Vitamin D Supplements in the Indian Market.

It is now known that vitamin D deficiency is a worldwide health problem. In our country, as food fortification is lacking, supplementation with pharmaceutical preparations is the only means of treatment of vitamin D deficiency. We aimed to study the composition and availability of various vitamin D preparations in the Indian market, data about which was collected from annual drug compendium. The preparations were assessed for total number, different formulations, constituents and amount of each constituent present in the formulation. Vitamin D3 is available in the form of cholecalciferol, alfacalcidiol and calcitriol as single ingredient products and in combination with calcium and other micronutrients. Most of the supplements contain calcitriol (46.5%) or alfacalcidiol (43%) as tablets (51.1%) and capsules (35.2%). Cholecalciferol, the preferred form for prophylaxis and treatment of vitamin D deficient states, constitutes only 10% of the available market preparations. High market sales of calcium supplements containing calcitriol indicate increasing intake of calcitriol rather than cholecalciferol; which could predispose to toxicity. There is a need for marketing and rational prescribing of the appropriate vitamin D supplement in ostensibly healthy Indian population. Implementation of population-based education and intervention programmes with enforcement of strict regulations could generate awareness and curb unsupervised intake of vitamin D containing dietary supplements. This health challenge mandates effective nutritional policies, fortification and supplementation programmes and partnership between government, healthcare and industry to safeguard the health of Indian population at large.

It has been widely accepted that vitamin D deficiency (VDD) is a global health problem that impacts not only musculoskeletal health but also varied acute and chronic diseases[1]. Low vitamin D has been associated with an increased risk of diabete smellitus, cardio vascular disease, certain cancers, cognitive decline, autoimmune disorders and pregnancy complications[2]. It has been estimated that 20 to 80% of US, Canadian and European men and women are vitamin D deficient[134]. In Middle East and Asia, VDD is highly prevalent in both children and adults[125]. Even in India, numerous studies across various regions of the country indicate that approximately 70-90% of apparently healthy population is vitamin D deficient[6789]. Low vitamin D status is prevalent irrespective of age, sex, profession, rural/urban settings or regional distribution[1011](Table 1).

TABLE 1

VITAMIN D SERUM LEVELS IN DIFFERENT POPULATION GROUPS ACROSS INDIA

The major source of vitamin D is exposure to sunlight. It has been presumed that Indians are vitamin D sufficient due to adequatesunshine throughout the year[6]. However, reduced cutaneous synthesis of vitamin D could be attributed to limited UV exposure owing to increased skin pigmentation, topical application of sunscreen, certain sociocultural practice sandurban lifestyle[6]. Secondary sources includedietary intake of foods naturally richin vitamin D such as salmon, codliveroil, sundried mushrooms or vitamin D fortified foods[228]. In our country, availability, acceptability and cost of these dietary products limits their widespread use by the general population. This complex interplay between lack of adequate sun exposure, deficient intake and effective food fortification strategies makes Asian Indian population particularly susceptible to vitamin D insufficiency/deficiency. Thus, vitamin D supplementation in the form of pharmaceutical preparations is one of the most effective ways to prevent and treat VDD in high-risk groups[29]. We, therefore undertook a study to ascertain that availability and composition of various pharmaceutical preparations of vitamin D in the Indian market.

MATERIALS AND METHODS

This study was conducted to determine the number and composition of the various vitamin D pharmaceutical preparations. Data for the study was collected from an annual Drug Compendium entitled The Drug Today 2013 (October–December 2013 issue) and product labels. The preparations were assessed for total number, different formulations, constituents and amount of each constituent present in the formulation.

RESULTS

Analysis of various vitamin D preparations:

A total of 258 vitamin D formulations are available in the Indian market. Vitamin D is commonly available in two forms: Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Only two preparations contain vitamin D2 (ergocalciferol). More than 99.9% of the preparations contain vitamin D3 in the form of alfacalcidiol (25 hydroxycholecalciferol), calcitriol (1,25 dihydroxycholecalciferol) or cholecalciferol (inactive vitamin D). Most of the preparations contain calcitriol (n=120,46.5%) or alfacacidiol (n=111;43.02%). Approximately 10% of preparations contain cholecalciferol (n=27, 10.5%)(fig. 1, Tables 2 and 3).

Fig. 1

Various vitamin D preparations available in Indian market.

All the available cholecalciferol preparations (CC) (10.5%) contain only vitamin D3. 39 % of calcitriol preparations contain vitamin D3 in combination with minerals /vitamins (C-MV) and 7.5% contain vitamin D3 alone (C). 23.22% of alfacalcidiol preparations contain vitamin D3 in combination with minerals /vitamins (A-MV) and 19.8% contain vitamin D3 alone (A)

TABLE 2

VITAMIN D3 PREPARATIONS AVAILABLE IN THE MARKET

TABLE 3

COMMONLY AVAILABLE VITAMIN D BRANDED PREPARATIONS IN THE MARKET

Different formulations of vitamin D:

The most common formulation for oral administration is in the form of tablets (n=132, 51.1%) and capsules (n=91, 35.2%). Though alfacalcidiol and calcitriol are commonly available as tablets and capsules; cholecalciferol is in the form of granules in sachets (n=17, 62.9%). Other dosage forms include syrups and softgel capsules. Though oral administration in the form of drops is commonly recommended for infants and children, adolescents and adults are usually prescribed tablets, capsules or granules for supplementation. While all cholecalciferol preparations are available as a single constituent; more than 75% of alfacalcidiol preparations also contain calcium (n=85, 76.5%). Majority of calcitriol preparations are combined with zinc or zinc sulphate (n=87, 72.5%). Vitamin D preparations also contain various other minerals/vitamins such as magnesium, cupric, boron, methylcobalamin, vitamin E, vitamin K, vitamin C, pyridoxine, folic acid, beta-carotene, glutamic acid, manganese, omega 3 and docosapentaenoic acid. Tablets and capsules contain 10 IU (0.25 μg) -10000 IU (25 mg) of vitamin D and are usually administered on a daily basis. Sachets of cholecalciferol containing granules of vitamin D amount to 60,000 IU of vitamin D are administered weekly. Vitamin D2 (doxercalciferol) preparation is available in tablet form (two formulations) containing 20 IU (0.5 μg) and 100 IU (2.5 μg) respectively (Table 3).

Cost analysis:

Cost analysis reveals that tablets/capsules of alfacalcidiol (equivalent to 10 IU of vitamin D) and calcitriol (0.25 μg) commonly costs Indian National Rupees (INR) 5.5 and INR 7, respectively (Table 4). Whereas, cholecalciferol granules (equivalent to 60,000 IU) costs INR 20. The common treatment regime for VDD is 60000 IU weekly for eight weeks, which costs approximately INR 160. Furthermore, vitamin D given monthly as maintenance therapy for a year would cost INR 240.

TABLE 4

THE COST (IN INDIAN NATIONAL RUPEES) OF VARIOUS DOSAGE FORMS OF VITAMIN D3 PREPARATIONS

DISCUSSION

Vitamin D deficient state has become one of the most prevalent and underdiagnosed medical conditions in the world[130]. Recent evidence suggests that lack of adequate sun exposure is the most important factor for this global pandemic as very few foods naturally contain vitamin D (wild caught salmon and UV exposed mushrooms)[2]. Analysis in children and adults indicate that dietary sources are grossly inadequate in providing the Recommended Dietary Allowances (RDA) for vitamin D. In our population, cutaneous production of vitamin D is further limited by increased melanin content of skin or sun avoidance by use of sunscreens, extensive clothing cover due to sociocultural practices or staying indoors for most of the day[6]. Deficient vitamin D status can be corrected either by vitamin D fortification (addition of micronutrients to processed foods) or supplementation (the provision of relatively large doses of micronutrients, usually in form of pills, capsules or syrup).Vitamin D fortification is an effective and passive way to increase vitamin D intake in both general population and vulnerable groups[313233]. However, it mandates political commitment and involvement of various ministries (health, agriculture and social welfare) to develop nationwide strategies for a better vitamin D status in the population. In our country, where vitamin D fortification initiative is lacking, supplementation is the only alternative[34].

In our analysis, we found that multiple supplements of vitamin D are available. The two common forms are vitamin D3 (alfacalcidiol, cholecalciferol and calcitriol) and vitamin D2 (ergocalciferol). Evidence suggests that cholecalciferol is superior to ergocalciferol in terms of potency, elevating and sustaining 25 (OH) D concentrations and maintaining the storage form of vitamin D[3536]. In our analysis, we were not able to ascertain the cause of lack of availability of vitamin D2 preparations in the Indian market. Majority of preparations available in the market contain vitamin D3 (99.9%). About half of the preparations (46.5%) contain calcitriol in the form of tablets or capsules of 0.25 mcg. Calcitriol has a rapid onset of action with short half-life of 6 h. It is most useful in chronic kidney disease and type I and type II vitamin D deficient rickets (VDDR) with decreased synthesis of calcitriol. Though calcitriol is the most commonly available form, it is not the preferred agent for treatment of nutritional deficiency or stoss therapy (single large oral/ intramuscular therapy). It is associated with a high incidence of hypercalcemia and requires serum calcium monitoring. Furthermore, when calcitriol is used as a supplement, 25(OH) D levels do not indicate clinical vitamin D status. Calcitriol does not build up stores and is an expensive preparation[37]. Around 43% of the preparations contained alfacalcidiol (25 dihydroxy cholecalciferol). It is most commonly available as tablets or capsules of 10 IU, usually in combination with calcium (76.5% of alfacalcidiol preparations). Alfacalcidiol has a rapid onset of action with a half life of 2-3 weeks. It does not require hepatic 25-hydroxylation, and is therefore most useful in patients with liver disease. Approximately 10% of vitamin D3 preparations are available as cholecalciferol. It is the inactive, unhydroxylated form of vitamin D3, synthesized in skin from 7 dehydrocholesterol. It has a slow onset of action with a half-life of 12-30 days. Thus, it is the preferred form for prophylaxis or treatment of vitamin D deficient states[37].

Vitamin D can be administered daily, weekly, monthly, or every 4 months to sustain an adequate serum 25 (OH) D concentrations[383940]. A high bolus dose of vitamin D (up to 300,000 IU) can be used initially in persons with extreme VDD. Repeated boluses of high-dose vitamin D at 6- to 12-month intervals have been used in a nursing home setting, but a steady-state serum 25(OH) D concentration is likely to be maintained by more frequent, lower doses of vitamin D. An effective strategy to treat vitamin D deficient state in children and adults is to administer 50,000 IU of vitamin D3 once a week for 6-8 weeks respectively<^{43. To prevent recurrence, administration of 600 to 1000 IU/day is effective[43]. In our country, most market preparations contain 60, 000 IU, and are usually recommended for 6 to 8 weeks for obtaining adequate serum 25 (OH) D concentrations. A monthly maintenance therapy is usually required and should be continued for over one year[44]. Another study suggested that a single high dose of 120,000-180,000 IU of oral cholecalciferol was adequate to elevate 25(OH) D out of the deficiency range. However, maintenance dose is required for sustaining the desired concentration of 25(OH) D[4445]. Our analysis suggests that this treatment regime would initially cost approx. INR 160 and a maintenance therapy for a year would cost INR 240. However, the treatment costs are usually higher as calcium supplements are coadministered with vitamin D therapy}

Vitamin D supplementation varies with the RDA, tolerable upper levels in different age groups and in certain circumstances[46]. The Institute of Medicine (IOM), USA guidelines suggest a vitamin D sufficient level of 20 ng/ml to optimize bone health[47]. In contrast, US Endocrine Society recommends that serum 25 (OH) D levels of 30 ng/ml (vitamin D sufficiency) should be attained for children and adults to optimize the probability of good health and avoid other risk associated with vitamin D deficient status (Table 5). Furthermore, it is now acknowledged that previously recommended vitamin D intake of 200 IU/day in the American recommended intakes or 400 IU/day in the WHO report are grossly inadequate[46]. Thus, RDA of 600-800 IU is recommended to maintain adequate levels of vitamin D[46]. In our country, Indian Council of Medical Research (ICMR) recommends a daily supplement of 400 IU/day of vitamin D for Indians under situations of minimal exposure to sunlight[34]. However, in light of recent evidence, there is a need to update these guidelines regarding vitamin D intake and supplementation in adults, vulnerable population and susceptible groups[484950]. It is now recognized that vitamin D is not as toxic as once thought to be. IOM recommends that up to 4,000 IUs of vitamin D/day is safe for most children and adults. Studies in various populations have shown that adults can tolerate 10,000 IU of vitamin D/day for at least five months without altering their serum calcium or urinary calcium output[50]. However, in rare cases, vitamin D toxicity can cause hypercalcemia, hyperphosphatemia, nephrocalcinosis, and soft tissue calcification, thus contributing to high risk of mortality[51].

TABLE 5

VITAMIN D STATUS IN RELATION TO 25-HYDROXY VITAMIN D LEVELS

Studies indicate general and widespread use of dietary supplements across populations[5253]. Though these supplements often are used with the intention of attaining health benefits by preventing chronic diseases, cumulative effects of widespread supplement use, together with food fortification, have raised concern regarding exceeding upper recommended levels and, thus, long-term safety[53]. In case of vitamin D, unsupervised intake of alfacalcidiol and calcitriol, which are not recommended for vitamin D deficient states, could result in adverse effects/toxicity[54]. Thus, it is recommended that supplements should only be used with strong medically based cause, such as symptomatic nutrient deficiency disease[53]. 'Blanket prescription' of these supplements in all patients for prolonged use should be stopped. Physicians need to evaluate the patient's dietary nutrient consumption, intake of any other multivitamin supplement, potential interactions and prescribe them only on an individual basis

Widespread VDD in the Indian population is a cause for grave concern. Adequate measures are imperative to prevent VDD at the outset. There is a need for educating the masses about sensible sun exposure for vitamin D synthesis and dietary intake of vitamin D rich foods. Fortification of commonly available foods could prevent vitamin D insufficiency in our large population. There is an urgent need to prioritize development of national level programs to provide regulated vitamin D fortified foods at affordable prices for Indian population at large. As far as vitamin D supplements are concerned, their easy availability and chronic self-administration mandates awareness on the part of the consumer, pharmacist, chemists, physicians and regulatory bodies to prevent misuse and serious harm. As evident by high market sales, high intake of calcitriol in the form of dietary calcium supplement in the general population could result in serious hypercalcemia, calcium stones and metastatic calcification. The prescribing physicians need to be aware of this potential risk and should prescribe supplements only on an individual basis for requisite duration. These supplements should be adequately labeled indicating the amount of each constituent with special instructions/precautions/warnings, if any. Stringent regulations are required to keep a check on their marketing and availability. Adequate legal actions are required for pharmaceutical companies/drug firms not adhering to regulatory provisions.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.