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1 ABUHB Prescribing Guideline Diagnosis and Management of Vitamin D Deficiency In ADULTS (including guidance for Non Specialists) This document aims to provide comprehensive guidance on the cost effective DIAGNOSIS and MANAGEMENT of Vitamin D DEFICIENCY and INSUFFICIENCY in ADULTS. It does not include guidance on which vitamin D preparation(s) to recommend/provide/prescribe for supplementation. It should be noted that this guidance: 1. has been drawn up using other similar NHS produced guidelines (notably the Cardiff & Vale 2012 and E. Lancashire Guideline) as the basis, 2. has undergone a process of consultation with ABUHB specialists involved with the management of Vitamin D insufficiency/deficiency AND 3. has been endorsed by ABUHBB Medicines & Therapeutics Committee. Section of the BNF provides additional information on Vitamin D. National Recommendations on Vitamin D For adults, the Chief Medical Officer for Wales recommends 1 that: All pregnant and breastfeeding women should take a daily supplement containing 10 micrograms of vitamin D, to ensure the mother s requirements for vitamin D are met and to build adequate fetal stores for early infancy. People aged 65 years and over and people who are not exposed to much sun should also take a daily supplement containing 10 micrograms of vitamin D. Vitamin D physiology Vitamin D 3 (colecalciferol) is normally synthesized in the skin through the action of UV light on cholesterol. In the UK, this can only occur from April to September. Vitamin D is converted in the liver to 25 hydroxyvitam min D which is the major storage form and what is measured in the laboratory. Colecalciferol is also available in the diet, and largely obtained from seafood and its derivatives. It is unusual to get more than 20% of total intake from a normal diet. In order to exert its effects on bone metabolism and calcium absorption, Vitamin D must first be converted to 1,25 dihydroxyvitamin D, which occurs through the action of parathyroid hormone (PTH). This is a self regulating process, evidence of Vitamin D deficiency then being manifest through high levels of PTH. At present, most of our knowledge and evidence base for management of Vitamin D related issues comes from effects on bone metabolism. Until large prospective studies have reported on emerging issues in relation to the potential for reducing heart disease, diabetes and cancer risk, no specific guidance is given here. Treatment is not the same as supplementation: the recommended daily intake of 400 units of vitamin D will be insufficient to treat an adult with severe vitamin D deficiency. Risk factors for Vitamin D deficiency 2 Inadequate UV light exposure Poor oral intake Northern latitude Vegan or vegetarian Air pollution (or fish free diet) Occlusive garments Malabsorption, short Pigmented skin bowel, or cholestaticc Habitual sunscreen use liver disease Institutionalised or housebound Colestyramine use 2 : Metabolic risk Reducedd synthesis Elderly Chronic kidney disease Increased Breakdown Drugs (rifampicin, anticonvulsants, HAART therapy for HIV, glucocorticoids). Reducedd stores Liver disease Multiple, short interval pregnancies Status: APPROVED Approved by: ABHB MTC Page 1 of 8 Issue Date: March 2012 (updated October 2014) Review Date: October 2016

2 Clinical features of Vitamin D deficiency: Signs and symptoms in ADULTS Pain and proximal muscle weakness (rib, hip, pelvis thigh and foot pain are typical) Hypocalcaemia (a late effect) which might result in: Seizures Tetany Assessing individuals for Vitamin D deficiency Population screening by measuring vitamin D levels is not justified. Characteristics Risk factors only (see above) Risk factors AND symptoms/signs Advice and management Lifestyle Advice Consider long term preventative therapies Investigations Therapeutic intervention (plus Lifestyle Advice) followed by long term maintenance therapy Lifestyle Advice Dietary sources Good sources of vitamin D include: Oily fish including trout, salmon, mackerel, herring, sardines, anchovies, pilchards, and fresh tuna. Amount will depend on preparation Cod liver oil (not advised in pregnancy due to vitamin A content) and other fish oils Egg yolk Supplemented breakfast cereals Margarine has statutory supplementation in the UK Sunlight Ultraviolet B (UVB) radiation is the best way to boost vitamin D, but it is unclear how much sunlight is needed to raise blood levels to a particular level. Environmental and personal factors affect vitamin D production in the skin making it difficult to make a one size fits all recommendation. Exposure of 10 to 15 minutes to the UK summer sun, without suncream, several times a week is probably a safe balance between adequate vitamin D levels and any risk of skin cancer. 3 Sunbeds are not recommended as a way to top up vitamin D. Investigations Listed in suggested sequence 1. U&Es, Bone, GGT & FBC a. To identify hypocalcaemia and provide a baseline for monitoring b. Renal function (to exclude renal cause) c. FBC (iron deficiency commonly co exists) Note: This testing profile would initially give you Na, K, Cl, Urea, Creat, T. Prot., Alb, Ca, PO4, Alk Phos, GGT & FBC. The inclusion of GGT as a 1 st line test avoids requesting an LFT and the need to wait for the Alk Phos results before requesting GGT as a 2 nd line test hydroxyvitamin D levels (see below for guidance on whether to assay) Specialist Tests Only: 3. Anti tissue transglutaminase (TTG) antibody levels and serum IgA ONLY advised in patients with low 25 hydroxyvitamin D levels and unexplained hypocalcaemia or hypomagnesaemia. Or if there is iron/ folate deficiency. Approved by: ABHB MTC Page 2 of 8 Review Date: October 2016

3 Measurement & Interpretation of serum 25 hydroxyvitamin D concentrations When to assay serum 25 hydroxyvitamin D concentrations: classical symptoms/signs of vitamin D deficiency Risk factors for vitamin D deficiency Abnormal biochemistry (e.g. raised Alk Phos or low serum calcium). Measure 25 hydroxyvitamin D Level NO (unless doubt exists as to diagnosis) Treat as deficient CONSIDER Note there is a minimum retest interval of 3 months to vitamin D requests. < 25 nmol/l DEFICIENCY: high dose treatment initially, then long term maintenance treatment required nmol/l INSUFFICIENCY: long term maintenance treatment required > 50 nmol/l Adequate > 250 nmol/l Potential for toxicity Daily doses in excess of 250micrograms or units are generally required to achieve this. 4 Provided basic investigations are undertaken before treatment and renal disease, liver disease, primary hyperparathyroidism and inflammatory conditions have been excluded, then vitamin D toxicity is very rare. Early symptoms of toxicity include symptoms of hypercalcaemia such as thirst, polyuria and constipation. To convert nmol/l to μg/l divide by 2.5 (1 μg/l is equivalent to 1 nanogram/ml) Health Care Professionals wishing to discuss laboratory investigations should contact: Duty biochemist in ABHB on tel: (This number should ONLY be used by healthcare professionals) Individuals with the following features should be referred to a specialist: 1. Atypical biochemistry or atypical clinical manifestations 2. Deficiency due to malabsorption 3. Failure to respond to treatment after 3 months 4. Focal bone pain 5. Liver disease, lymphoma and metastatic cancer 6. Parathyroid disorders 7. Renal disease 8. Renal stones 9. Sarcoidosis 10. Tuberculosis 11. Unexplained deficiency 12. Unexplained weight loss Approved by: ABHB MTC Page 3 of 8 Review Date: October 2016

4 Advice on prescribing of Vitamin D and calcium supplements for ADULTS Daily treatment with Vitamin D (either cholecalciferol or ergocalciferol) is associated with a rise in measured vitamin D levels, representing an increased amount of stored Vitamin D. In adults, each 100 units of vitamin D taken daily will normally raise vitamin D levels by 2.5 nmol/l (1 μg/l). Patient characteristics DEFICIENCY <25 nmol/l in ADULT Once corrected remember to then give long term maintenance treatment below. Intestinal Malabsorption/ Chronic liver disease in ADULTS INSUFFICIENCY nmol/l in ADULT OR long term MAINTENANCE therapy following treatment of deficiency in adults **this includes those with known risk factors AND signs/symptoms AND abnormal biochemistry without assaying vitamin D levels HEALTHY, no risk factors, symptom free (Intake and synthesis presumed adequate) Advice and management 1 st Line: INVITA D3 oral solution (in single use plastic ampoules ) TWO oral ampoules (25000 units each = units) PER WEEK for 6 weeks (6 week course costs 17.80). 2 nd Line: DESUNIN 800 unit tablets FOUR 800 unit tablets/capsules DAILY for 12 weeks (12 week course costs 40.32) OR FULTIUM D unit capsules ONE capsule DAILY for 12 weeks (12 week course costs 37.30) Note: Fultium D 3 capsules contain gelatin see under Special considerations on page 5. Where oral therapy not appropriate: ERGOCALCIFEROL/COLECALCIFEROL [UNLICENSED] INJECTION (or ) units* given as a SINGLE intramuscular DOSE. 1 Then give long term maintenance treatment below. *To convert units to micrograms of ergocalciferol, divide by 40. This DEFICIENCY often requires higher doses of pharmacological vitamin D than for primary deficiency (see BNF). The BMJ article 2 suggests doses such as ERGOCALCIFEROL/COLECALCIFEROL [UNLICENSED] INJECTION units (7.5mg) given MONTHLY for 3 months as an intramuscular injection, followed by units by intramuscular injection once or twice a year. 1 st Line: SELF TREATMENT with over the counter high strength vitamin D preparation of up to 2000 or 2500 units daily (equivalent to 50 to 62.5 micrograms daily). See Available Vitamin D preparations. 2 nd Line: INVITA D3 oral solution (in single use plastic ampoules ) ONE or TWO oral ampoules (25000 units each = units) PER MONTH long term (12 months costs 35.60). 3 rd Line: DESUNIN 800 unit tablets OR FULTIUM D unit capsules ONE or TWO 800 units tablets/capsules DAILY long term (12 months costs 87.60) Note: Fultium D 3 capsules contain gelatin see under Special considerations below. Where oral therapy not appropriate: ERGOCALCIFEROL/COLECALCIFEROL [UNLICENSED] INJECTION units (7.5mg) given as a SINGLE intramuscular dose once or twice a year. 1 See Lifestyle Advice. Consider daily self treatment with purchased supplement of 400 to 800 units (10 to 20 micrograms) vitamin D daily amount likely to prevent rickets, but unlikely to significantly raise vitamin D levels to optimal in most people. InVita D3 plastic ampoules can be snapped open and squeezed to administer, see for further information. TWO may be appropriate for maintenance in a previously deficient patient. Available Vitamin D preparations InVita D3 oral solution, Fultium D 3 capsules and Desunin tablets are only available on prescription (POM). Approved by: ABHB MTC Page 4 of 8 Review Date: October 2016

5 InVita D3 oral solution ampoules do NOT contain soya, arachis oil, lactose or gelatine full prescribing information is at: Desunin tablets do NOT contain soya, arachis oil or gelatine full prescribing information is at: Fultium D 3 capsules do NOT contain arachis oil. The capsule shells do contain gelatin full prescribing information for the 8000 unit capsules is at: and for the unit capsules is at: Higher dose vitamin D preparations (up to unit) are available to purchase over the counter (OTC) where appropriate this method of supply should be encouraged. 5 Special considerations in relation to oral preparations: 1. Ability to take or absorb oral medication (e.g. malabsorption). 2. Relevant excipients for any dietary/allergy restrictions. a. colecalciferol in supplements is derived from wool oil (lanolin). b. products containing soya or arachis oil are not suitable for those with nut allergies. MHRA advice 6 is that exposure may lead to severe allergic reactions, including anaphylaxis. Doctors and pharmacists should enquire whether patients have any relevant allergies before supplying these medicines. c. gelatin in capsules may be of porcine origin and the difficulties this presents to muslims should be considered. 7 Opting for colecalciferol tablets (e.g. Desunin) avoids the need to determine the source of gelatin in OTC capsules. 3. Tolerability in selected patients. Injection There is a UK licensed injection of ergocalciferol: 7.5mg ( units)/ml in oil, Injection for intramuscular use only. 1mL amp = 7.45, 2mL amp = An intermittent regimen for primary vitamin D deficiency would be off label (see above). Supply difficulties with ergocalciferol have resulted in the use of colecalciferol units by intramuscular injection. Liquid specials The availability of InVita D3 (a UK licensed high dose oral solution for the prevention and treatment of vitamin D deficiency in children and adults) means that named patient liquid specials of vitamin D (UNLICENSED) should no longer need to be prescribed. Calcium supplementation Use of InVita D 3, Fultium D 3 capsules or Desunin tablets avoids individuals having to take calcium unnecessarily the un palatability of the calcium component may reduce adherence to the combined calcium and vitamin D preparations. Where there is severe deficiency accompanied by hypocalcaemia, leading to secondary hyperparathyroidism, treatment with vitamin D should be accompanied at least initially by calcium supplementation 1 to 2 grams daily consider referral for advice. Much more vigilant monitoring of calcium levels is required to prevent hypercalcaemia (see Monitoring Requirements on Page 6). Dietary calcium deficiency is common in some patient groups (low meat and milk product intake) and may be significantly exacerbated where there is a high dietary intake of phytate (chapatti flour, wholegrain and wholemeal flour) which binds calcium in the intestine. These patients should be advised to take 1 to 2g of calcium daily long term and to purchase this over the counter. Monitoring requirements Important. All patients receiving therapy for vitamin D deficiency should be monitored as follows: 1 month: request serum calcium and renal profile. 3 months: request serum bone and renal profiles plus; 25 hydroxyvitamin D level. Note there is a minimum retest interval of 3 months to vitamin D requests Important. All patients receiving calcium supplementation for hypocalcaemia, in addition to pharmacological doses of vitamin D need more frequent monitoring of plasma calcium every month in the first few months of treatment to determine length of time calcium supplementation is needed and to avoid hypercalcaemia. Approved by: ABHB MTC Page 5 of 8 Review Date: October 2016

6 Patients or carers should be informed about the symptoms of hypercalcaemia e.g. weight loss, sickness, vomiting, headache, abdominal pain, apathy, and polyuria. Alfacalcidol (One Alpha )/Calcitriol capsules Specialist initiation only (both designated Amber without Shared Care in the Gwent Traffic Light system) These short acting, potent vitamin D analogues have no routine place in the management of primary vitamin D deficiency and should be reserved for use in renal disease, liver disease, primary hypoparathyroidism and pseudohypoparathyroidism. 8 (For further information see BNF section and NPSA Signal ) Pregnancy & Breastfeeding The Chief Medical Officer for Wales recommends that: All pregnant and breastfeeding women should take a daily supplement containing 10 micrograms of vitamin D, to ensure the mother s requirements for vitamin D are met and to build adequate fetal stores for early infancy. In 2008 NICE (in CG 62 on antenatal care 10 ) had advised: All women should be informed at the booking appointment about the importance for their own and their baby s health of maintaining adequate vitamin D stores during pregnancy and whilst breastfeeding. In order to achieve this, women may choose to take 10micrograms of vitamin D (as D 3 ) per day, as found in the HEALTHY START multivitamin* supplement. Particular care should be taken to enquire as to whether women at greatest risk are following advice to take this daily supplement. These include: women of South Asian, African, Caribbean or Middle Eastern family origin women who have limited exposure to sunlight, such as women who are predominantly housebound, or usually remain covered when outdoors women who eat a diet particularly low in vitamin D, such as women who consume no oily fish, eggs, meat, vitamin D fortified margarine or breakfast cereal women with a pre pregnancy body mass index above 30 kg/m 2. * Note each Healthy Start 11 women s vitamin tablet contains 400micrograms of folic acid, 70mg of vitamin C and 10migrograms of vitamin D. The tablets do not contain vitamin A (high levels of vitamin A may cause birth defects) Approved by: ABHB MTC Page 6 of 8 Review Date: October 2016

7 Appendix Status Treatment regime Maintenance regime Traffic Light Classification 1 st Line: DEFICIENCY (<25 nmol/l) in ADULT Once corrected remember to then give long term maintenance treatment below. InVita D unit oral solution (in single use plastic ampoules) 2 nd Line: DESUNIN 800 unit tablets or FULTIUM D unit capsules or The contents of TWO plastic ampoules (2x25000 units) PER WEEK for 6 weeks FOUR capsules/tablets (4x800 units) DAILY for 12 weeks or The contents of ONE or TWO plastic ampoules (25000 or units) PER MONTH long term ONE or TWO 800 unit capsules/tablets DAILY long term GREEN (suitable for non specialist initiation) FULTIUM D unit capsules ONE 3200 unit capsule DAILY for 12 weeks Fultium D caps are only licensed for the treatment of vitamin D deficiency INSUFFICIENCY (25 50 nmol/l) in ADULT 1 st Line: SELF TREATMENT with over the counter high strength vitamin D preparation up to 2000 or 2500 units daily (equivalent to 50 to 62.5 micrograms daily). N/A 2 nd Line: InVita D unit oral solution (in single use plastic ampoules) The contents of TWO plastic ampoules (2x25000 units) PER MONTH long term 3 rd Line: DESUNIN 800 unit tablets or FULTIUM D unit capsules ONE or TWO 800 unit capsules/tablets DAILY long term GREEN (suitable for non specialist initiation) Where oral therapy not appropriate: ERGOCALCIFEROL or COLECALCIFEROL [UNLICENSED] INJECTION units given as a SINGLE intramuscular dose once or twice a year HEALTHY nmol/l Consider 400 to 800 units daily (equivalent to 10 to 20 micrograms daily) self treatment purchased OTC N/A Approved by: ABHB MTC Page 7 of 8 Review Date: October 2016

8 References: 1 CEM/CMO/2012/4 of February Pearce SHS, Cheetham TD. Diagnosis and management of Vitamin D deficiency. BMJ 2010;340: exposure and vitamin d advice.aspx 4 Hathcock JN et al. Risk assessment of vitamin D. American Journal of Clinical Nutrition, Vol. 85, No. 1, 6 18, January World Health Organisation. Regional Office for the Eastern Mediterranean. July Full document available at 8 Primary vitamin D deficiency in adults. Drug and Therapeutics Bulletin 2006; April 44(4): health professionals/vitamins/ Approved by: ABHB MTC Page 8 of 8 Review Date: October 2016