Commentary on the medico‐legal aspects of prescribing vitamin D

The medical and legal risks associated with prescribing unlicensed vitamin D products were recently highlighted in the article by Davies et al. 1. This prompted a letter from Rhein who raised the concern that this may dissuade practitioners from prescribing vitamin D 2, and exacerbate the failure to address adequately the widespread problem of vitamin D deficiency and insufficiency 3. Rhein asks whether European licensed preparations could be used in the absence of suitable or affordable UK licensed preparations, with appropriate checks. We address this point with a practical approach to understanding the licensed status of different preparations of vitamin D and the relevance with respect to prescribing and dispensing them, particularly with the recent licensing of vitamin D. We are not setting out to provide guidance on the specific requirements for vitamin D replacement in vitamin D deficiency and insufficiency, or advice on specific dosing regimens, or selection of specific vitamin D preparations, for which we encourage the reader to consult their local or national guidelines. However, when following such guidelines, the prescriber should be reasonably satisfied that the likely benefits of prescribing higher doses of vitamin D products exceed the likely risks of harm. For example, with respect to evidence of benefit in terms of mortality, the Cochrane Review on vitamin D supplementation for prevention of mortality in adults by Bjelakovic et al. 4 which included 32 trials of vitamin D3, found that a dose of vitamin D3 below 800 units a day significantly decreased mortality (RR 0.92, 95% CI 0.87, 0.97, P = 0.005, I2 = 0%). However, a dose of vitamin D3 ≥ 800 units a day had no significant effect on mortality (RR 0.96, 95% CI 0.92, 1.00, P = 0.07, I2 = 0%). No effect on mortality was found with vitamin D2. In this commentary we present the risks of different categories of vitamin D products, with respect to their licensed status, within the context of the medico-legal framework. In the UK, licensed medicines should be prescribed/ used first line where possible to adhere to the Human Medicines Regulations 2012 which allows marketing of a medicinal product for a specified medical indication. Identification of a UK licensed product is made by the medicine having a product licence (PL) number (UK Marketing Authorization) or EU number (Pan-European Marketing Authorization). The latter are products with a license for the purpose of importation into the UK. The MHRA are responsible for the regulation of medicines in the UK in accordance with the Human Medicines Regulations 2012 (SI 2012/1916). The use of a licensed product provides reassurance to health professionals that the medicinal product will release the correct amount of drug, a favourable assessment of the benefit vs. the risk of harm has been established from clinical trials, and that robust and rigorous quality assessment/quality control processes have ensured that the dosing of each formulation is consistent with minimal intra- and inter-variation between batches. Therefore licensed medicines represent the lowest risk to the prescriber, the dispenser and the patient. The MHRA have recently licensed a number of vitamin D preparations, including high and low doses to suit individual patient needs. This addresses the concerns raised by Rhein 2 regarding practitioners being dissuaded from prescribing unlicensed vitamin D. Prescribers therefore, now have a variety of licensed vitamin D products to prescribe in favour of an unlicensed, or off-label medicine or a non-medicinal dietary supplement. The new licensed products are also inexpensive, although are slightly more expensive than the unlicensed products. Furthermore, they carry no additional importation costs. Examples of UK licensed vitamin D products are provided in Table 1. A UK medicine used outside of its licensed indication is termed ‘off-label’. If a UK licensed medicinal product cannot meet the clinical needs of a patient, the use of an off-label medicine is favoured over an unlicensed medicine. This is because the licensed medicine has been tested for quality, safety and efficacy. Although the safety and efficacy may be altered if it is used for a different indication, and therefore the prescriber's liability is increased, it is better to prescribe this over an unlicensed medicine which has not been assessed. The licensed indication of ergocalciferol i.m. injection 300 000 units ml–1 is for patients with malabsorption of vitamin D associated with gastrointestinal, liver or biliary disease, resulting in hypophosphataemia, rickets and osteomalacia. Doses should not normally exceed 40 000 units day–1 for adults, although treatment should be individualized. Frequent serum and urinary calcium, phosphate and urea nitrogen determinations should be carried out. Caution is also needed when used in patients with vitamin D resistant rickets as the range between the toxic and therapeutic dosage is narrow. Interactions also need to be considered with other drugs, including digitalis glycosides, verapamil, anti-convulsants and thiazide diuretics 5. The use of ergocalciferol i.m. injection 300 000 units ml–1 for vitamin D deficiency in the absence of malabsorption related to these underlying or associated conditions, would therefore represent the off-label use of an UK licensed product. Provided that fully informed written consent is obtained from the patient (although not routine practice), this approach might be considered to carry less legal consequence than the products described under sections 3–5. However, the licensing of oral vitamin D in different strengths and formulations should thus result in the prescriber and dispensers being deterred from off-label use of a parenteral product. Moreover, its use is limited in clinical practice by the fact it needs to be given under specialist supervision, has many cautions and may cause pain at the site of injection, and therefore should have a limited, if any, role outside of its licensed indication. Until recently, prescribers relied on the use of unlicensed medicines, due to recommendations of higher doses of vitamin D than licensed UK preparations. If a UK licensed form of vitamin D is not available, a medicine licensed in a country within the EU or a country with a Mutual Recognition Agreement (other countries with similarly recognized medicines standards e.g. Australia and Switzerland) or the US can be imported. The medicine will be manufactured to the same quality standards as the UK. However, the risks are associated with the medicine's packaging and labelling. This is a governance issue and therefore the medicine carries similar risks as an unlicensed medicine from this perspective. Whilst the prescriber can be rest assured that the medicine is fit for purpose, the risk is associated with the dispenser, and the person administering the medicine, ensuring that the medicine is given at the correct dose and frequency from the packaging details. For example, with Dekristol (see Table 1), the summary of product characteristic (SPC), patient information leaflet (PIL) and the packaging are all in German. As stated in section 1, the licensing of high and low doses of vitamin D should allow vitamin D to be prescribed and dispensed without the need to import an unlicensed product from a country with a Mutual Recognition Agreement. An unlicensed medicinal product should only be used where a licensed product either from the UK, EU or Mutual Recognition Agreement country, cannot meet the clinical needs of a patient. A ‘Specials’ medicine is one made under a Manufacturing Special's Licence issued by the MHRA. Specials are made to the same Good Manufacturing Practice (GMP) standards as licensed medicines, but do not require any safety or efficacy data. In addition to these risks, the prescribing of unlicensed vitamin D products has a large impact on the prescribing spend as highlighted by Davies et al. 1. Although the decision is the responsibility of the prescriber, pharmacists need the skills to safely supply a medicine and should always adhere to the standards of conduct, ethics and performance guidance, set by the General Pharmaceutical Council (GPhC). Pharmacists should confirm with the prescriber whether they had intended to prescribe an unlicensed medicine in order to help prevent these risks (related to the lack of any safety or efficacy data) 6. In addition, information leaflets are not normally provided with Specials. The licensing of colecalciferol 3000 units ml–1 oral solution is now available for supply against NHS prescriptions. Thus, no unlicensed or Specials oral liquid formulations of colecalciferol, as per MHRA guidance note 14 6, should be ordinarily provided or dispensed against NHS prescriptions. Unlicensed medicines in the EU carry potential risks for prescribers and pharmacists as well as patients. There is no certainty regarding their safety, efficacy, quality/GMP in addition to risks associated with labelling/packaging, although some may be manufactured in a facility which adheres to GMP standards. These medicines should only ever be used as an absolute last resort. Unlicensed medicines do not provide the quality assurance process recognized by the MHRA 6. Such risks were highlighted by Davies et al. 1 who described the wide variation between the expected amount and the actual content of vitamin D measured in several studies, ranging from 8% to 201% 7, 8, with, in extreme cases, the actual measured vitamin D being 100–4000 times greater than the expected dose, associated with severe toxicity. Thus, pharmacists should be vigilant and confirm with the prescriber that they had intended to prescribe an unlicensed medicine. There are many vitamin D preparations that are promoted and sold as health food supplements, in contrast to medicines. These supplements do not require a prescription and thus do not rely on any interaction between the patient and prescriber. For patients in whom a prescription for vitamin D is not required, the community pharmacist should discuss the options available for purchasing over the counter supplementation. As per the NHS Community Pharmacy Contractual Framework Essential Service for Support for Self Care, Pharmacists are required to provide the appropriate advice to help patients self-manage minor conditions 9. This includes supplementation of vitamins, through advising the public about nutrition 10. As Davies et al. state, the majority of vitamin D is prescribed and dispensed in the community 1. Here, the risks to prescribers and pharmacists may exceed those of secondary care. In the latter, guidelines tend to be more readily available and pharmacists are able to screen the patient's serum 25-hydroxy-vitamin D (25-OHD). Prescribers working in the community should seek specialist advice if they are unsure about which preparation to prescribe in relation to its licensed status (e.g. from a local or national Medicines Information Centre). The MHRA licensed preparations of vitamin D will provide better availability of products in the community and therefore better continuity of care. The MHRA licensing of a variety of vitamin D products has made the prescribing and dispensing of vitamin D safer, with regards to the medico-legal aspect to clinicians and pharmacists. For example, if a high dose of vitamin D replacement is needed, there is now a MHRA-licenced 20 000 unit dose available that can be given orally, meaning unlicensed preparations should no longer be necessary. As per MHRA guidance note 14, licensed preparations should be provided against an NHS prescription, in contrast to unlicensed or Specials oral liquid formulations (of colecalciferol). If for any reason, a vitamin D product is used without a Marketing Authorization, the prescriber should be satisfied from the available evidence that there is a pressing need to prescribe it. The pharmacist should always clarify with the prescriber that the prescription for an unlicensed vitamin D product (including Specials) was intentional. Off-label use of licensed intramuscular ergocalciferol should also be of decreased necessity given the greater availability of doses and formulations orally, avoiding risks to the prescriber in using this drug outside of its licensed (and untested) indication. There are no competing interests to declare.

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