Fosteum

Primus Pharmaceuticals, Inc.

FULL PRESCRIBING INFORMATION

Each FOSTEUM capsule contains 27 mg of genistein aglycone (genistein), derived from a natural source, for a total daily intake of 54 mg. In clinical trials, this level of intake has been shown to increase bone mineral density (BMD). Genistein is chemically described as 4',5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one. It is the aglycone form of the glucoside isoflavone molecule genistin. The empirical formula of genistein is C₁₅H₁₀O₅; its molecular weight is 270.2. The structural formula is:

Each FOSTEUM capsule contains 20 mg citrated zinc bisglycinate, a glycine amino acid chelate of zinc formed in the presence of citric acid that provides approximately 4 mg of elemental zinc per capsule. Zinc is an essential mineral co-factor required by enzymes involved in bone metabolism and has important physiological functions in other tissues throughout the body. Elemental zinc has also been shown to have synergistic effects with genistein on bone formation. This zinc bisglycinate, formed in the presence of citric acid, has been shown to have improved absorption over inorganic zinc salts, such as zinc sulfate. Zinc bisglycinate, a chelate of zinc, is complex with an empirical formula of C4H8O4Zn; its molecular weight is 215.5. Its structural formula is:

When generated in the presence of citric acid, citrate and additional glycinate ions (not shown) also participate in this structure, forming citrated zinc bisglycinate, contributing to the complexity of the molecule.

The highly concentrated, pure form of genistein plus citrated zinc bisglycinate and vitamin D₃ in FOSTEUM is specially formulated for the dietary management of the metabolic processes of osteopenia and osteoporosis that cannot be achieved by a change in the normal diet. FOSTEUM provides the distinctive nutrients needed by osteopenic and osteoporotic patients. It restores the metabolic balance of bone turnover toward normal levels.

Epidemiological studies have shown that the risk of osteopenia and osteoporosis in Asian populations is generally 20-30% lower than in Western populations. This lowered risk has been associated with diet, specifically with intake of isoflavones, including genistein, of more than 20 mg per day, and protein from certain legumes of more than 5 g per day. At first glance, it is paradoxical that Asian countries with some of the lowest calcium intakes worldwide have a relatively low rate of osteoporotic hip fractures. Other dietary components, such as isoflavones, may affect the maintenance of bone density in these populations. Isoflavones are found in a variety of natural products. Data exist that support the reduction in bone loss when individuals adopt a diet rich in isoflavones. Moreover, the absence of high isoflavone intake when individuals transition to a more Western style diet results in increased bone loss. Clinical evidence has shown that pure genistein increases bone density in women who have been diagnosed with osteopenia or osteoporosis. Genistein exists in very low concentrations in natural products (generally less than 1%). This amount is not adequate to meet the dietary need of patients with osteopenia or osteoporosis. Concentrating and specially formulating the genistein in FOSTEUM allows the dietary need to be met in a convenient capsule form.

Daily Reference Intake for elemental zinc is 8 mg/day for women and 11 mg/day for men, as established by the Institute of Medicine of the National Academies as published by the National Academy of Sciences (IOM) in 2004. Supplementation with zinc and other minerals has been shown to improve spinal bone mineral density in post-menopausal women. Zinc is an essential co-factor for enzymes involved in the synthesis of bone matrix constituents. As people age, the level of zinc intake generally drops, potentially leading to zinc deficiency and reduced bone quality. Zinc has been shown to act synergistically with the genistein in FOSTEUM to favorably influence bone metabolism.

Vitamin D₃ is synthesized in the skin after exposure to UV radiation. A large segment of the American population is vitamin D deficient due to lack of sun exposure or skin aging, especially in northern latitudes and among the elderly who do not produce enough vitamin D₃. In the absence of sufficient vitamin D₃ production by the body, the vitamin must be obtained from the diet. Many Americans have inadequate dietary vitamin D intake. Calcitriol, the active form of vitamin D, is required for absorption of calcium from the intestine, regulation of serum calcium, bone formation and bone resorption among other activities.

FOSTEUM acts by restoring and maintaining the balance of bone turnover toward normal levels in osteopenia and osteoporosis. Clinical and preclinical data suggest that the genistein in FOSTEUM both reduces osteoclast-mediated bone resorption and stimulates the bone forming activity of osteoblasts. The zinc in FOSTEUM acts synergistically with the genistein, and the cholecalciferol improves the absorption of calcium and its deposition into the mineral matrix of bone.

Osteopenia and osteoporosis generally occur because of hormonal changes associated with the aging process or the use of certain classes of drugs. Bone loss associated with these conditions is primarily due to the metabolic imbalance that occurs when osteoclast activity is greater than osteoblast activity. The imbalance of bone resorption in excess of bone formation is progressive and often leads to fractures. These minimal trauma fractures may lead to significant morbidity and mortality. Successful dietary management of the metabolic processes underlying osteopenia and osteoporosis helps to restore the balance of bone resorption versus bone formation and consequently increases bone density over time.

The genistein in FOSTEUM reduces the activity of osteoclasts and promotes the formation of osteoblasts from progenitor stem cells to increase their number and activity in bone. The net effect is an enhancement of bone formation which restores bone remodeling toward normal levels and results in an increase in bone mineral density (BMD) over time. Through these clinical dietary modifications, FOSTEUM manages the metabolic processes of osteopenia and osteoporosis.

More specifically, preclinical studies suggest the following mechanisms of action: Genistein acts to reverse the effects of estrogen loss by decreasing cytokine production and increasing transforming growth factor ß (TGFß) levels. The net effect is a decrease in receptor activator of nuclear factor kappa B ligand (RANK-L) production, an increase in osteoprotegerin (OPG) levels, and a consequent decrease in overall osteoclast activity. Genistein also increases insulin-like growth factor-1 (IGF-1) leading to an increased number of proto-osteoblasts developed from mesenchymal stem cells. Genistein restores endothelial cell signals resulting in increased recruitment of these precursor cells to form osteoblasts. Genistein also reverses early apoptosis of osteoblasts. These actions likely produce a net increase in osteoblast activity and concomitant decrease in osteoclast activity.

In clinical trials, the genistein in FOSTEUM decreased urinary levels of the bone resorption markers deoxypyridinoline (DPYR) and pyridinoline (PYR), and increased serum levels of the bone formation markers bone-specific alkaline phosphatase (BAP), osteocalcin (OC), and IGF-1. These data suggest that genistein increases BMD over time by decreasing bone resorption and increasing bone formation.

Studies have shown that zinc has a positive effect on bone formation. The zinc in FOSTEUM is the citrated bisglycinate form, which has been shown to have improved absorption from the intestine compared to inorganic zinc salts.

Cell cultures of rat femoral-metaphyseal tissue treated with zinc and genistein produced a greater increase in BAP, DNA and bone calcium content compared with either agent alone. Other studies have demonstrated that genistein and zinc produce synergistic effects on osteoclast apoptosis and bone mineralization. Animal studies support these findings by showing that the combination of zinc and genistein increases mineralization in bone over genistein alone. In both men and women, zinc was shown to potentiate the effect of high genistein-containing fermented food on bone markers by further increasing the levels of BAP and OC. Based on these data, genistein and zinc increase osteoblast activity while decreasing osteoclast activity to a greater extent than either genistein or zinc alone.

The physiologically active form of vitamin D, calcitriol, regulates calcium and phosphate absorption and modulates serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption. Vitamin D deficiency is associated with a negative calcium balance, increased parathyroid hormone levels, bone loss and increased risk of skeletal fracture. Severe deficiency results in hyperparathyroidism, hypophosphatemia, bone loss, proximal muscle weakness and osteomalacia.

The genistein in FOSTEUM is freely absorbed in the gut, where it is at least partly converted to one metabolite, 7-O-beta-glucuronide, before it crosses the mucosa from the intestinal lumen. In hepatic first pass metabolism, genistein is converted via a two-stage process involving initial CYP450-mediated hydroxylation, followed by glucuronidation and sulfonation to the principal conjugated circulating metabolites. Genistein metabolites are converted back into the aglycone form in a variety of tissues. The aglycone is believed to be the principal active form, but conjugates have shown some activity in estrogen-receptor binding assays. Genistein and its conjugates are excreted via urine and bile.

In clinical studies, the effects of genistein in FOSTEUM on blood chemical, hepatic and renal functional measures were compared in post-menopausal subjects receiving genistein plus calcium carbonate (calcium) and vitamin D3 with post-menopausal, age-matched subjects receiving only calcium and vitamin D3. No changes were noted over a three year period in either group and all measures remained within normal limits.

Since the precursor form of vitamin D3 is transformed to the active form in the liver and then kidney, it is expected that patients with severe liver or kidney impairment may not transform the vitamin adequately.

Effects of the genistein in FOSTEUM on breast density, vaginal cytology and endometrial thickness were tested in double-blind, placebo-controlled clinical trials. One trial with 30 post-menopausal subjects in each arm found that genistein did not affect endometrial thickness over a one year period compared to placebo. In other controlled trials, daily administration of 54 mg of genistein over one, two and three year periods produced no increases in endometrial thickness or breast density in post-menopausal women. Furthermore, a subset of 113 post-menopausal women showed no change in vaginal cytology following one year of daily genistein therapy. These data suggest that the genistein in FOSTEUM does not produce adverse estrogenic effects in reproductive tissues.

In a study of 60 post-menopausal subjects comparing the cardiovascular markers of those receiving the genistein in FOSTEUM to a matched group receiving placebo, homocysteine and C-reactive protein (CRP) were assessed at baseline and again at 6 months. No statistically significant differences were seen between groups. Soluble intercellular adhesion molecule-1 (iCAM), vascular cell adhesion molecule-1 (vCAM), fibrinogen and F2-isoprostane levels were assessed at baseline and again at 12 and 24 months in 389 post-menopausal subjects randomized to receive either genistein, calcium and vitamin D₃ or calcium and vitamin D₃ only (placebo). At both 12 and 24 months, the levels of all four cardiovascular markers were reduced in the genistein group compared to both baseline and placebo at all time points. No significant changes in lipid profile were observed in either the genistein or placebo group over the course of the study. These data indicate that genistein does not adversely affect markers of cardiovascular risk. An additional study of 53 post-menopausal women measured changes in flow-mediated vasodilation and plasma nitric oxide status. The genistein in FOSTEUM significantly increased plasma nitrite/nitrate levels and reduced levels of endothelin-1 compared to placebo. After 12 months of use, forearm blood flow increased significantly during reactive hyperemia in the genistein group compared to placebo. Flow-mediated dilation in the proximal and distal brachial arteries both increased significantly after genistein administration. The purified genistein in FOSTEUM improved endothelial function in a cohort of post-menopausal women.

FOSTEUM has not been tested in pregnant or nursing women.

FOSTEUM has not been studied for its effect on bone in human males. No specific studies on genistein aglycone and feminization in human males exist.

FOSTEUM has not been tested in pediatric patients.

In a two-year clinical trial, 389 subjects were randomized to either genistein plus calcium and vitamin D3 n=198, or calcium and vitamin D3 alone n=191. A total of 52 subjects in both groups discontinued due to adverse events. Study discontinuation in these subjects was due to gastrointestinal symptoms, including abdominal and epigastric pain, dyspepsia, vomiting and constipation. Discontinuation was reported in both groups. The incidence of adverse events was statistically higher in the genistein group over both years of the study. The major adverse events are shown in the table below without attribution of causality.

Some of these adverse event occurrences may be attributable to the intake of 1,000 mg per day of calcium carbonate by subjects in both groups. Taking FOSTEUM with food may reduce or eliminate some gastrointestinal symptoms.

To determine the disposition of the genistein in FOSTEUM, a steady-state pharmacokinetic (PK) study was conducted in post-menopausal women aged 50-66. Ten subjects took FOSTEUM without food (fasted group) and 10 subjects took FOSTEUM with food (fed group) twice daily for seven (7) days. On the eighth day, blood was collected at 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48 and 96 hours after ingesting FOSTEUM with (fed group) or without (fasted group) food. Concentrations of serum aglycone (protein bound and unbound) and total genistein (aglycone plus circulating conjugated forms) were determined at each time point for standard pharmacokinetic analyses.

Levels of free genistein aglycone were in the low nanomolar range and below the level of quantification in several subjects. Therefore, meaningful pharmaco-kinetic parameters could not be calculated from the data. Consistent with previous studies, the majority of circulating genistein existed in the conjugated form. Pharmacokinetic analyses for total genistein reported in the table below revealed no significant difference in any parameter between the fed and fasted groups, suggesting that FOSTEUM may be taken with or without food. The serum half-life (t1/2) among all subjects was 9.6 hours. Based on this profile, BID is recommended.

Effect on Bone Mineral Density

Efficacy of the genistein in FOSTEUM was demonstrated in a multi-center, double-blind, placebo-controlled clinical study of 389 randomized post-menopausal patients with osteopenia or osteoporosis (genistein n=198; placebo n=191). All subjects received calcium (1,000 mg/day) and vitamin D₃ (800 IU/day) in two divided doses.

After two years, significant increases were seen in BMD at both lumbar spine and femoral neck relative to both baseline and placebo in patients who received genistein. In a third year extension, 138 patients continued on blinded study product. Patients taking the genistein in FOSTEUM showed a continued increase in BMD at both lumbar spine and femoral neck. In this cohort, 85% of the patients in the genistein arm showed increased BMD.

Bone markers were measured and found to support the proposed mechanism of action as levels of formation markers were increased and levels of resorption markers were reduced in the genistein group compared with baseline as shown in the table below.

Genistein's efficacy was also shown in a one year trial of 90 osteopenic or osteoporotic, post-menopausal subjects vs. placebo and vs. HRT. Baseline values were matched for all parameters. The BMD values at 12 months are shown in the table below:

There is limited information regarding acute vitamin D3 toxicity in humans. Single doses of ergocalciferol (vitamin D2) up to 600,000 IU have been given without noted toxicity. In patients suffering from diseases, such as leukemia, lymphoma or sarcoidosis, that are associated with unregulated overproduction of calcitriol, supplemental vitamin D3 may worsen hypercalcemia and/or hypercalciuria. Regular monitoring of urine and serum calcium may be indicated in this population.

Symptoms of vitamin D toxicity include hypercalcemia, hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia, weakness and lethargy. Serum and urine calcium levels should be monitored in patients with suspected vitamin D toxicity. Standard therapy includes restriction of dietary calcium, hydration and systemic glucocorticoids in patients with severe hypercalcemia.

FOSTEUM is an off-white capsule with "FOSTEUM" and "52003" printed in blue on the cap and body respectively. They are supplied as follows:68040-603-16 unit-of-use bottle of 60 capsules with desiccant (30-day supply)

Manufactured for:
Primus Pharmaceuticals, Inc.
Scottsdale, AZ 85251
www.primusrx.com

Manufactured by:
Cornerstone Research & Development, Inc.
Farmington, UT 84025

Avéma Pharma Solutions
Miami, FL 33172

U.S. Patent Nos. 5,935,996 and 5,516,925. Patents pending. U.S. Patent No. 5,516,925 is under license from Albion Laboratories, Inc, Clearfield, UT.

©2011 Primus Pharmaceuticals, Inc. All rights reserved. ISS. 0111 #13008