foods ingredients in Volume 21 CFR Section 172.345(f).

Flavonoids

Flavonoids are a group of phytochemical compounds found in all vascular plants, including fruits and vegetables. They are a part of a larger class of compounds known as polyphenols. Many of the therapeutic or health benefits of colored fruits and vegetables, red wine, and green tea are directly related to their flavonoid content.

The specially formulated flavonoids found in LIMBREL (flavocoxid) , or their related compounds (i.e., other flavonoids, anthocyanins), cannot be obtained from conventional foods in the normal American diet at the same level as found in LIMBREL (flavocoxid) . This quantity of daily flavonoid intake generally would need to be significantly greater for patients with hypochlorhydria or low intrinsic factor, both of which occur most often in the elderly population. OA may not be managed simply by a change to the normal diet due to the high volume of vegetable and fruit matter that would need to be consumed.

Baicalin

The primary Free-B-Ring flavonoid is baicalin (5,6,7-trihydroxyflavone,7-O-β-D-glucuronopyranoside), derived from the phytochemical food source material Scutellaria baicalensis, with a molecular weight of 446.37. Its molecular formula is C21H18O11, with the following chemical structure:

Baicalin Structural Formula Illustration

The primary flavan is composed of catechin (3,3',4',5,7-pentahydroxyflavan (2R,3S form)), and its stereo-isomer, epicatechin (3,3',4',5,7-pentahydroxyflavan (2R,3R form)) from the phytochemical food source material Acacia catechu with a molecular weight of 290.27. Its molecular formula is C15H14O6, with the following chemical structure:

Catechin Structural Formula Illustration

Other Ingredients

LIMBREL (flavocoxid) contains the following “inactive” or other ingredients as fillers, excipients, and colorings: magnesium stearate, microcrystalline cellulose, Maltodextrin NF, gelatin (as the capsule material), titanium dioxide, FD&C Blue #1, and FD&C Green #3. Capsules do not contain fructose, glucose, sucrose, lactose, gluten or flavors.

Medical Foods

Medical food products are often used in hospitals (e.g., for burn victims or kidney dialysis patients) and outside of a hospital setting under a physician's care (e.g., for PKU, AIDS patients, cardiovascular disease, osteoporosis) for the dietary management of diseases in patients with particular medical or metabolic needs due to their disease or condition. Congress defined "medical food" in the Orphan Drug Act and Amendments of 1988 as "a food which is formulated to be consumed or administered enterally [or orally] under the supervision of a physician, and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.“ LIMBREL (flavocoxid) has been developed, manufactured, and labeled in accordance with both the statutory and the FDA regulatory definition of a medical food. LIMBREL (flavocoxid) is to be used under a physician's supervision.

Physical Description

LIMBREL (flavocoxid) is a yellow to light brown powder. It is partially soluble in water and glycerol, soluble in ethanol, methanol, and acetonitrile. It is practically insoluble in hexane. Each capsule of LIMBREL contains 250 mg or 500 mg of flavocoxid, as noted in the Primary Ingredients Section.

What are the possible side effects of bioflavonoids?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects are more likely to occur, and you may have none at all.

Tell your doctor, pharmacist, herbalist, or other healthcare provider about any unusual or bothersome side effect. You may report side effects to FDA at...

Read All Potential Side Effects and See Pictures of Limbrel »

What are the precautions when taking flavocoxid (Limbrel)?

Before taking flavocoxid, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This product should not be used if you have certain medical conditions. Before using this product, consult your doctor or pharmacist if you have: a history of stomach ulcers, active stomach ulcers.

Before using this product, tell your doctor or pharmacist your medical history.

This product is not recommended for use during pregnancy. Consult your doctor for more details.

It is not known whether this product passes into breast milk. Therefore, breast-feeding is not recommended while using this product....

Read All Potential Precautions of Limbrel »

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Recommended Use

LIMBREL (flavocoxid) is intended for the clinical dietary management of the metabolic processes of osteoarthritis (OA).

Disclaimed Use

LIMBREL (flavocoxid) has not been investigated for use in the clinical dietary management of rheumatoid arthritis (RA), acute pain or primary dysmenorrhea.

DOSAGE AND ADMINISTRATION

Recommended Administration

For the clinical dietary management of the metabolic processes of OA, take either one 250 mg or one 500 mg capsule every 12 hours for 500 mg to 1,000 mg total daily consumption as directed by a physician. LIMBREL (flavocoxid) is safe taken with or without other foods. If patients forget to take the prescribed amount, take it as soon as they remember and then resume the normal schedule as directed by a physician.

HOW SUPPLIED

LIMBREL (flavocoxid) is supplied in 250 mg and 500 mg capsules. LIMBREL (flavocoxid) 250 mg capsules are in two-part turquoise green capsules with a smooth surface imprinted “LIMBREL (flavocoxid) ” on one end and “52001” on the other end, supplied as:

#. Size
68040-601-16 Bottle of 60 capsules (250 mg)
68040-601-18 Carton of 120 capsule (250 mg) packets containing 20 packs of 6-capsule packets each as a sample package (Not For Resale)
68040-601-12 Carton of 20 capsule (250 mg) packets containing 1 capsule each as a sample package (Not For Resale)
68040-601-13 Carton of 20 capsule (250 mg) blister cards containing 2 capsules each as a sample package (Not For Resale)
68040-601-02 Blister Card of 2 capsules (250 mg) as a sample (Not For Resale)
68040-601-01 Packet of 1 capsule (250 mg) as a sample (Not For Resale)

LIMBREL (flavocoxid) 500 mg capsules are in two-part turquoise green capsules with a smooth surface imprinted with two white stripes on the cap, and imprinted “LIMBREL (flavocoxid) ” and “52002” on the body, supplied as:

# Size
68040-602-16 Bottle of 60 capsules (500 mg)
68040-602-12 Carton of 20 capsule (500 mg) packets containing 1 capsule each as a sample package (Not For Resale)
68040-602-01 Packet of 1 capsule (500 mg) as a sample (Not For Resale)

Store at room temperature, 59-86oF (15-30oC) [see USP Controlled Room Temperature]. Protect from light and moisture. LIMBREL (flavocoxid) is supplied to pharmacies in a recyclable plastic bottle with a child-resistant cap. Dispense in a light-resistant container as defined in the USP/NF with a child-resistant closure.

Dispensed by prescription.

Manufactured by: Cornerstone Research and Development Farmington, UT 84025 and PAL Laboratories Miami, FL 33172. Manufactured for: Primus Pharmaceuticals, Inc. Scottsdale, AZ 85251 1-480-483-1410. www.limbrel (flavocoxid) .com. Revised 0907. FDA revision date: n/a

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

In a randomized, double-blind placebo-controlled safety study of 60 days, subjects ingested either 125 mg of LIMBREL (flavocoxid) or placebo. Rates of symptomatic adverse events were low and did not differ between the LIMBREL (flavocoxid) and placebo arms. There were also no usage-related changes in routine hematological or biochemical safety parameters.

In a controlled clinical trial of 90 days duration, the incidence of clinical side effects and changes in routine hematological and biochemical parameters and incidence of fecal occult blood positivity were identical for the LIMBREL (flavocoxid) and placebo groups. Adverse events reported included increased varicose veins, elevated hypertension, fluid accumulation in the knee, psoriasis in the LIMBREL (flavocoxid) 125 mg BID arm, psoriasis in the LIMBREL (flavocoxid) 250 mg BID arm, and reduced flexibility in the placebo arm.

Adverse reactions were also collected in a double-blind, randomized clinical trial of 30 days, although this study was not designed to specifically assess usage-related differences in adverse events. Overall, no serious adverse events were reported for LIMBREL (flavocoxid) . There was a non-significant trend toward more frequent edema and nonspecific musculoskeletal events in the naproxen arm. No significant changes were observed within or between arms for weight, systolic blood pressure, or diastolic blood pressure. As expected in a trial of this duration, no fecal occult blood was detected in study subjects, including those taking naproxen.

Special Studies

Gastrointestinal

In a retrospective study, 8 healthy adult subjects, ranging in age from 41 to 60 years, ingested LIMBREL (flavocoxid) daily for periods ranging from 5 to 11 months (mean 7 months). Daily amount ranged from 300 mg to 1,500 mg (mean of 825 mg). Six subjects were male and 2 were female. No subjects reported a prior history of gastrointestinal ulceration. Analysis for fecal occult blood was conducted on three consecutive days. No subjects in this trial were positive for fecal occult blood.

In a second retrospective study, 13 healthy adult subjects ranging in age from 38 to 58 ingested LIMBREL (flavocoxid) daily for periods ranging from 5 to 15 months (mean of 8 months). Daily administration ranged from 150 mg to 600 mg (mean of 375 mg). Seven subjects were male and 6 subjects were female. No subjects reported a prior history of gastrointestinal illness. Analysis for fecal occult blood was conducted on three consecutive days. No subjects in this trial were positive for fecal occult blood. One subject had an event of occult bleeding prior to the measurement date, withdrew from the product, and was unavailable for retrospective analysis. This subject was found to have an unreported prior history of gastrointestinal ulceration. The most commonly reported LIMBREL (flavocoxid) adverse event in all clinical trials is diarrhea and flatulence occuring in 5-8% of subjects. No subject has discontinued participation in a trial because of these symptoms.

Endoscopic examinations have not been conducted in LIMBREL (flavocoxid) users.

Special Populations

Patients Anticoagulated with Warfarin

LIMBREL (flavocoxid) was administered to 59 patients who were taking warfarin chronically. Prothrombin times measured 2 weeks after the addition of LIMBREL (flavocoxid) were unchanged in the majority of patients. In 2 patients the prothrombin time was lengthened and in 2 patients was shortened beyond 2 standard deviations. It is not known whether these represented variation in laboratory testing or reflect a CYP450 polymorphism affecting warfarin metabolism. Because of this, physicians are advised to check prothrombin time one to two weeks after initiating LIMBREL (flavocoxid) in patients anticoagulated with warfarin.

Clinical studies have not been performed to assess the safety and efficacy of LIMBREL (flavocoxid) in pediatric, geriatric, hepatic insufficiency, renal insufficiency, and immunologically compromised patient populations.

Post-Marketing Surveillance

In post marketing surveillance of over 60,000 patients and 100,000 prescriptions of LIMBREL (flavocoxid) , a total of 53 cases of side effects were reported. The most serious side effects were 4 cases of edema, 1 case of upper gastrointestinal bleeding, and 3 cases of elevation of liver tests (ALT, AST and Alkaline phosphatase) all of which resolved without residual effects after discontinuing LIMBREL (flavocoxid) . Notably, no serious or acute cardiovascular events have been reported. One case of first trimester miscarriage has been reported in a patient taking 7 prescription drugs concomitantly (including 2 drugs with warnings against use during pregnancy). The relevance of this case to LIMBREL (flavocoxid) is unknown. No other serious events have been reported.

Read the Limbrel (flavocoxid) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Please refer to CLINICAL PHARMACOLOGY: Drug Interactions.

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

No information provided.

PRECAUTIONS

Gastrointestinal (GI) Effects

LIMBREL (flavocoxid) is expected to produce low toxicity in upper GI because of its mechanism of action, particularly its inhibition of 5-LOX and modest inhibition of COX-1. COX-1 inhibition causes the up-regulation of 5-LOX in the stomach, which converts AA to leukotrienes (particularly LTB4). LTB4 attracts WBCs to the stomach mucosa, which cause and expand ulcerations. Data from an interim analysis of a preliminary study showed that the number of upper GI adverse events of LIMBREL (flavocoxid) to be about the same as placebo and less than half that of naproxen. Clinical experience by physicians has shown LIMBREL (flavocoxid) to be well tolerated in patients with a history of mild ulceration.

Pediatric, Pregnancy and Lactation

There are no formal studies with LIMBREL (flavocoxid) in patients under the age of 18 years of age or pregnant or lactating patients. For this reason, LIMBREL (flavocoxid) is not recommended for pediatric, pregnant or lactating patients.

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

There are no known cases of LIMBREL (flavocoxid) over usage. Animal studies have shown that consuming the equivalent of at least 10 times the recommended human usage of 500 to 1,000 mg/day did not produce adverse events. However, as in most over usage situations, symptoms following an over usage of LIMBREL (flavocoxid) could vary according to the patient. If an over usage were to occur, patients should be managed by systematic and supportive care as soon as possible following product consumption.

CONTRAINDICATIONS

LIMBREL (flavocoxid) is contraindicated in an extremely small number of patients with hypersensitivity to any component of flavocoxid or to flavonoids. Foods rich in flavonoid contents include: colored fruits and vegetables, dark chocolate, tea (especially green tea), red wine, and Brazil nuts.

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

LIMBREL (flavocoxid) acts on COX-1, COX-2 and 5-LOX pathways. LIMBREL (flavocoxid) is NOT selective for either COX-1 or COX-2 enzymes. LIMBREL (flavocoxid) acts by restoring and maintaining the balance of fatty acids in OA. LIMBREL (flavocoxid) dampens AA metabolism at relatively equal levels in the COX pathway (mediated by conversion of AA via the COX-1 & COX-2 enzymes), as well as inhibiting the metabolism of AA by the 5-LOX enzyme. This balanced inhibition of metabolism in the COX pathway yields relatively equal levels of thromboxanes, prostaglandins, and prostacyclins that are key mediators of systemic organ function. Inhibition of these mediators in the COX pathway, in conjunction with inhibition of leukotrienes in the LOX pathway, results in a ”dual inhibition“ mechanism that manages inflammation with minimal effects on organ function. Inhibition of 5-LOX has been shown in cell-based assays to reduce the production of LTB4, an agent that fosters WBC chemotaxis and the subsequent release of histamines, ROS, and pro-inflammatory cytokines. In addition, direct inhibition of the 5-LOX enzyme has been observed in enzymatic assays. This balanced down-regulation of these enzymatic pathways is relatively weak when compared to the effects of traditional NSAIDs and selective COX-2 inhibitors, thus allowing the body to produce AA metabolites at relatively equal levels to maintain physiologic function.

LIMBREL (flavocoxid) also acts as a strong antioxidant to limit the oxidative conversion of AA by ROS to other damaging fatty acid products including hydroxyl radicals, superoxide anion radicals and hydrogen peroxide. LIMBREL (flavocoxid) has demonstrated an oxygen radical absorbance capacity (ORAC) of 5,517 μmolTE/g, as compared to Vitamin E (1,100 μmolTE/g) and Vitamin C (5,000 μmolTE/g).

Through these enzyme inhibition and antioxidant mechanisms, LIMBREL (flavocoxid) is beneficial for the clinical dietary management of the metabolic aspects of osteoarthritis. Inflammation, joint discomfort, and reduced flexibility are shown in published studies to be clinical manifestations of OA. At a biochemical and metabolic level, inflammation is not simply a marker of the disease process, but also plays an important role in OA progression. Chronic inflammation with elevated metabolic production of inflammatory metabolites has an etiological role in the progression of OA. Thus, successful dietary management of the metabolic processes ofOA, results in a reduction of its characteristic inflammation by correcting OA's distinctive imbalance in AA metabolism.

Hepatic, Renal, and Gastrointestinal Histology

LIMBREL (flavocoxid) 's effect on hepatic, renal, gastric, and duodenal tissue histology was tested in four animal toxicity studies; two for acute use and two for sub- chronic use.

In the acute use studies, healthy juvenile male and female mice received a 2,000 mg/kg oral dose (10,000 mg per day human equivalent, or at least 10 times the recommended human use of 500 - 1,000 mg per day) or placebo daily for 14 days. In two different sub-chronic use studies, three groups of healthy adult male and female mice consumed either 50 mg, 250 mg or 500 mg/kg doses (250 mg, 1,250 mg and 2,500 mg per day human equivalent) for 28 and 91 days respectively.

In all studies, the test subjects were evaluated relative to placebo control groups of healthy subjects with similar ages and sexes. Observations across all groups revealed no organ or behavioral abnormalities, nor differences in weight gain. Neither study showed changes in hepatic, renal, gastric, or duodenal histology. Blood electrolytes were unchanged, and liver enzyme levels and markers of renal function were all within normal limits.

Food Effects

LIMBREL (flavocoxid) is safe taken with or without other foods. Taking LIMBREL (flavocoxid) one hour before or after meals may help to increase the absorption of LIMBREL (flavocoxid) 's key ingredients. This observation is based upon a pharmacokinetic study in humans, as well as in-market clinical experience in analyzing physician and patient product reports. Food does not affect the metabolism of LIMBREL (flavocoxid) and may buffer effects of slight indigestion.

Metabolism

LIMBREL (flavocoxid) is primarily carried bound to albumin in the blood and only a minor amount ( < 10%) is metabolized via glucuronidation and sulfation by hepatic metabolism involving cytochrome P450 isoenzymes (CYP). A primary ingredient constituent, baicalin, undergoes hydrolysis of the glucuronide moiety in the upper intestine via the action of intestinal flora and is absorbed as the aglycone, baicalein. Glucuronidation and sulfation of baicalein occurs intra-hepatically. In vitro CYP assays using a microsomal enzyme system demonstrated minimal CYP inhibition (see below).

Drug Interactions

In vitro studies indicated that LIMBREL (flavocoxid) is not a significant inhibitor of cytochrome P450 1A2, 2C9, 2C19, 2D6, or 3A4. These isoenzymes are principally responsible for 95% of all detoxification of drugs, with CYP3A4 being responsible for detoxification of approximately 50% of drugs. Based on the results of this assay, LIMBREL (flavocoxid) does not appear to have a pronounced effect on drug metabolizing enzymes.

LIMBREL (flavocoxid) was tested at a 10 μM concentration in human recombinant (sf9 cells) using spectrophotometric quantization of 7-benzyloxy-4-(trifluoromethyl)-coumarin as substrate. In this test model, if inhibition does not reach at least 50% at 10 μM, CYP inhibition is considered to be insignificant and no further development of titration curves is deemed necessary. Inhibition by LIMBREL (flavocoxid) ranged from 11% inhibition to 23% inhibition of selected isozymes when studied at a 10 μM concentration.

LIMBREL (flavocoxid) , therefore, does not appear to have a pronounced effect on the inhibition of hepatic drug metabolizing enzymes based on this 10 μM concentration. The data for CYP inhibition is shown below:

Table 1. Cytochrome P450 Assay

CYP Isoenzyme % Inhibition by LIMBREL
1A2 23%
2C9 11%
2C19 16%
2D6 15%
3A4 11%

Clinical Experience

LIMBREL (flavocoxid) has demonstrated significant functional improvements when used for the clinical dietary management of the metabolic processes of OA.

Double-blind, Randomized Clinical Study vs. Naproxen

LIMBREL (flavocoxid) was evaluated in a double-blind, randomized, active comparator (naproxen) controlled clinical study that enrolled 103 subjects with moderate or moderate-severe OA of the knee. Subjects were randomly assigned to receive either LIMBREL (flavocoxid) (500 mg BID) or naproxen (500 mg BID) for 4 weeks. Primary endpoints were the short WOMAC composite index (Western Ontario and McMaster Universities Osteoarthritis Index), investigator VAS for global response, subject VAS scales for global response and discomfort. Subjects were sex-matched and recruited from ages 35 to 85 years with an average age of 57-60 years per arm. There were no differences in demographic characteristics or in baseline WOMAC or VAS scores between the two arms. Subjects taking NSAIDs and/or gastroprotective medication underwent a 2-week washout period before beginning the trial. Subject activity was not restricted, and subjects were free to withdraw from the trial at any time for any reason. Dropouts were minimal in both arms. Two subjects, one from each arm, failed to complete the trial for personal reasons unrelated to the study.

In thisstudy, both LIMBREL (flavocoxid) and naproxen arms noted significant reduction in the signs and symptoms of knee OA. All within-arm improvements in efficacy endpoints were statistically significant (p 0.001). The LIMBREL (flavocoxid) and naproxen arms performed nearly identically, and the between group differences were not statistically significant for any efficacy endpoint. See Figures 1-4 below for efficacy results of LIMBREL (flavocoxid) vs. naproxen in this study.

Figure 1. Improvement in WOMAC*

Improvement in WOMAC* Illustration

Figure 2. Improvement in Physician VAS (Global Disease Assessment)**

 Improvement in Physician VAS (Global Disease Assessment)**  Illustration

Figure 3. Improvement in Subject VAS (Global Disease Assessment)

Improvement in Subject VAS (Global Disease Assessment) Illustration

Figure 4. Improvement in Subject VAS (Discomfort Assessment) ††

Improvement in Subject VAS (Discomfort Assessment) Illustration

Fisher's exact test was computed for improved vs. not improved (sum of unchanged and worsened) for all parameters (see Table 2). Both arms had a large percentage of subjects with significant improvement (75% to 88%). Differences were not significant between arms for percent of patients with improvement. There was a slight, non-significant trend toward greater improvement in physician global disease assessment VAS in the LIMBREL (flavocoxid) arm and WOMAC in the naproxen arm.

Table 2. Percent of OA Patients with Improvement

  LIMBREL (flavocoxid)
500 mg BID
(N=52)
Naproxen
500 mg BID
(N=51)
p-value
WOMAC 79% 88% < 0.001
Physician VAS (global disease assessment) 83% 75% < 0.001
Subject VAS (global disease assessment) 87% 88% < 0.001
Subject VAS (discomfort assessment) 87% 88% ≤ 0.001

Double-blind, Randomized Clinical Study vs. Placebo

LIMBREL (flavocoxid) was evaluated in a 90-day randomized, double blind, placebo-controlled clinical trial of 60 subjects. Subjects were sex-matched and recruited from ages 40 to 75 years with an average age of 55-57 years per arm. Subjects taking NSAIDs engaged in a two-week washout period before beginning the trial. Subject activity was not restricted, and subjects were free to withdraw from the trial at any time for any reason. Three subjects withdrew from the study for personal reasons unrelated to study procedures or products.

In patients with OA, use of LIMBREL (flavocoxid) at 125 mg and 250 mg BID resulted in significant improvements in WOMAC functional endpoints of stiffness and mobility over those scores of placebo users. In this study, patients using LIMBREL (flavocoxid) 250 mg twice daily experienced greater improvements in functional stiffness and functional mobility at 90 days than did patients using 125 mg twice daily. See Tables 3 and 4 below for a comparison of LIMBREL (flavocoxid) results to placebo for each noted measure.

Table 3. 90-day Functional Stiffness WOMAC Scores

  Mean % Change* p-value Conclusion
LIMBREL 250 mg/day -27.2% p=0.005 Significant improvement
LIMBREL 500 mg/day -38.0% p=0.002 Significant improvement
Placebo +3.1% p=0.324 No significant improvement
* Negative values indicated improvement in functional stiffness.

Table 4. 90-day Functional Mobility WOMAC Scores

  Mean % Change* p-value Conclusion
LIMBREL 250 mg/day +19.2% p=0.018 Significant improvement
LIMBREL 500 mg/day +28.4% p=0.001 Significant improvement
Placebo +2.3% p=0.895 No significant improvement
* Positive values indicated improvement in functional mobility.

Open Label Study

LIMBREL (flavocoxid) has been shown to be effective in an open label human trial with a mean duration of use of 6.5 months. This trial consisted of 24 subjects: 13 males and 11 females ranging from 26 to 60 years of age. The primary endpoints were WOMAC functional mobility (65% improvement; p=0.002) and functional stiffness (62% improvement; p=.001) scores before vs. after taking LIMBREL (flavocoxid) .

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

No information provided. Please refer to the PRECAUTIONS section.

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

No information provided. Please refer to the PRECAUTIONS section.

Last reviewed on RxList: 7/24/2008
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Limbrel Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

FLAVOCOXID - ORAL

(flay-voe-COX-id)

COMMON BRAND NAME(S): Limbrel

USES: Flavocoxid is used to manage osteoarthritis. It helps to decrease swelling (inflammation) and pain. Flavocoxid is a medical food product made up of substances from plant sources called flavonoids and flavans.

Some supplement products have been found to contain possibly harmful impurities/additives. Check with your pharmacist for more details about the brand you use.

The FDA has not reviewed this product for safety or effectiveness. Consult your doctor or pharmacist for more details.

HOW TO USE: Take this product by mouth with or without food, usually every 12 hours or as directed by your doctor.

Use this product regularly in order to get the most benefit from it. Remember to use it at the same times each day. Do not increase your dose or take it more often than prescribed.

Inform your doctor if your condition does not improve or worsens.

Disclaimer

Limbrel Consumer (continued)

SIDE EFFECTS: Nausea, diarrhea, or gas may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but serious side effects occur: yellowing eyes/skin.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Limbrel (flavocoxid) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking flavocoxid, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This product should not be used if you have certain medical conditions. Before using this product, consult your doctor or pharmacist if you have: a history of stomach ulcers, active stomach ulcers.

Before using this product, tell your doctor or pharmacist your medical history.

This product is not recommended for use during pregnancy. Consult your doctor for more details.

It is not known whether this product passes into breast milk. Therefore, breast-feeding is not recommended while using this product. Consult your doctor before breast-feeding.

Disclaimer

Limbrel Consumer (continued)

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this product with others.

Keep all regular medical and laboratory appointments.

Non-drug treatment for arthritis that is approved by your doctor (e.g., weight loss if needed, strengthening and conditioning exercises) may help improve your flexibility, range of motion, and joint function. Consult your doctor for specific instructions.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised May 2011. Copyright(c) 2011 First Databank, Inc.

Limbrel Patient Information Including Side Effects

Brand Names: Amino-Opti-C, Limbrel, P-1000, Pan C 500, Peridin-C, Rutin, Span C

Generic Name: bioflavonoids (Pronunciation: BYE oh FLAV oh noids)

What are bioflavonoids (Limbrel)?

Bioflavonoids are found in the rind of green citrus fruits and in rose hips and black currants.

Bioflavonoids have been used in alternative medicine as an aid to enhance the action of vitamin C, to support blood circulation, as an antioxidant, and to treat allergies, viruses, or arthritis and other inflammatory conditions.

Not all uses for bioflavonoids have been approved by the FDA. Bioflavonoids should not be used in place of medication prescribed for you by your doctor.

Bioflavonoids is often sold as an herbal supplement. There are no regulated manufacturing standards in place for many herbal compounds and some marketed supplements have been found to be contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Bioflavonoids may also be used for other purposes not listed in this product guide.

What are the possible side effects of bioflavonoids?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Less serious side effects are more likely to occur, and you may have none at all.

Tell your doctor, pharmacist, herbalist, or other healthcare provider about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Read the Limbrel (flavocoxid) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about bioflavonoids?

Not all uses for bioflavonoids have been approved by the FDA. Bioflavonoids should not be used in place of medication prescribed for you by your doctor.

Bioflavonoids is often sold as an herbal supplement. There are no regulated manufacturing standards in place for many herbal compounds and some marketed supplements have been found to be contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Use bioflavonoids as directed on the label, or as your healthcare provider has prescribed. Do not use this product in larger amounts or for longer than recommended.

Side Effects Centers

Limbrel Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking bioflavonoids?

Do not use this product if you are allergic to bioflavonoids or if you have:

Before using bioflavonoids, talk to your doctor, pharmacist, herbalist, or other healthcare provider. You may not be able to use bioflavonoids if you have certain medical conditions.

Do not give any herbal/health supplement to a child without the advice of a doctor.

How should I take bioflavonoids?

When considering the use of herbal supplements, seek the advice of your doctor. You may also consider consulting a practitioner who is trained in the use of herbal/health supplements.

If you choose to take bioflavonoids, use it as directed on the package or as directed by your doctor, pharmacist, or other healthcare provider. Do not use more of this product than is recommended on the label.

Take this medicine with a full glass of water.

Do not use different formulations of bioflavonoids at the same time without first talking to your doctor. Using different formulations together increases the risk of an bioflavonoids overdose.

If your condition does not improve, or if it appears to get worse, contact your doctor.

Store bioflavonoids at room temperature away from moisture and heat.

Side Effects Centers

Limbrel Patient Information including If I Miss a Dose

What happens if I miss a dose?

Consult your doctor, pharmacist, herbalist, or other healthcare provider for instructions if you miss a dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking bioflavonoids?

There are no known restrictions on food, beverages, or activities while you are taking bioflavonoids unless otherwise directed by your health care provider.

What other drugs will affect bioflavonoids?

There may be other drugs that can interact with bioflavonoids. Tell your healthcare provider about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your healthcare provider.

Where can I get more information?

Consult with a licensed healthcare professional before using any herbal/health supplement. Whether you are treated by a medical doctor or a practitioner trained in the use of natural medicines/supplements, make sure all your healthcare providers know about all of your medical conditions and treatments.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 4.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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