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Therapeutic Justification /Rationality

EACH HARD GELATIN CAPSULE CONTAINS:

Methylcobalamin 1500 mcg, Alpha Lipoic acid 200 mg, Pyridoxine HCl 3

mg, Folic acid 1.5 mg and Biotin 200 mcg.


INTRODUCTION

Vitamin B8 or biotin is one of the most active biological substances known. An

extremely small amount of this vitamin has a marked effect on the growth of

yeast and certain bacteria. It forms part of several enzyme systems. Biotin is

freely soluble in hot water, but sparingly in cold water. It is insoluble in fat

solvents and sparingly soluble in alcohol. Water, sulpha drugs, oestrogen, food

processing techniques, alcohol, and in particular, large quantities of egg white

can destroy this vitamin.

Biotin is a water-soluble vitamin that is generally classified as a B-complex

vitamin. Biotin is required by all organisms but can be synthesized only by

bacteria, yeasts, molds, algae, and some plant species .Biotin is a B vitamin

that functions as a coenzyme in the metabolism of carbohydrates, fats, and

amino acids. Although it is vitally necessary to the body, only exceedingly small

quantities are needed, and since biotin is synthesized by intestinal bacteria,

naturally occurring biotin deficiency disease is virtually unknown. The disease

state can be produced artificially by including large quantities of raw egg white

in the diet; the whites contain avidin, a biotin antagonist. Especially good

sources of this widely distributed vitamin include egg yolk, kidney, liver,

tomatoes, and yeast. There is no known toxicity to biotin.


METABOLISM

Biotin is necessary for cell growth, the production of fatty acids, and the

metabolism of fats and amino acids. It plays a role in the citric acid cycle,

which is the process by which biochemical energy is generated during aerobic

respiration. Biotin not only assists in various metabolic reactions, but also

helps to transfer carbon dioxide. Biotin is also helpful in maintaining a steady

blood sugar level. Biotin is often recommended for strengthening hair and

nails. Consequently, it is found in many cosmetics and health products for the

hair and skin.

Vitamin B8 or biotin is vital for a healthy immune system. It is involved in the

metabolism of carbohydrates, proteins, and fats. It is essential for the growth

and health of the hair. It prevents premature greying of the hair as well as hair

loss. This vitamin helps to maintain the skin and the nervous system in a

sound condition. It controls proper distribution of color pigment.

DEFICIENCY SYMPTOMS

Since it is of great importance in human nutrition, deficiency of biotin causes

muscular weakness, pains, pins and needles (pricking of the skin), lassitude,

and lack of appetite. It may cause eczema, dandruff, hair loss and seborrhoea.

Other common problems which may occur are skin disorders, heart
abnormalities, lung infections, anaemia, extreme fatigue, confusion, mental

depression, and drowsiness. The fleshy part of the tongue may waste away.

PROBABLE DEFICIENT SUBJECTS

Certain rare inborn diseases can leave people with depletion of biotin due to

the inability to metabolize the vitamin normally. A dietary deficiency of biotin,

however, is quite uncommon, even in those consuming a diet low in this B

vitamin. Nonetheless, if someone eats large quantities of raw egg whites, a

biotin deficiency can develop, because a protein in the raw egg white inhibits

the absorption of biotin. Cooked eggs do not present this problem. Long-term

antibiotic use can interfere with biotin production in the intestine and increase

the risk of deficiency symptoms, such as dermatitis, depression, hair loss,2

anemia, and nausea. Long-term use of anti-seizure medications may also lead

to biotin deficiency.3 Alcoholics and people with diseases of the stomach have

been reported to show evidence of poor biotin status. However, the usefulness

of biotin supplementation for these people remains unclear.4 In animals, and

possibly in humans, biotin deficiency can cause birth defects.5 As biotin

deficiency may occur in as many as 50% of pregnant women,6 it seems

reasonable to use a prenatal multiple vitamin and mineral formula that

contains biotin. Biotin deficiency is rare, as intestinal bacteria generally

produce an excess of the body's recommended daily requirement. For that

reason, statutory agencies in many countries (e.g., the Australian Department

of Health and Ageing) do not prescribe a recommended daily intake of Biotin.


2. Mock DM. Skin manifestations of biotin deficiency. Semin Dermatol

1991;10:296302.

3. Said HM, Redha R, Nylander W. Biotin transport in the human intestine:

inhibition by anticonvulsant drugs. Am J Clin Nutr 1989;49:12731.

4. Zempleni J, Mock DM. Biotin biochemistry and human requirements. J Nutr

Biochem 1999;10:12838 [review].

5. Zempleni J, Mock DM. Marginal biotin deficiency is teratogenic. Proc Soc Exp

Biol Med 2000;223:1421 [review].

6. Mock DM, Quirk JG, Mock NI. Marginal biotin deficiency during normal

pregnancy. Am J Clin Nutr 2002;75:2959.

RECOMMENDED DOSE

The amount of biotin found in most diets, combined with intestinal production,

appears to be adequate for preventing deficiency symptoms. Researchers have

estimated that 30 mcg per day appears to be an adequate intake for adults. 7

Typically, consumption from a Western diet has been estimated to be 3070

mcg per day. Larger amounts of biotin (816 mg per day) may be supportive for

people with diabetes by lowering blood glucose levels and by preventing

diabetic neuropathy. 8,9Biotin in the amount of 2.5 mg per day strengthened the

fingernails of two-thirds of a group of people with brittle nails, according to one

clinical trial. 10
8. Coggeshall JC, Heggers JP, Robson MC, Baker H. Biotin status and plasma

glucose in diabetics. Ann NY Acad Sci 1985;447:38993.

9. Koutsikos D, Agroyannis B, Tzanatos-Exarchou H. Biotin for diabetic

peripheral neuropathy. Biomed Pharmacother 1990;44:5114.

10. Hochman LG, Scher RK, Meyerson MS. Brittle nails: response to daily

biotin supplementation. Cutis 1993;51:3035.

Intakes between 0.010 and 0.20 mg/day are both safe and adequate (COMA,

1991).

Anecdotal reports suggest that typical daily doses of 10 mg are without adverse

effects and toxicity has not been reported in individuals receiving as much as

200 mg per day. Clinical data are limited but studies have reported no biotin-

related adverse effects following the administration of 9 mg/day for up to 4

years, 10 mg/day for 15 days, 4 mg/day for 3 weeks or 2.5 mg/day for 6-15

months.

Maebashi et al., 1993

Biotin (9 mg, in combination with 3 g of an anti-microbial drug, Miya-BM) was

administered daily, by the oral route (in three divided doses), for up to 4 years,

to 20 patients (sex and age unspecified) suffering from non-insulin dependent

diabetes. The number of patients followed up after 24, 30, 36 and 48 months
was 15, 15, 10 and 5, respectively. There was no control group included in the

study. Fasting blood glucose levels decreased to normal within 2 months and

remained normal thereafter with continuing treatment. Serum insulin levels

were not significantly changed. The authors reported that there were no

observed clinical aggravations or undesirable side effects. This study cannot be

used for risk assessment because of the unusual design and the small number

of subjects.

Velazquez et al., 1995

In a double blind placebo controlled study, protein deficient children (n=22)

were administered 10 mg biotin/day for fifteen days. Plasma biotin

concentrations and lymphocyte carboxylase enzymes were measured. The

authors reported no adverse effects. This study cannot be used to define the

safety of biotin in children with a normal protein intake.

ESTABLISHMENT OF GUIDANCE LEVEL

The numerous clinical case reports in the literature describe the outcome of

oral biotin administration to patients (infants, juveniles and adults) with biotin-

responsive inborn errors of metabolism and other forms of biotin deficiency.

Furthermore, in cases where foetal biotin-responsive disorders have been

suspected, biotin has been administered prenatally, via the mother. Typically,
doses of 10 mg/day (250 x the average intake of the adult male in the UK) have

been studied for therapeutic effects, without reported adverse side effects.

Supplemental doses of 9 mg/day given to human volunteers for up to 4 years

have not been associated with adverse effects. The study is limited in that it

was performed in diabetics, there was no control group and only a few

individuals remained in the study after 4 years. The authors concluded that

there were no adverse effects related to the biotin treatment, although they

reported a tendency for the treatment to lower blood sugar. Due to the low

number of individuals studied, and the small proportion of volunteers followed

up long term, an uncertainty factor of 10 for inter-individual variation has been

applied in this case to allow for inter-individual variation. Thus, for guidance

purposes only, a supplemental daily intake of 0.9 mg biotin (equivalent to

0.015 mg/kg bw/day in a 60 kg adult) would not be expected to produce

adverse effects, although this value may not be applicable to all life stages.

Assuming a maximum intake of 0.066 mg/day from food, an estimated total

intake (from all sources) of 0.97 mg/day biotin (equivalent to 0.016 mg/kg

bw/day in a 60 kg adult) would not be expected to result in any adverse effects.


CONCLUSION

Several studies have reported different doses of Biotin {Intakes between 0.010

and 0.20 mg/day are both safe and adequate (COMA, 1991), Anecdotal reports

suggest that typical daily doses of 10 mg are without adverse effects and

toxicity has not been reported in individuals receiving as much as 200 mg per

day, 9 mg biotin/day (Maebashi et al., 1993), 10 mg biotin/day (Velazquez et

al., 1995)}.

Supplemental doses of 9 mg/day given to human volunteers for up to 4 years

have not been associated with adverse effects. Thus, a supplemental daily

intake of 0.9 mg biotin (equivalent to 0.015 mg/kg bw/day in a 60 kg adult)

would not be expected to produce adverse effects, although this value may not

be applicable to all life stages. Assuming a maximum intake of 0.066 mg/day

from food, an estimated total intake (from all sources) of 0.97 mg/day biotin

(equivalent to 0.016 mg/kg bw/day in a 60 kg adult) would not be expected to

result in any adverse effects.

Based upon the different scientific literature & data it is concluded that the

change in the strength of Biotin from the earlier approved product

Methylcobalamin 1500mcg+ Alpha Lipoic acid 200mg+ folic acid 1.5mg+

pyridoxine 3mg+ biotin 30mcg to Methylcobalamin 1500 mcg, Alpha

Lipoic acid 200 mg, Pyridoxine HCl 3 mg, Folic acid 1.5 mg and Biotin
200 mcg do not have any side or adverse effect on human subjects. So the

product can be approved in the following composition:

Methylcobalamin 1500 mcg, Alpha Lipoic acid 200 mg, Pyridoxine HCl 3

mg, Folic acid 1.5 mg and Biotin 200 mcg.

REFERENCES

COMA (1991). Dietary Reference Values for Food Energy and Nutrients for the

United Kingdom. Report of the Panel on Dietary Reference Values, Committee

on Medical Aspects of Food and Nutrition Policy. HMSO, London.

Maebashi, M., Makino, Y., Furukawa, Y., Ohinata, K., Kimura, S., Sato, T.

(1993). Therapeutic evaluation of the effect of biotin in hyperglycemia in

patients with non-insulin-dependent diabetes mellitus. Journal of Clinical

Biochemistry and Nutrition 14, 211-218.

Velazquez, A., Teran, M., Baez, A., Gutierriez, J., Rodriguez, R. (1995). Biotin

supplementation affects lymphocyte carboxylases and plasma biotin in severe

protein-energy malnutrition. American Journal of Clinical Nutrition 61, 385-91.