Fosteum Package Insert

Product Information

FOSTEUM™ Capsules
genistein (27 MG)
zinc chelazome®* (20 MG)
cholecalciferol (200 IU)

FOSTEUM is a specially formulated prescription medical food product for the clinical dietary management of the metabolic processes of osteopenia and osteoporosis. FOSTEUM must be administered under physician supervision.

DESCRIPTION

FOSTEUM™ consists of a specially formulated proprietary blend of high purity genistein from soy, zinc chelazome* and cholecalciferol (vitamin D3). Genistein reduces osteoclast activity while stimulating osteoblast activity. The zinc works synergistically with genistein, while both zinc and vitamin D3 work independently as well to promote mineralization activity in bone. Vitamin D3 also facilitates calcium absorption from the intestine.

Genistein

Each FOSTEUM capsule contains 27 mg of genistein, isolated and purified from soy, for a total daily intake of 54 mg, a level 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. Genistein 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:

Genistein structure

Zinc chelazome

Each FOSTEUM capsule contains 20 mg zinc chelazome, a glycine amino acid chelate of zinc formed in the presence of an organic acid that provides approximately 4 mg of elemental zinc per capsule. Zinc is an essential mineral used 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 form of zinc has been shown to have improved absorption over other zinc chelates. The empirical formula is C4H8O4Zn; its molecular weight is 215.5. The structural formula is:

Zinc chelazome structure

Cholecalciferol

Each FOSTEUM capsule contains cholecalciferol equivalent to 200 IU vitamin D3. Vitamin D3 is the natural form of vitamin D produced when skin is exposed to the sun. Vitamin D3 is a necessary vitamin required for the absorption of calcium from the intestine and the use of absorbed calcium in the mineralization of bone. Cholecalciferol is the natural precursor of calcitriol (1,25-dihydroxycholecalciferol). It is described as (3ß,5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-3-ol. The empirical formula is C27H44O; its molecular weight is 384.6. The structural formula is:

Cholecalciferol structure

Other Ingredients

FOSTEUM contains the following other ingredients, as fillers: dicalcium malate, magnesium oxide, microcrystalline cellulose, magnesium stearate, silicon dioxide and Vcaps® (veggiecaps) as the capsule. FD&C Blue #2 is used for the imprint on the capsule. FOSTEUM does not contain fructose, glucose, sucrose, lactose, gluten, maltodextrin, tree nuts, peanuts, flavors or products of animal or seafood origin.

Medical Food

Medical Food products are used, under a physician’s supervision, 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 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.” FOSTEUM has been developed, manufactured and labeled in accordance with both the statutory and the FDA regulatory definition of a medical food. FOSTEUM is to be used under a physician’s supervision.

Generally Recognized As Safe

The ingredients in FOSTEUM are Generally Recognized As Safe (GRAS). This is a standard that the U.S. Food and Drug Administration (FDA) requires of all ingredients added to food products; it means that the product is generally recognized by qualified experts as safe for its intended use.

OSTEOPENIA AND OSTEOPOROSIS

Osteopenia and osteoporosis are gradations of the same disease state involving loss of bone mass. Osteopenia may progress to osteoporosis.

DIETARY NEED

The highly concentrated, pure form of genistein plus zinc 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 normal bone turnover.

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 soy isoflavone, including genistein, of more than 20 mg per day, and soy protein 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 soybeans and other soy products. Data exist that support the reduction in bone loss when individuals adopt a diet rich in soy protein and isoflavones. Moreover, the absence of high soy 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 soy food products (generally less than 1%). This amount is not adequate to meet the dietary need of patients with osteopenia or osteoporosis but can be met by the specially formulated FOSTEUM. Patients consuming FOSTEUM have a diminishing ability to digest food as they age. The quantity of genistein in this product is designed to provide the daily intake these individuals require in order to overcome the potential reduced gastrointestinal absorption capacity in older individuals most at risk for osteopenia and osteoporosis.

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 postmenopausal 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 genistein to increase BMD.

Vitamin D3 can be synthesized after exposure to UV radiation, but is deficient in a large segment of the American population due to lack of sun exposure, especially in northern latitudes and in elderly populations. In the absence of sufficient vitamin D3 from sun exposure, the vitamin must be obtained from the diet, but most Americans have inadequate vitamin D intake. The active form of vitamin D, calcitriol, is required for absorption of calcium from the intestine, regulation of serum calcium, bone formation and bone resorption among other activities.

CLINICAL PHARMACOLOGY

Mechanism of Action

FOSTEUM acts by restoring and maintaining the balance of bone turnover in osteopenia and osteoporosis. The genistein in FOSTEUM acts to counter the loss of estrogen, thereby increasing the number, lifespan and activity of osteoblasts. Concurrently, genistein dampens the activity of osteoclasts. The zinc acts synergistically with the genistein, and the cholecalciferol improves the absorption of calcium and its deposition into the mineral matrix of bone.

Bone loss is shown in published studies to be the primary clinical manifestation of osteopenia and osteoporosis. The metabolic imbalance found in osteopenia and osteoporosis generally occurs because of hormonal changes associated with the aging process, or the side effects caused by 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. Such fractures may lead to significant morbidity and mortality. Thus, successful dietary management of the metabolic processes underlying osteopenia and osteoporosis helps to restore the balance of bone resorption versus bone formation. A diet containing calcium, vitamin D3 and soy products is often not sufficient. The normalization of relative osteoblast to osteoclast activity provided by Fosteum intake results in a reduction of bone loss by correcting the distinctive imbalance in metabolism that characterizes these disease states through administration of a specially formulated combination of nutritional ingredients.

Genistein

The genistein in FOSTEUM dampens 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 activity which thereby restores proper bone remodeling 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, animal 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. At the same time, genistein 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 together create net increase in osteoblast number, greater activity and longer lifespan, which results in greater bone formation capacity, thus restoring homeostasis to bone re-modeling.

Zinc chelazome

Studies have shown that zinc has a positive effect on bone formation. The zinc in FOSTEUM is the chelazome form, which has been shown to have improved absorption from the intestine compared to other forms of zinc.

Cell cultures of rat femoral-metaphyseal tissue treated with zinc and genistein produced a greater increase in bone alkaline phosphatase, DNA, and bone calcium content compared with either component alone. Other studies have further characterized the effects of genistein and zinc by demonstrating that they 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 soy food on bone markers by further increasing the levels of bone alkaline phosphatase and carboxylated osteocalcin. Based on these data, genistein and zinc increase osteoblast activity while decreasing osteoclast activity to a greater extent than either genistein or zinc alone.

Cholecalciferol

When ultraviolet light acts on 7-dehydrocholesterol (provitamin D3) in skin, it is converted to 9,10-secosterol (previtamin D3). Without adequate sun exposure, such as in northern climates, with covering clothing, indoor habitation or sunscreen use, individuals become deficient in vitamin 3 and vitamin D3 becomes an essential dietary nutrient.
Previtamin D is converted into 25-hydroxycholecalciferol in the liver by the P450 enzyme CYP27. This molecule is further converted in the kidney by the P450 enzyme CYP27B1 to 1,25-dihydroxycholecalciferol (calcitriol). This active form, 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.

METABOLISM

Genistein

Genistein 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 to calcitriol via a two-stage process involving initial CYP450-mediated hydroxylation, followed by further conversion to the principal conjugated circulating metabolites, genistein-glucuronides and -sulfates. Genistein metabolites are converted into the aglycone form in a variety of tissues. The aglycone is believed to be the principle active form, but conjugates have shown some activity in estrogen-receptor-binding assays. Genistein and its conjugates are excreted into urine or bile.

Zinc

Zinc chelazome consists of zinc chelated by glycine in the presence of an organic acid. When ingested, the compound is absorbed via passive diffusion from the small intestine and is expected to be hydrolyzed into its zinc and glycine components in the intestinal lumen. Subsequently, glycine is expected to be utilized in normal protein metabolism and zinc is expected to be bound to albumin and distributed throughout the body. The majority of zinc in the human body is found in muscle and bone. Excretion occurs predominantly via the feces.

Cholecalciferol

Ultraviolet light acts on 7-dehydrocholesterol (provitamin D3) in skin, where it is converted to 9,10-secosterol (previtamin D3). Previtamin D3 is converted into 25-hydroxycholecalciferol in the liver by the P450 enzyme CYP27. This molecule is further converted in the kidney by the P450 enzyme CYP27B1 to the active hormone 1,25-dihydroxycholecalciferol (calcitriol).

CLINICAL EXPERIENCE

Hepatic and Renal Effects

The effects of genistein in FOSTEUM on hepatic or renal tissue histology were examined by following organ-specific markers in clinical trials. In these studies, the test subjects were evaluated relative to placebo control groups of matched subjects. No changes were noted over a three year period across all groups. Blood electrolytes were unchanged and liver enzyme levels and markers of renal function were all 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 on Reproductive Tissue

Genistein’s effects on breast density, vaginal cytology and endometrial thickness were tested in double-blind, placebo controlled clinical trials. One trial with 30 women 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 postmenopausal women. Furthermore, a subset of 115 postmenopausal women showed no change in vaginal cytology following one year of daily genistein therapy. These data suggest that genistein does not produce adverse estrogenic effects in reproductive tissues.

Cardiovascular Safety

In a study of 60 patients comparing the cardiovascular markers of those taking genistein to placebo, homocysteine and c-reactive protein (CRP) were assessed at baseline and again at 6 months. No statistically significant differences were seen compared to placebo. 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 patients randomized to receive either genistein or placebo. At both 12 and 24 months, the levels of all four cardiovascular markers were reduced compared to both baseline and placebo. 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 postmenopausal women measured changes in flow-mediated vasodilation and plasma nitric oxide status. Genistein 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 postmenopausal women.

Menopausal Symptoms

In a study comparing the genistein in FOSTEUM to hormone replacement therapy (HRT) and placebo (n=90), patients taking genistein showed a reduction in the number and severity of hot flashes by over 50% each compared to women taking placebo. In a larger follow-on study compared to placebo (n=247), genistein progressively decreased hot flash number and severity over a one year period. At the twelve month follow-up, genistein produced a 50% decrease in number and severity of hot flashes compared to baseline, whereas the placebo group was unchanged.

Blood Glucose and Insulin Resistance

Genistein was also found to significantly reduce fasting glucose and insulin levels, as well as insulin resistance, in 350 postmenopausal women over a 2 year period and in a subset of 138 patients over a 3 year period.

Drug Interactions

Genistein

When genistein in FOSTEUM was tested in an in vitro pooled human liver microsome assay, there was significant inhibition of CYP450 2C8 and 2C9 yielding IC50s of 2.5 and 2.8 µM, respectively. A pharmacokinetic study using a single 50 mg genistein dose in six healthy women yielded a Cmax of 1.26 + 0.27 µM. In a two year study of 389 osteoporotic or osteopenic women consuming 27 mg bid of genistein, steady-state concentrations of genistein were found to be between 0.7 and 0.8 µM. In addition, a 14-day steady-state pharmacokinetic study in 20 healthy women who consumed 54 mg of genistein once daily showed a Cmax of approximately 0.8 µM.

Cholecalciferol

Cimetidine, thiazides and anticonvulsants may increase catabolism of vitamin D3. Cholestyramine and other bile acid sequestrants, as well as mineral oil, orlistat and olestra may impede absorption of vitamin D3 from the intestine.

TOXICITY

Genistein

Genistein showed no toxicity in rats over a 14-day observation period following acute dosing up to 2000 mg/kg. Long-term toxicity studies up to 52 weeks duration using oral administration of 0-500 mg/kg/day in rats and dogs showed minimal toxicity. Changes were primarily observed at the 500 mg/kg/day dose. From these studies the no observed adverse effect level for genistein in rats was determined to be 50 mg/kg/day and in dogs >500 mg/kg/dau. These intake levels are at least 50-fold greater than the recommended dose of the genistein in FOSTEUM on a mg/kg basis.

Zinc

The National Academy of Sciences upper acceptable limit for self-administration is 40 mg/day of elemental zinc, the equivalent of ten FOSTEUM capsules per day. Zinc is considered acutely toxic at 200 mg elemental zinc per day, the equivalent of 50 FOSTEUM capsules per day.

Cholecalciferol

Cholecalciferol may produce toxicity with long term, high-dose consumption. While medical doses of vitamin D3 up to 10,000 IU per day are sometimes administered under physician supervision, the upper acceptable limit for self-administration is 2,000 IU per day per the Daily Reference Intakes of the Institute of Medicine published by the NAS in 2004. Signs and 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.

SPECIAL POPULATIONS

Pregnant or Nursing Women

FOSTEUM has not been tested in pregnant or nursing women.

Pediatrics

FOSTEUM has not been tested in pediatric patients.

Gall Bladder Impairment

Patients who have inadequate bile production may not adequately absorb vitamin D3.

Renal Impairment

In patients who have renal insufficiency, conversion of 25-hydroxycholecalciferol to the active hormone, calcitriol, may be impaired.

Males

Genistein has not been specifically studied for bone building activity in human males. Genistein has been tested in male animals in one acute dosing study. While not intended to be a safety study, no feminizing characteristics or changes in testis size were observed. Other animal studies of soy and isoflavones show a feminizing effect during fetal and pre-pubescent development resulting in hypogonadism, but the same effect has not been observed in post-pubescent males. No specific studies on genistein and feminization in human males exist.

INDICATIONS AND USAGE

Indications

FOSTEUM is indicated for the clinical dietary management of the metabolic processes of osteopenia and osteoporosis.

Usage

FOSTEUM is recommended to be co-administered with calcium unless the diet provides sufficient intake. The Institute of Medicine recommends that patients over the age of 50 should consume 1,200 mg of calcium per day. Particular patients, however, may require different amounts as determined by a physician.

Interactions with Food

FOSTEUM can be taken with or without other foods. Food does not affect the metabolism of FOSTEUM and may buffer effects of slight indigestion. FOSTEUM may be taken with any beverage desired.

PRECAUTIONS AND CONTRAINDICATIONS

General

Causes of osteopenia or osteoporosis other than menopause or aging should be considered.

Hypersensitivity

FOSTEUM is contraindicated for anyone having a hypersensitivity to any ingredient in the product. See page 2 for a full list of ingredients.

Patients with Cancer

Since no studies have been done in these populations, as a precaution, FOSTEUM is contraindicated for patients with a history of cancer of the breast or reproductive organs.

Vitamin D Deficiency

FOSTEUM is not intended to treat vitamin D deficiency, generally characterized in the literature by serum levels of 25-hydroxycholecalciferol below 9 ng/mL. FOSTEUM contains 400 IU of cholecalciferol in two recommended capsules per day, but the NAS recommended daily dose in patients over the age of 70 is 600 IU/day. FOSTEUM should be taken with a calcium/vitamin D3 supplement sufficient to meet the daily requirement or as recommended by a physician. Patients with gastrointestinal malabsorption may require higher doses of vitamin D3 and measurement of serum levels of 25-hydroxycholecalciferol may be indicated in this population.
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.

ADVERSE EVENTS

In a two-year clinical trial of 389 randomized subjects (genistein n=198; placebo n=191), study discontinuation due to gastrointestinal symptoms, including abdominal and epigastric pain, dyspepsia, vomiting and constipation, was reported in both groups. The incidence of these events was statistically higher in the genistein than the placebo group over both years of the study as shown in the table below. Adverse events are shown without attribution of causality.

ADVERSE EVENTS Year 1 Year 2
GENISTEIN (n=178) PLACEBO (n=172) GENISTEIN (n=150) PLACEBO (n=154)
Abdominal Pain 4 (2.2%) 2 (1.1%) 2 (1.3%) 1 (0.6%)
Epigastric Pain 3 (1.7%) 0 (0.0%) 2 (1.3%) 0 (0.0%)
Dyspepsia 2 (1.1%) 1 (0.6%) 7 (4.7%) 2 (1.3%)
Vomiting 2 (1.1%) 2 (1.1%) 2 (1.3%) 1 (0.6%)
Constipation 5 (2.8%) 3 (1.7%) 8 (5.3%) 3 (1.9%)

Some of these occurrences may be attributable to the intake of 1,000 mg per day of calcium by subjects in both groups. If a patient experiences gastrointestinal symptoms, they may be reduced or eliminated by consuming FOSTEUM with food.

PHARMACODYNAMICS

Genistein

Genistein is an isoflavone isolated from soy that inhibits the activity of osteoclasts and stimulates the activity of osteoblasts, resulting in a measured increase in bone mineral density. The action of genistein on bone is supported by a decrease in the markers of bone resorption, such as serum C-terminal telopeptide of type I collagen (CTX), deoxypyridinoline and pyridinoline, and by the increase in markers of bone formation, such as bone-specific alkaline phosphatase and insulin-like growth factor 1.

PHARMACOKINETICS

Genistein

Doses of genistein at 27 and 54 mg were given to 20 postmenopausal women (ages 20-45 years with BMIs between 18 and 24) after an overnight fast for 14 days. Blood was drawn and plasma genistein levels followed over a 24 hour period after the final dose. As shown in the table below, the maximum level was reached in the plasma after 4 and 5 hours respectively. The half-life of the 27 mg dose occurred around 8 hours, while the half-life for the 54 mg dose occurred at 9 hours. Based on this pharmacokinetic profile, bid dosing is recommended.

  tmax h T 1/2 h
Genistein 27 mg 4.2±0.48 7.9±0.9
Genistein 54 mg 5.2 ±0.43 9.1 ±1.1

CLINICAL STUDIES

Dietary Management of Osteopenia/Osteoporosis

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 postmenopausal patients with osteopenia or osteoporosis (genistein n=198; placebo n=191). Both the genistein arm and the placebo arm received calcium and vitamin D3.

Mean Percent Change in BMD over 24 Months

SITE 12 months vs. baseline 24 months vs. baseline
GENISTEIN (n=178) PLACEBO (n=172) GENISTEIN (n=150) PLACEBO (n=154)
Femoral Neck 2.4% -2.2% 5.1% -5.3%
Lumbar Spine 2.9% -3.6% 5.8% -6.3%

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 one-year extension of a two-year study on a subset of 138 patients, a continued increase in BMD was observed in the genistein arm for both lumbar spine and femoral neck. In this subgroup, analyzed separately for the two and three year time points, genistein continued to produce a significant increase in BMD of the lumbar spine and femoral neck in the third year of the trial. In this cohort, 85% of the patients in the genistein arm responded with increased BMD. These data suggest that genistein in FOSTEUM has a sustained beneficial effect on BMD over three years.

Mean Percent Change in BMD over 24 and 36 Months (Subgroup Analysis)

SITE 24 months vs. baseline 36 months vs. baseline
GENISTEIN (n=71) PLACEBO (n=67) GENISTEIN (n=71) PLACEBO (n=67)
Femoral Neck 6.2% -4.9% 8.0% -7.7%
Lumbar Spine 5.7% -8.7% 8.8% -11.7%

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

Mean Percent Change in BMD at 12 Months vs. Baseline

SITE GENISTEIN (n=30) HRT (n=30) PLACEBO (n=30)
Femoral Neck 3.6% 2.4% -0.7%
Ward’s Triangle 4.0% 3.0% -0.4%
Lumbar Spine 3.0% 3.8% -1.6%

Mean Percent Change in Bone Markers at 36 Months vs. Baseline

  GENISTEIN PLACEBO
BAP +48.1% -1.0%
PYR -19.1% +7.3%
DPYR -15.5% 0.0%

Fracture Prevention

The studies that have been performed on the genistein in FOSTEUM to date have not been intended to assess fracture as a primary endpoint. These studies have, however, been shown to reduce markers of bone resorption, increase markers of bone formation and increase BMD in clinical trials, as shown in the tables above. In the 389 patient clinical trial comparing genistein to placebo over a two-year period, there were three fractures of the sacrum in the placebo group. No fractures were observed in the genistein group over two years.

Concomitant Use

No studies have been performed assessing the efficacy or safety of concomitant use of FOSTEUM with HRT, bisphosphonates, SERMs or anabolics. Given that the mechanism of action of bisphosphonates and that of FOSTEUM are different, it would be reasonable to expect that the actions of the two would be complementary. Since no studies have been done and because HRT, SERMs and FOSTEUM work with similar mechanisms of action, we do not recommend concomitant use of these products.

OVER USAGE

Genistein

There are no known cases of of overusage of the genistein in FOSTEUM. Animal studies have shown that consuming the equivalent of 75 FOSTEUM capsules at one time did not produce adverse events. However, as in most over usage situations, symptoms following an over usage of FOSTEUM 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.

Zinc

Symptoms of acute zinc toxicity occur after ingestion of 2 g or more of elemental zinc, the equivalent of 500 FOSTEUM capsules at one time. Chronic zinc toxicity, resulting from induced copper deficiency, is increasingly common as the use of large doses of zinc in supplements becomes more routine. Those on long-term supplementation or high doses of zinc-containing cold medication, zinc lozenges, etc., should be monitored for zinc and copper status.

Cholecalciferol

Significant lethality occurred in mice treated with a single high oral dose of calcitriol (57,000 IU). Calcitriol is the hormone metabolite of cholecalciferol.

There is limited information regarding acute toxicity in humans. Single doses of ergocalciferol (vitamin D2) up to 600,000 IU have been given without noted toxicity.

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.

DOSAGE AND ADMINISTRATION

FOSTEUM should be taken twice a day, approximately 12 hours apart, and may be taken with or without food. FOSTEUM has no food limitations including grapefruit or coffee. There are no postural limitations. FOSTEUM should be taken with a calcium supplement sufficient to meet the recommended intake. Additionally, if the patient is over 70 or has other factors contributing to an increased requirement for vitamin D3, an appropriate vitamin D3 supplement should be recommended. Calcium, with or without vitamin D3, should be taken in divided doses during the course of the day to optimize absorption. The current National Academy of Sciences recommendation for calcium from all sources is 1,200 mg/day for women over 50. FOSTEUM supplies 200 IU vitamin D3 per capsule for a daily total of 400 IU. The recommended intake of vitamin D3 for women over 70 is 600 IU/day.

HOW SUPPLIED

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 bottles of 60 capsules with desiccant (30-day supply)
  • 68040-603-18 carton of 10 2-day sample envelopes (40 capsules total)
  • 68040-603-05 envelope of 4 sample pouches (4 capsules total)
  • 68040-603-01 sample pouch containing 1 capsule.

Storage

Store at room temperature 59° – 86°F (15° – 30°C). Protect from light and moisture. Store capsules in original bottle until usage. Keep out of reach of children.

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

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

Manufactured by:
Pan American Labs
Miami, FL 33172

U.S. Patent Nos. 5,935,996 and 5,516,925. Patents pending. U.S. Patent No. 5,516,925 and *Chelazome® are under license from Albion Laboratories, Inc, Clearfield, UT.
©2007 Primus Pharmaceuticals, Inc. All rights reserved.
ISS. 0507 #13008

Last modified on 07-26-2007