- Clinical Pharmacology
- Indications & Usage
- Side Effects
- Dosage & Administration
- How Supplied
- Patient Counseling Information
- Supplemental Patient Material
- Boxed Warning
- Patient Package Insert
FULL PRESCRIBING INFORMATION
DivistaTM is specially designed as a once a day nutritional adjuvant to the current standard of care for patients with, or at risk of developing type 2 diabetes mellitus (T2DM). DivistaTM provides a method for reducing hyperglycemia and stabilizing the level of serum cholesterol.
DivistaTM is unique in that it utilizes two patented nutritional ingredients, Chromax® (chromium picolinate) and Diachrome® (chromium picolinate and biotin), along with Omega-3 fatty acids to aid in enhancing insulin sensitivity and improve blood sugar metabolism, while promoting healthy lipids and supporting healthy triglyceride levels.
Chromium: is an essential trace mineral required by the human body for normal carbohydrate and lipid metabolism (Wilson and Gondy, 1995). A number of diabetes-like signs and symptoms are seen in chromium deficiency including impaired glucose tolerance, fasting hyperglycemia, glucosuria, elevated circulating insulin and peripheral neuropathy. Dietary chromium intake less than 25% has been reported to adversely affect insulin sensitivity in subjects with mildly impaired glucose tolerance (Anderson, 2000). Over time, urinary chromium losses may contribute to insulin resistance and exacerbate compromised insulin sensitivity in individuals with type 2 diabetes mellitus (T2DM). (Anderson et al., 1991 ; Cefalu and Hu, 2004)
It has been reported that chromium complexes bind to an oligopeptide in order to become biologically active (Davis 1997). The chromium-bound peptide then binds to the insulin receptor and activates tyrosine kinase, amplifying insulin action (Cefalu and Hu, 2004; Wang et al., 2006). In vivo studies have shown that chromium picolinate stimulates intracellular GLUT-4 transporters to translocate from intracellular to the plasma membrane leading to enhanced glucose uptake in muscle cells. (Cefalu et al., 2002, Cefalu and Hu, 2004)
Daily Adequate Intake (AI) of chromium as set by the Institute of Medicine (IOM) is 35 μg for men and 25 μg for women (Food and Nutrition Board (FNB), 2002). A Daily Value (DV) for chromium in food and supplement labels of 120 μg per day was set in 1997 (Trumbo et al.,2001). Based on current research a Tolerable Upper Limit for chromium has not been established by the IOM.
Biotin: is a water-soluble B-complex vitamin necessary for protein, fat and carbohydrate metabolism. It is associated with the proper endogenous production of necessary fatty acids, lymphocytes, digestive enzymes and tissue metabolism. It feces, whereas absorbed amounts of biotin, which exceed the storage capacity of the organism are eliminated in the urine. Shortly after an oral take up of biotin, the biotin concentration in the plasma increases several times, but after 24 h the average value is reached again. In pharmacological dosages (mg-range), biotin stimulates the differentiation of epidermal cells. The effect is independent from the biotin status and influences all keratin structures, like hair, skin and nails.
Recent studies have shown that the elderly with 300 ng/l have a lower biotin level than younger adults and children, whose optimal range lies between 400 and 500 ng/l (Helbich Endermann et al., 1999). The biotin concentration in urine of all age groups is approximately 30 to 40 times higher than the respective serum concentration.
Chromium: Metabolism: The biologically active trivalent state of chromium (Cr3+) is responsible for its nutritional activity. The principal route by which trivalent chromium enters the body is the digestive system. Absorbed chromium circulates as free Cr3+, as Cr3+ bound to transferrin or other plasma proteins (Yamamoto et al. 1987, 1988; Vincent, 2000), or as complexes, such as glucose tolerance factor (GTF) (ATSDR 1998, EPA 1998a). Circulating trivalent chromium can be taken up by tissues, and its distribution in the body depends on the species, age, and chemical form.
The GTF may function by facilitating interaction between insulin and its receptor site, but additional investigations will be required to elucidate the exact mechanisms involved in the essentiality of trivalent chromium. The low molecular weight, chromium-binding complex identified from such sources as bovine milk and rabbit liver has been shown to have in vitro activities comparable to those of GTF with respect to insulin action (Yamamoto et al. 1987, 1988). Chromium is excreted primarily in the urine by glomerular filtration or bound to a low mol-wt organic transporter.
Biotin: Metabolism: Within cells, carboxylases are biotinylated via holocarboxylase synthase, requiring ATP and magnesium. Biotin is recycled from carboxylases via the action of proteolytic enzymes and biotinidase. Biotin is catabolized to a number of metabolites, including bisnorbiotin, biotin sulfoxide, biotin sulfone, and others.
Chromium: Elimination: Absorbed chromium is excreted mainly in the urine; small amounts are lost in hair, perspiration and bile. The 24-hour urinary excretion rates for normal human subjects are reported to be 0.22 μg/day (Gargas et al., 1994), consistent with the relatively low-absorption rate (approximately 0.5%) and typical daily chromium consumption rates (62-85 μg/day) (Anderson et al., 1983).
The tissue distribution, urinary and fecal loss and subcellular hepatocyte distribution and concentration of labels suggest that chromium picolinate has a lifetime of less than 1 day in vivo model. (Hepburn et al., 2002) Half life estimations are based on the three compartment model suggest that elimination from compartment one is relatively fast with a reported half life of seven hours. Elimination from compartments two and three are much slower with reported half lifes of fifteen days and three years respectively. (Gargas, 1994)
Biotin: Elimination: Biotin and biotin metabolites such as bisnorbiotin, biotin-d,l-sulfoxide, bisnorbiotin methyl ketone, and biotin sulfone are excreted in the urine.
There are no reported studies regarding the pharmacokinetic parameters of chromium picolinate or biotin in the geriatric population.
There are no reported studies regarding the pharmacokinetic parameters of chromium picolinate or biotin in the pediatric population.
Chromium: It has been noted that concomitant administration of antacids interferes with chromium absorption whereas aspirin and vitamin C administration potentiate absorption (Ref). However, the overall interference and potentiation of chromium absorption in these cases is minimal and not of clinically relevant concern.
Chromium may compete for one of the binding sites on the iron transport protein, transferrin (Lukaski et al., 1996). Serum iron concentrations and serum ferritin concentrations were unchanged by either resistive training or chromium picolinate supplementation. The high-dose chromium picolinate supplementation for 12 wk did not influence hematologic indexes or indexes of iron metabolism (Campbell, 1997).
Administration of 100 mg vitamin C with 1 mg of chromium resulted in higher plasma levels of chromium than with 1 mg of chromium alone (Food and Nutrition Board, 2001).
Diets high in simple sugars (e.g. sucrose), compared to diets high in complex carbohydrates (e.g. whole grains) increase urinary chromium excretion in adults. This effect may be related is a cofactor required of four enzymes that are involved in carboxylation reactions (acetyl-CoA carboxylase, pyruvate carboxylase, methylcrotonyl-CoA carboxylase, and propionyl- CoA carboxylase) (Dakshinamurti and Cheah-Tan 1968, Dakshinamurti et al., 1970) Biotin has been shown to stimulate hepatic glucokinase, increase pancreatic insulin production through glucokinase mRNA expression and enhance glucose uptake in muscle cells (Spence and Koudelka, 1984, Rodriguez et al., 2001, Trumble et al., 1991). It has been reported that biotin may also decrease expression of phosphoenolpryuvate carboxykinase, an enzyme necessary to down regulate hepatic gluconeogenisis (Dakshinamurti and Li, 1994). In animal and human clinical studies, biotin has been shown to enhance glucokinase activity and lower blood glucose (Romero-Navaro et al., 1999, Furukawa, 1999). Biotin appears to potentiate glucose-induced insulin release but does not appear to directly affect insulin release (Yoshikawa et al., 2002). /Symptoms of overt biotin deficiency include hair loss and a scaly red rash around the eyes, nose, mouth, and genital area. Neurological symptoms in adults have included depression, lethargy, hallucination, and numbness and tingling of the extremities. Individuals with hereditary disorders of biotin metabolism resulting in functional biotin deficiency have evidence of impaired immune system function, including increased susceptibility to bacterial and fungal infections. Zhang et al. (1997) reported low blood biotin levels in 43 non-insulin dependent diabetes mellitus patients with impaired utilization of glucose.
The AI for biotin assumes that current average intakes of biotin (35 mcg to 60 mcg/day) are meeting the dietary requirement (FNB-IOM, 1998). The IOM currently recommends an AI level for biotin of 35-60 μg/day for adults. (Food and Nutrition Board, 2000). The Daily Value (DV) for biotin in food and supplement labels is 300 μg per day. Based on current research a Tolerable Upper Limit for biotin has not been established by the IOM.
Folic Acid: Folic Acid is one of the important hematopoetic agents necessary for proper regeneration of the blood-forming elements and their function. Folic acid is a precursor of a large family of compounds which serve as coenzymes in carbon transfer reactions.
These reactions are required for the synthesis of purine and pyrimidine bases, interconversion of glycine and serine, biosynthesis of methionine methyl groups and degradation of histidine. Additionally, folic acid increases jejunal glycolytic enzymes and is involved in the desaturation and hydroxylation of long-chain fatty acids in the brain. A deficiency in folic acid results in megaloblastic anemia.
DivistaTM (Diachrome® (Chromax® chromium picolinate), Biotin, B6, B12, Folic Acid, Omega-3 Fatty Acids) is a prescription preparation indicated in the adjunctive treatment in patients at risk of developing type 2 diabetes mellitus (T2DM). DivistaTM regulates blood glucose levels, improves insulin sensitivity, and reduces hyperglycemia. DivistaTM is also designed to stabilize serum cholesterol levels to promote cardiovascular health. Optimal results have been observed after 90 days of administration,
however improvements may be seen as soon as 30 days. Results will vary
depending of the level of glycemic control of the patient at the start
of the regimen.
DivistaTM is contraindicated in individuals who are hypersensitive or allergic to any active or inactive ingredients contained in the product including fish or fish oil.
Warning: Ingestion of more than 3 grams of omega-3 fatty acids from fish oils per day may have potential antithrombotic effects, including an increased in bleeding time and INR (international normalized ratio). DHA should be avoided in patients with inherited or acquired bleeding diathesis, including those taking anticoagulants.
Warning: Folic acid alone is improper therapy in the treatment for pernicious anemia and other megaloblastic anemias where Vitamin B12 is deficient.
General: Folic acid in doses above 0.1 mg - 0.4 mg daily may obscure pernicious anemia, in that hematological remission can occur while neurological manifestations remain progressive.
There have been no additional or confirmational reports, nor have there been any substantiated serious adverse events reported by subjects participating in chromium picolinate clinical studies considered related to the product.
As with all nutritional supplements, pregnant or lactating women or individuals with serious health conditions should consult a physician.
Carcinogenesis, mutagenesis, impairment of fertility: Neither chromium picolinatenor biotin has been shown to be mutagenic or carcinogenic in vivo.
Folic acid: Allergic sensitizations have been reported following both oral and parenteral administration of folic acid.
The oral reference dose (RFD) for chromium, the upper limit of exposure thought to protect high risk populations including infants and pregnant women from toxicity, is 70,000 μg/ day. (Maher, 1999)
Adults (persons over 12 years of age), one (1) softgel daily, orally, or as prescribed by a physician. Do not exceed recommended dosage. Do not administer to children under the age of 12.
DivistaTM are opaque blue gelatin softgels imprinted “Divista 110”. Child resistant bottles of 60 softgel capsules. NDC# 52747-110-60. Dispense in a tight, light resistant container as defined by in the USP/NF. Store at room temperature 15° to 30°C (59° to 86° F). Keep in cool, dry place. Softgels are not USP.
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Chromium Picolinate CAPSULE