Prescriber Q & A

1. Does Limbrel require a prescription?
2. Why have I not heard about Limbrel?
3. Is Limbrel safe?
4. Is Limbrel effective?
5. Is Limbrel effective in rheumatoid arthritis (RA)?
6. Does Limbrel contain a recognized class of ingredients?
7. Is Limbrel regulated by FDA?
8. What is medical nutrition or a medical food?
9. What are the differences between medical food and dietary supplements?
10. Is Limbrel a selective COX-2 Inhibitor?
11. What is Dual Inhibition?
12. Are there clinical data supporting Limbrel?
13. How strong of an antioxidant is Limbrel?
14. Can Limbrel’s dose be safely increased beyond 250mg BID?
15. What side effects have been observed in clinical practice?
16. Which patients should not use Limbrel?
17. Have there been any drug interactions with Limbrel?
18. Can Limbrel be taken by patients already taking a blood thinner such as coumadin?
19. How is Limbrel manufactured?
20. How much does Limbrel cost?
21. Is Limbrel reimbursed?
22. How can my patients obtain Limbrel?
23. What is the difference between a Medical Food and Rx Drug?
24. Are there on-going clinical studies on Limbrel?
25. What are other examples of medical food products?
26. How does the physician determine the metabolic deficiency in osteoarthritis?
27. How long does it take Limbrel to begin to manage osteoarthritis via nutritional management?
28. Should Limbrel be taken with or without other foods?
    

1. Question: Does Limbrel require a prescription?

Answer: Yes, Limbrel does require a prescription. It is sold only as an Rx product, and the FDA regulatory product class of medical foods requires that it be used under the supervision of a physician. It is distributed through retail pharmacies behind the pharmacy counters.
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2. Question: Why have I not heard about Limbrel?

Answer: Limbrel listing can be found in the 2009 PDR. Currently, we may not have a sales representative in your local area, but we are actively expanding our coverage. To request a rep visit or sample shipment, please click here.
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3. Question: Is Limbrel safe?

Answer: Limbrel’s ingredients have been designated as GRAS (Generally Recognized As Safe) according to strict FDA (Food and Drug Administration) standards. The standards for an ingredient to achieve GRAS status require not only technical demonstration of non-toxicity and safety, but also general recognition and agreement on that safety by experts in the field. Ingredients in conventional foods in the U.S. also hold GRAS status and are therefore considered safe for public consumption. Many supplement and food ingredients with widely accepted therapeutic benefits have been approved as GRAS ingredients, such as Folic acid, Vitamin C and Calcium. The GRAS status of each ingredient also evidences an up-front safety, determined by consumption by wide geographic and demographic populations.

In clinical studies, Limbrel has been shown to have side effects comparable to placebo. To date, the number of side effects reported by physicians and patients about Limbrel has been less than 0.2% , exceptionally low compared to most other prescription products.

Furthermore, Limbrel’s ingredients have been tested in animal toxicology studies at doses between 5 and 20 times the human equivalent amount. In these studies, no significant adverse events were reported and no changes were observed in histology, blood serology, cell numbers, liver enzymes or electrolyte levels. Finally, studies in Fischer 344 rats, those genetically sensitive to gastrointestinal effects such as bleeding caused by chronic use of NSAIDs, showed no changes in stomach mucosa with chronic dosing of Limbrel.
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4. Question: Is Limbrel effective?

Answer: Limbrel is effective in the dietary management of the metabolic processes of osteoarthritis. In fact, Limbrel’s onset of action has been reported to be as little time as a few hours to 4-5 days after taking Limbrel for mild to moderate osteoarthritis. Limbrel’s effectiveness in managing osteoarthritis comes from its unique mode of action, including COX/LOX dual mechanism of action and antioxidative activities. In addition to a balanced inhibitory action down the COX-1/COX-2 pathways, Limbrel acts on the 5-LOX pathway – another inflammatory pathway involved in the progression of osteoarthritis. Limbrel also is a powerful antioxidant, “soaking up” free radicals that are known to contribute to cartilage degradation in osteoarthritis.

In clinical studies , Limbrel has been shown to safely and effectively manage osteoarthritis through dietary means, including significantly improving osteoarthritis patients’ functional mobility.
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5. Question: Is Limbrel effective in rheumatoid arthritis (RA)?

Answer: Limbrel’s effectiveness in RA has not been researched or clinically tested. Additionally, the research to determine the distinctive nutritional requirements of RA patients to support Limbrel as a medical food product for RA has not been completed. Therefore, Limbrel is not promoted for RA, and any usage for RA would be solely at the physician’s initiative.
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6. Question: Does Limbrel contain a recognized class of ingredients?

Answer: Limbrel contains a widely recognized class of polyphenol ingredients commonly referred to as flavonoids. These are natural compounds from plant-based food sources which are generally accepted to provide certain therapeutic benefits and are often found in many fruits, vegetables and nuts. The specific chemical structure of the primary constituent ingredients found in Limbrel are provided in Limbrel’s package insert. Further, Limbrel contains both Free-B-Ring Flavonoids (baicalin defined as 5,6,7-trihydroxyflavone,7-O-β-D-glucuronopyranoside with a molecular formula of C21H18O11) and Flavans (catechin defined as 3,3’,4’,5,7-pentahydroxyflavan with a molecular formula of C15H14O6) which are both particular types of flavonoids. Flavonoids as a class can be found in most authoritative chemical and botanical reference materials.
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7. Question: Is Limbrel regulated by FDA?

Answer: Yes, Limbrel is regulated by FDA. Limbrel meets the standards and requirements set forth by FDA to define its regulatory product class, which is medical food. Limbrel is also subject to manufacturing facility inspections, including product and label reviews by FDA.
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8. Question: What is medical nutrition or a medical food?

Answer: Primus uses medical nutrition as synonymous with medical foods. These two terms denote the nature of the product as well as the regulatory product class (i.e., medical food as defined by Congress and by FDA). Medical food products are often used in hospitals for the nutritional (dietary) management of patients with particular medical needs due to their disease or condition. Examples include hospital tube feeding, amino acid products for burn victims, and B12 and folate products for patients with hyperhomocysteinemia. Limbrel has been developed, manufactured, and labeled in accordance with both the statutory and the FDA regulatory definition of a medical food. Congress defined "medical food" in the Orphan Drug Act Amendments of 1988. "Medical food" is defined at Volume 21 U.S. Code Section 360ee(b)(3) as "a food which is formulated to be consumed or administered enterally 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." Prior to Congress defining medical foods in 1988 as a distinctive regulatory product class, medical foods were covered under FDA’s drug regulations.
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9. Question: What are the differences between medical food and dietary supplements?

Answer: Limbrel is a medical food product and NOT a dietary supplement. What is confusing is that both of these regulatory classes of products utilize vitamins, minerals, and food-based and herbal ingredients. For example, folic acid is found in both types of products. Further, relatively few medical professionals are familiar with the actual statutory definition of medial nutrition (i.e., medical foods). Perhaps most importantly, medical food products must be used under physician supervision whereas dietary supplements are consumer products. From a medical perspective, the differences between medical food and dietary supplement product classifications are as follows:

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10. Question: Is Limbrel a selective COX-2 Inhibitor?

Answer: No, Limbrel is NOT a selective COX-2 Inhibitor. More generally, Limbrel is not a drug. A selective COX-2 inhibitor strongly favors the inhibition of the COX-2 enzyme over COX-1, and may drastically decrease the levels of COX-2 enzyme activity in the body. This has been shown to be a contributing factor in higher rates of stroke and heart attack for certain COX-2 inhibitors.

On the other hand, Limbrel inhibits COX-1 and COX-2 at a ratio of almost 1:1, a more balanced action while leaving the body with necessary levels of COX-2 enzyme that it needs to generate proper amounts of arachidonic acid (AA) metabolites to maintain normal body functions.

In addition, Limbrel is the first and only prescription product to help nutritionally manage the 5-Lipoxygenase (5-LOX) pathway to reduce the production of Leukotriene B4 (LTB4 ), a potent chemoattractant molecule of white blood cells which can cause additional inflammation at the site of injury. Elevated LTB4 has been shown to contribute to gastric damage in mucosal lesions.* In fact, Limbrel’s unique COX/LOX Dual Mechanism of Action dampens AA metabolites, but allows the body to maintain pools of these necessary AA metabolites to perform essential functions. At the same time, Limbrel’s dual mechanism of action still manages the underlying metabolites which with chronic over production contribute to the progression of osteoarthritis.

*Husdon, N, et al., Enhanced Gastric Mucosal Leukotriene B4 Synthesis in Patients Taking Non-steroidal Anti-Inflammatory Drugs, Gut 1993;34:742-7.
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11. Question: What is Dual Mechanism of Action?

Answer:  Dual Mechanism of Action refers to Limbrel’s management of arachidonic acid (AA) metabolism across both the COX and LOX pathways to help restore a metabolic balance. This is especially important in the COX pathway composed of COX-1 and COX-2 where inhibition of either one over the other can result in gastric, renal, and cardiovascular problems. For example, inhibition of prostaglandins in COX-1 enzymatic conversion of AA necessary for gastric mucosal maintenance results in an increase in ulceration due to the production of leukotrienes that attract white blood cells to produce inflammatory which cause an ulcer. If one selectively inhibits the COX-2 enzymatic conversion of AA to prostacyclins, then thromboxanes from the COX-1 pathway dominate and vasoconstrict the arteries causing poor renal perfusion which can result in high blood pressure and peripheral edema. There is also a “shunting” of AA metabolism down the LOX pathway where vasoconstrictive leukotrienes are generated further constricting arteries. Such selective inhibition and shunting of metabolism can also lead to cardiovascular complications.

Limbrel provides inhibition management of LOX inflammatory metabolites in addition to balanced inhibition on COX-1 & COX-2 pathways. This dietary management of the metabolic aspects of osteoarthritis is critical to the mechanism of Limbrel.

Limbrel has a ratio of COX-2 to COX-1 activity of approximately 1:1.*

Of note, dual mechanism of action and selectivity refer to the modes of action of given products.  These terms do not refer to the regulatory class or the designated FDA category of given products.  Products in different regulatory classes may share some similarities in their modes of action.†

*Data on file at Primus Pharmaceuticals, Inc.
†Lipsky LP, Abramson SB, Crofford L, et al. 1998. The classification of cyclooxygenase inhibitors. (Editorial) J Rheumatol;25(12):2298-303
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12. Question: Are there clinical data supporting Limbrel?

Answer: Yes, strong clinical and scientific data support Limbrel and its constituent ingredients. In randomized placebo-controlled, double-blind as well as open-label studies, Limbrel has been clinically shown to deliver significant improvements in WOMAC measures for patients with osteoarthritis of the hip and/or knee. All primary clinical endpoints – functional mobility, functional stiffness and functional joint discomfort – showed significant improvements. The results of some Limbrel studies have been submitted for publication.

Additionally, one of the main components of Limbrel has been used in prescription products in Japan that have received approvals from the Pharmaceutical and Food Safety Bureau (the Japanese equivalent to the FDA) for over 20 years.
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13. Question: How strong of an antioxidant is Limbrel?

Answer: Limbrel is a very strong antioxidant. When compared to Vitamin C and Vitamin E in oxygen radical absorbance capacity (ORAC) assays, an assay designed to measure the ability to “soak” up reactive oxygen species (ROS, also known as oxygen free radicals), Limbrel’s ingredient combination, flavocoxid, has a high ORAC value (~5,500).* This value is higher than the comparable ORAC value of Vitamin C (~5,000) and Vitamin E (~1,100).* Limbrel’s antioxidant potency is even significantly higher than that of blueberries and grapes, well-known sources of antioxidants. In terms of the metabolic process associated with osteoarthritis, the ability of a product to absorb oxygen free radicals can be beneficial to cartilage. ROS oxidatively or chemically converts arachidonic acid (AA) to F2-Isoprostanes, 4-Hydroxynonenal, and malondialdehyde which are elevated in the synoviocytes and chondrocytes of osteoarthritis patients and have been shown to directly degrade cartilage.

*Data on file, Primus Pharmaceuticals, Inc.
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14. Question: Can Limbrel’s dose be increased beyond 250mg BID?

Answer: Consuming more than 250 mg BID of Limbrel should be only under a physician’s direction. Animal studies have shown that consuming the equivalent of up to 20 times the recommended human use (500mg/day) did not produce adverse effects.
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15. Question: What side effects have been observed in clinical practice?

Answer: In the clinical trials, the side effect incidence rates for Limbrel were comparable to or slightly higher than placebo. The reported adverse events for Limbrel include hypertension, varicose veins, fluid in knee, and psoriasis. There were no reports of anyone experiencing gastrointestinal difficulties in a 90-day human clinical trial.

The most common side effects that patients report with Limbrel are nausea, diarrhea and flatulence, which are often mild and do not usually require discontinued use of Limbrel. Serious upper GI reactions are rare, and in fact, clinical experience by physicians has shown Limbrel to be well tolerated in patients with a history of mild ulceration. Mild elevations in liver tests and rare cases of severe liver reaction symptoms (e.g. jaundice) have been reported, and were resolved within 2-4 weeks after Limbrel was discontinued. Liver abnormalities may be the result of a hypersensitivity reaction to one of the components of Limbrel. Extremely rare cases of allergic lung reactions that required treatments have also been reported. No kidney toxicity has been reported.

On-going safety data are collected through post-marketing surveillance for Limbrel. Patient and physician reported side effects are tracked and followed up. Click here for the most current post-marketing surveillance report for Limbrel.
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16. Question: Which patients should not use Limbrel?

Answer: Limbrel is indicated for the nutritional management of the metabolic aspects of osteoarthritis. Limbrel has not been investigated for use in the nutritional management of rheumatoid arthritis (RA), acute pain, or primary dysmenorrhea. There are no formal studies among the following patient groups: patients with a history of severe stomach ulcers, patients under the age of 18, and pregnant or lactating women. Clinical practice by physicians has shown that Limbrel is well-tolerated by patients with a history of mild ulcer.
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17. Question: Have there been any drug interactions with Limbrel?

Answer: Since Limbrel was first introduced in Puerto Rico in mid 2004, we have not received any physician reports of adverse events due to drug interactions with Limbrel. Limbrel was tested for potential drug interactions via a Cytochrome P450 (CYP450) assays. The test results strongly suggest that flavocoxid would not be likely to inhibit the biotransformation of prescription drugs. The CYP450 test does not indicate whether flavocoxid agonizes or antagonizes the action of the drug. Data from a human clinical study and animal studies does demonstrate that flavocoxid did not affect prothrombin (PT) or partial thromboplastin time (PTT) at either the 250 mg or 500 mg daily amount.
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18. Question: Can Limbrel be taken by patients taking a blood thinner such as coumadin?

Answer: In animal studies Limbrel had no effect on prothrombin (PT) times, no augmentation of aspirin or coumadin effects on PTT or PT and no effect on platelet aggregation when tested in platelet rich rabbit plasma.* In human clinical trials, Limbrel showed no changes in PT or PTT over a 90-day period at either 250 or 500 mg per day.* Nonetheless, we suggest that Limbrel be used cautiously in patients taking anticoagulants or anti-platelet agents, that patients be advised to look for and promptly report any evidence of unusual bleeding or bruising. Appropriate laboratory studies should be monitored on a regular basis in patients taking Limbrel with anticoagulants or anti-platelet agents.

* Data on file at Primus Pharmaceuticals, Inc.
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19. Question: How is Limbrel manufactured?

Answer: Limbrel is manufactured to FDA’s cGMP (current Good Manufacturing Practices) established and required for prescription drugs. The ingredients are USP and pharmaceutical grade. These standards ensure pharmaceutical level product quality, and go beyond FDA’s requirements for MFs generally.
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20. Question: How much does Limbrel cost?

Answer: Limbrel offers a substantial savings on an average of 15-20% for cash patients when compared to other leading prescription osteoarthritis products. For patients with health care coverage, they can expect about $25 to $50 co-pay, similar for other prescription osteoarthritis products. Individual plans may vary.
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21. Question: Is Limbrel reimbursed?

Answer: Limbrel is covered by many major health care plans, such as Aetna, United, Humana, Cigna (with prior authorization), Wellpoint, numerous Blue Cross/Blue Shields and many others.
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22. Question: How can my patients obtain Limbrel?

Answer: Limbrel is only available by prescription. Limbrel is distributed through pharmacies, so patients should take their prescriptions to their pharmacies to purchase Limbrel. If Limbrel is not currently in stock in a patient’s pharmacy, the pharmacist can order Limbrel for next-day delivery from the wholesale pharmacy distributors listed below.

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23. Question: What is the difference between a Medical Food and a Rx Drug?

Answer:

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24. Question: Are there on-going clinical studies on Limbrel?

Answer: There are several clinical studies on Limbrel already underway by respected thought leaders in addition to the current clinical studies which have been submitted for publication. More studies, including NIH funded studies, are also being executed to provide further scientific and clinical supports for the safety and effectiveness of Limbrel. These studies have been IRB approved.
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25. Question: What are other examples of medical food products?

Answer: Medical food products are not new. They have been widely used in hospitals, but have had relatively low awareness as a class of products among physicians, until recently. Click here for some examples of medical food products you might have heard of.
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26. Question: How does the physician determine the metabolic deficiency in osteoarthritis?

Answer: If the physician has made a clinical diagnosis that the patient definitely has osteoarthritis, then the patient generally has a metabolic deficiency underlying the disease. There are several types of deficiencies which can lead to osteoarthritis. The inflammatory process of metabolizing excess (due to osteoarthritis) arachidonic acid (AA) into higher-than-normal prostaglandins, prostacyclins, leukotrienes and thromboxanes generally leads to cartilage degradation. The oxidative process also generally leads to cartilage degradation. When patients have osteoarthritis and thus experience these metabolic conditions and concurrently do not derive a sufficient level of nutrients for osteoarthritis such as flavonoids (common sources are colored fruits & vegetables) and antioxidants in their diet, then they will have a metabolic deficiency. Such a deficiency is also called a dietary need for osteoarthritis. Specially formulated food ingredients can restore the metabolic process. Patients are especially deficient if their digestion and absorption systems are compromised particularly in the case of elderly patients or patients with achlorhidria. The physician can determine if a patient has a metabolic need in osteoarthritis by: first performing a clinical diagnosis of osteoarthritis and testing the patient’s oxidative status, second evaluating the dietary intake of the patient, and third assessing the digestion and absorption status of the patient.
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27. Question: How long does it take Limbrel to begin to manage osteoarthritis via nutritional management?

Answer: Limbrel’s onset of action varies according to the severity of osteoarthritis. In clinical practice, physicians find that patients with mild to moderate osteoarthritis feel an onset of action in as little time as several hours to 4-5 days after taking Limbrel. Moderate to severe osteoarthritis patients may feel onset of action in 5-10 days.
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28. Question: Should Limbrel be taken with or without other foods?

Answer: Limbrel is safe taken with or without other foods. Taking Limbrel one hour before or after meals help increases the absorption of Limbrel’s key ingredients into the blood by 10-15% (data on file). This observation is based upon a pharmacokinetic study in humans, as well as in-market clinical experience in analyzing physician and patient product reports. However, if your patients experience any indigestion, then we recommend that they take Limbrel with food. See Prescribing Information
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