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UK/FLY/2023/2636 v3| November 2023

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The ABC of Vitamin D

Now available on demand - This event outlines the role of vitamin D within the human body, along with the effects of vitamin D deficiency on health. It explores the evidence base for the pharmacological management of vitamin D deficiency and examines the clinical benefits of different treatment options for hypovitaminosis D.

Frequently Asked Questions

Have a question not answered below? Get in touch.

1. What is calcifediol?

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Calcifediol is a medication used to treat and prevent vitamin D deficiency in adults. It belongs to the category of 25-hydroxyvitamin D compounds and serves as a precursor to the biologically active form of vitamin D in the body, known as calcitriol. Calcifediol helps maintain optimal vitamin D levels for overall health. In the UK, it is available as an oral soft capsule called Domnisol (calcifediol monohydrate).

Figure 1: Images of Colecalciferol, Calcifediol and Calcitriol

2. In what ways do the contrasting pharmacokinetics of calcifediol alter its characteristics in comparison to colecalciferol?

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Domnisol (calcifediol monohydrate) has distinct pharmacokinetic advantages over colecalciferol, vitamin D3. Its extra hydroxyl group on carbon 25 allows for more favourable pharmacokinetic characteristics, making it an ideal treatment for obese patients, patients with fat malabsorption and patients with impaired hepatic functions. Unlike colecalciferol, Domnisol bypasses hepatic 25-hydroxylation and is closer to the active form of vitamin D in the metabolic pathway.1 It achieves target serum 25(OH)D concentrations more rapidly and exhibits a predictable and linear dose-response curve, regardless of baseline levels. In contrast, the dose response of colecalciferol can be less predictable due to factors such as variations in absorption and metabolic conversion, including age- and disease-related declines in hepatic 25-hydroxylase activity.1 The differences between colecalciferol and calcifediol. References
  1. Jodar E, Campusano C, de Jongh RT, Holick MF. Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency. Eur J Nutr. 2023;62(4):1579-1597. doi:10.1007/s00394-023-03103-1.

Treatment

3. What do the 25(OH)D levels tell us about the patient’s vitamin D level?

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The 25(OH)D (also known as 25-hydroxyvitamin D) levels are a measure of concentration of 25-hydroxyvitamin D in the bloodstream. It is the major circulating form of vitamin D and serves as reliable indicator of an individual’s vitamin D status. Hence, measuring 25(OH)D is commonly used to assess an individual’s vitamin D status.2

 25(OH)D concentration   Classification
 <25 nmol/L   Deficient
 25-50 nmol/L   Insufficient
 >50 nmol/L   Optimal

 Table 1: Classification of vitamin D status by 25(OH)D concentration* 3

*Please consider that optimal range for 25(OH)D levels may vary based on individual factors, such as age, health conditions, and specific medical recommendations.

References
2. Cashman KD, van den Heuvel EG, Schoemaker RJ, Prévéraud DP, Macdonald HM, Arcot J. 25-Hydroxyvitamin D as a Biomarker of Vitamin D Status and Its Modeling to Inform Strategies for Prevention of Vitamin D Deficiency within the Population. Adv Nutr. 2017;8(6):947-957. doi:10.3945/an.117.015578

3. Vitamin D deficiency in adults | Health topics A to Z | CKS | NICE. Accessed June 9, 2023. https://cks.nice.org.uk/topics/vitamin-d-deficiency-in-adults/

4. What is the recommended frequency for monitoring patients on maintenance treatment?

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Blood levels of 25(OH)D should be measured approximately 3 to 4 months after beginning maintenance therapy to confirm that target level has been reached. Thereafter, the levels should be measured at 6-monthly intervals to ensure that effective therapeutic levels are maintained. Domnisol SmPC

5. Do I need to worry about adherence, compliance and polypharmacy when prescribing Domnisol (calcifediol monohydrate)?

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Polypharmacy in primary and secondary care is growing, increasing adverse drug events, hospital admissions, increased healthcare costs and non-adherence.4 Vitamin D deficiency frequently occurs in older people, especially in individuals with comorbidity and polypharmacotherapy.5 Domnisol (calcifediol monohydrate) is typically prescribed as a monthly administration. The once-a-month administration assists with adherence, and compliance to treatment but also reduces polypharmacy.

Figure 2: Patient preference for different dosing frequency of vitamin D supplements6

References 4. Barnett NL, Oboh L, Smith K. Patient-centred management of polypharmacy: a process for practice. Eur J Hosp Pharm. 2016;23(2):113-117. doi:10.1136/ejhpharm-2015-000762 5. Kupisz-Urbańska M, Płudowski P, Marcinowska-Suchowierska E. Vitamin D Deficiency in Older Patients-Problems of Sarcopenia, Drug Interactions, Management in Deficiency. Nutrients. 2021;13(4):1247. doi:10.3390/nu13041247 6. Rothen JP, Rutishauser J, Walter PN, Hersberger KE, Arnet I. Oral intermittent vitamin D substitution: influence of pharmaceutical form and dosage frequency on medication adherence: a randomized clinical trial. BMC Pharmacol Toxicol. 2020;21:51. doi:10.1186/s40360-020-00430-5

6. Are there any benefits of continuous treatment after achieving required vitamin D levels?

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Perez-Castrillon et al., 2023 showed that when calcifediol treatment is maintained over time, vitamin D levels reach a plateau after the first 4 months and remain fairly stable for the following 8 months with no associated safety concerns. However, when calcifediol treatment was withdrawn after reaching required vitamin D levels in post-menopausal women (n=303), levels quickly decrease back to baseline. The results suggest that treatment should be maintained over time to avoid decrease of 25(OH)D levels.

Figure 3: Mean serum 25(OH)D concentrations during study (PP population, n = 170) 7

A strong decrease in 25(OH)D levels to baseline can be observed 4 months after calcifediol withdrawal (Group A2) compared with sustained administration (Group A1). Statistical comparisons are for Group A1 versus Group A2 ( p < 0.05; p < 0.001; +++, p < 0.0001) and for Group A1 versus Group B (*, p < 0.05; **, p < 0.001; p < 0.0001). Error bars: 95% CI.7 References 7. Pérez-Castrillón JL, Dueñas-Laita A, Gómez-Alonso C, et al. Long-Term Treatment and Effect of Discontinuation of Calcifediol in Postmenopausal Women with Vitamin D Deficiency: A Randomized Trial. J Bone Miner Res. 2023;38(4):471-479. doi:10.1002/jbmr.4776

7. What unit of measurement is used to determine the dosages for Domnisol (calcifediol monohydrate)?

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This is an important issue regarding dosage recommendations for vitamin D treatment. Colecalciferol dosing is commonly expressed in IU (International Units), which were established several decades ago.1 The Expert Committee on Biological Standardization states that 1 IU of vitamin D is equivalent to 0.025 mcg of crystalline vitamin D3 (colecalciferol).8 Experiments have shown that the effects of 1.5 mcg of colecalciferol are comparable to approximately 1 mcg of calcifediol. This means that smaller gravimetric doses of Domnisol (calcifediol monohydrate) are found to achieve the same therapeutic effect as colecalciferol. The previously established equivalency of colecalciferol dose in mcg and IU was established in animal models and cannot be extrapolated to calcifediol posology. As such, it is inappropriate to refer to calcifediol dose in terms of IU since it is more effective per microgram than colecalciferol (vitamin D3), in inducing antirachitic activity. To ensure clarity and accuracy, Domnisol (calcifediol monohydrate) doses are in micrograms or milligrams rather than IU.1 References 1. Jodar E, Campusano C, de Jongh RT, Holick MF. Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency. Eur J Nutr. 2023;62(4):1579-1597. doi:10.1007/s00394-023-03103-1 8. Report of subcommitee of Fat-Soluble Vitamins - Expert Committee of Biological Standardization - World Health Organization- technical report series No.3. https://apps.who.int/iris/bitstream/handle/10665/38884/WHO_TRS_3.pdf?sequence=1&isAllowed=y

Patient Groups

8. Is Domnisol (calcifediol monohydrate) suitable for use in obese patients?

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Domnisol can be used in adult patients with vitamin D deficiency (except those specifically mentioned as excluded in the Domnisol SmPC) and is suitable for use in obese patients because of the polar properties it exhibits.9 Vitamin D colecalciferol (fat-soluble vitamin) is trapped and stored within the increased adipose tissue in obese patients,10 resulting in lower circulating levels of active form of vitamin D in the bloodstream. However, Domnisol's polar characteristics enables it to be less likely to be sequestered in adipose tissue and may be preferable in patients with obesity.9 References 9. Quesada-Gomez JM, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporos Int. 2018;29(8):1697-1711. doi:10.1007/s00198-018-4520-y 10. Carrelli A, Bucovsky M, Horst R, et al. Vitamin D Storage in Adipose Tissue of Obese and Normal Weight Women. J Bone Miner Res. 2017;32(2):237-242. doi:10.1002/jbmr.2979 11. Cesareo R, Falchetti A, Attanasio R, Tabacco G, Naciu AM, Palermo A. Hypovitaminosis D: Is It Time to Consider the Use of Calcifediol? Nutrients. 2019;11(5):1016. doi:10.3390/nu11051016

9. Is Domnisol (calcifediol monohydrate) suitable for use in patients suffering with advanced liver disease?

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Domnisol can be used in adult patients with vitamin D deficiency (except those specifically mentioned as excluded in the Domnisol SmPC) and in patients suffering with advanced liver disease. In advanced liver disease or in patients taking certain medicines that interfere with the hepatic 25-hydroxylation (e.g. antiepileptic and antiretroviral drugs), the metabolism of vitamin D can be disrupted.12 Since Domnisol (calcifediol monohydrate) skips the liver hydroxylation, it is suitable for patients with impaired hepatic function.1 References 1. Jodar E, Campusano C, de Jongh RT, Holick MF. Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency. Eur J Nutr. 2023;62(4):1579-1597. doi:10.1007/s00394-023-03103-1 12. Wills MR, Savory J. Vitamin D metabolism and chronic liver disease. Ann Clin Lab Sci. 1984;14(3):189-197

10. Is Domnisol (calcifediol monohydrate) suitable in patients with decreased intestinal absorption?

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Domnisol (calcifediol monohydrate) is suitable in adult patients with vitamin D deficiency (except those specifically mentioned as excluded in the Domnisol SmPC) and in those with decreased intestinal absorption (e.g. patients with cystic fibrosis, Crohn’s disease, and coeliac disease). Unlike colecalciferol, intestinal absorption of Domnisol is not dependent on the presence of bile acids and micelle formation. Domnisol (calcifediol monohydrate) absorption from the gut is largely achieved by the vena porta.9 Quesada-Gomez et al., 2018 found that the intestinal absorption rate of calcifediol in normal subjects was 93%.9

Figure 5: Calcifediol being transported directly into the bloodstream via the portal vein9

References 9. Quesada-Gomez JM, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation? Osteoporos Int. 2018;29(8):1697-1711. doi:10.1007/s00198-018-4520-y

Ingredients and Other Questions

11. What is the source of gelatine used?

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Domnisol (calcifediol monohydrate) contains gelatine that is from bovine source.

12. Does Domnisol (calcifediol monohydrate) contain lactose?

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Domnisol (calcifediol monohydrate) does not contain lactose.

13. What are the benefits of using Domnisol (calcifediol monohydrate)?

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