Vitamin D Analogs

Potential changes to the recommended Upper Limit (UL) for vitamin D:
Experts Recommend Vitamin D 10,000 IU Upper Limit -------
The tolerable upper intake level for oral vitamin D3 should be increased five-fold, experts from the US-based Council for Responsible Nutrition (CRN) have said after a review of the science.

The risk assessment provides companies with a guide for safe upper levels for product formulations, and consumers with vital information on safe dosage levels from products.

“This risk assessment was needed to show that newer evidence supports the conclusion that vitamin D is much safer then previously thought, particularly because of all the emergence research that shows benefit for vitamin D at higher levels than consumers were traditionally taking,” lead author John Hathcock said.

Currently, the tolerable upper intake level (UL) in Europe and the US is set at 2000 International Units (IU), equivalent to 50 micrograms per day. However, recent research, particularly from clinical trials, suggests that this should be raised. The CRN scientists state that this could be raised to 10,000 IU (250 micrograms per day).

The reviewers, from the CRN, Mount Sinai Hospital in Toronto and Crieghton University in Nebraska, pooled data from 21 clinical trials using doses ranging from 10 to 2500 micrograms (100,000 IU). The risk assessment also included data from animal studies, some of which used “extraordinarily high doses of vitamin D3”.

“The lack of adverse effects in clinical trials that used intake up to 1250 micrograms [50,000 IU] vitamin D per day and the lack of adverse effects at lower doses inspires a high level of confidence in the data from the strongly designed clinical trials that used 250 micrograms [10,000 IU] vitamin D per day,” said the reviewers.

The researchers also note that for practically all the reported cases of vitamin D toxicity have involved doses that were in excess of those studied in the clinical trials. “Newer clinical trial data are sufficient to show that vitamin D is not toxic at intakes much higher than previously considered unsafe,” said the reviewers.

Vitamin D is made by the body on exposure to sunshine, or can be consumed in small amounts in milk, fish, liver and egg yolk. However because of the low amounts present in the diet, and lack of sunshine in northern climates, with some estimates claiming that as much as 60 percent of northern populations may be vitamin D deficient.

The reviewers note that normal dietary sources provide about 2.5 micrograms per day, while this can be increased up to 10 micrograms with fortified foods. Dietary supplements would provide higher doses.

“We applied the same method to our risk assessment as the Food and Nutrition Board had used years ago, and our results concluded vitamin D could be safely taken in much higher amounts,” Hathcock said.

Source
J.N. Hathcock, A. Shao, R. Vieth, R. Heaney. Risk assessment for vitamin D. American Journal of Clinical Nutrition; January 2007, Volume 85, Pages 6-18.

Potential changes to the recommended daily intake of Vitamin D:
Currently, the recommended daily intake of vitamin D is 200 IU for people up to 50 years old; 400 IU for people 51 to 70 years old; and 600 IU for people over 70 years old.

“The consensus among UC scientists who signed this statement is that 2000 IU per day of vitamin D3, a form of vitamin D, is the appropriate intake for most adult Americans,” said Norman, an international expert on vitamin D. “This intake is the National Academy of Sciences/Institute of Medicine’s upper limit for daily intake, and is 400 IU less than the National Academy of Sciences/Institute of Medicine’s ‘no adverse health effect’ level. Scientific concerns about this level of intake are minimal, based on the findings of the National Academy of Sciences.”

NNorman explained that a 2000 IU daily intake of vitamin D can be achieved by a combination of sunshine, food, supplements, and possibly even limited tanning exposure. “While more research on this topic is highly desirable, it should not delay recommending a 2000 IU daily intake of vitamin D for most people,” he said.
Source: https://newsroom.ucr.edu/cgi-bin/display.cgi?id=1968

The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate but not excessive daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

Because of improved calcium absorption from the gastrointestinal tract, some patients on calcitriol may be maintained on a lower calcium intake. Patients who tend to develop hypercalcemia may require only low doses of calcium or no supplements at all.

During the titration period of treatment with calcitriol, serum calcium levels should be checked at least twice weekly. When the optimal dosage of calcitriol has been determined, serum calcium levels should be checked every month (or as given below for individual indications). Samples for serum calcium estimation should be taken without a tourniquet.

Dialysis Patients
The recommended initial dose of calcitriol is 0.25 mcg/day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 mcg/day at 4 to 8 week intervals. During this titration period, serum calcium levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues. Phosphorus, magnesium, and alkaline phosphatase should be determined periodically.

Patients with normal or only slightly reduced serum calcium levels may respond to calcitriol doses of 0.25 mcg every other day. Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.

Oral calcitriol may normalize plasma ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction. In these individuals with autonomous parathyroid hyperfunction, oral calcitriol may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism.

Hypoparathyroidism
The recommended initial dosage of calcitriol is 0.25 mcg/day given in the morning. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease is not observed, the dose may be increased at 2- to 4-week intervals. During the dosage titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, calcitriol should be immediately discontinued until normocalcemia ensues. Careful consideration should also be given to lowering the dietary calcium intake. Serum calcium, phosphorus, and 24-hour urinary calcium should be determined periodically.

Most adult patients and pediatric patients age 6 years and older have responded to dosages in the range of 0.5 mcg to 2 mcg daily. Pediatric patients in the 1 to 5 year age group with hypoparathyroidism have usually been given 0.25 mcg to 0.75 mcg daily. The number of treated patients with pseudohypoparathyroidism less than 6 years of age is too small to make dosage recommendations.

Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of calcitriol may be needed.

Predialysis Patients
The recommended initial dosage of calcitriol is 0.25 mcg/day in adults and pediatric patients 3 years of age and older. This dosage may be increased if necessary to 0.5 mcg/day.

For pediatric patients less than 3 years of age, the recommended initial dosage of calcitriol is 10 to 15 ng/kg/day.

DOSAGE AND ADMINISTRATION [INFECTION]
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The optimal dose calcitriol injection must be carefully determined for each patient.

The effectiveness of calcitriol injection therapy is predicated on the assumption that each patient is receiving an adequate and appropriate daily intake of calcium. The RDA for calcium in adults is 800 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

The recommended initial dose of calcitriol injection, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 mcg (0.02 mcg/kg) to 2 mcg administered three times weekly, approximately every other day. Doses as small as 0.5 mcg and as large as 4 mcg three times weekly have been used as an initial dose. If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 mcg at two to four week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate. Then, the calcitriol injection dose should be reinitiated at a lower dose. Doses may need to be reduced as the PTH levels decrease in response to the therapy. Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels.

The following is a suggested approach in dose titration:

Supplied:
Capsule (Rocaltrol®): 0.25 mcg, 0.5 mcg.
Injection, solution: 1 mcg/mL (1 mL); 2 mcg/mL (2 mL)
Calcijex®: 1 mcg/mL (1 mL).
Solution, oral (Rocaltrol®): 1 mcg/mL (15 mL).

ADMINISTRATION — May be administered without regard to food. Give with meals to reduce GI problems. May be administered as a bolus dose I.V. through the catheter at the end of hemodialysis.
COMPATIBILITY — Stable in D5W, NS, sterile water for injection.

CLINICAL PHARMACOLOGY
Man's natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the skin to vitamin D3 (cholecalciferol). Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active as a regulator of calcium and phosphorus metabolism at target tissues. The initial transformation of vitamin D3 is catalyzed by a vitamin D3-25-hydroxylase enzyme (25-OHase) present in the liver, and the product of this reaction is 25-hydroxyvitamin D3 [25-(OH)D3]. Hydroxylation of 25-(OH)D3 occurs in the mitochondria of kidney tissue, activated by the renal 25-hydroxyvitamin D3-1 alpha-hydroxylase (alpha-OHase), to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3. Endogenous synthesis and catabolism of calcitriol, as well as physiological control mechanisms affecting these processes, play a critical role regulating the serum level of calcitriol. Physiological daily production is normally 0.5 to 1 mcg and is somewhat higher during periods of increased bone synthesis (eg, growth or pregnancy).

INDICATIONS AND USAGE
Predialysis Patients
Calcitriol Capsules are indicated in the management of secondary hyperparathyroidism and resultant metabolic bone disease in patients with moderate to severe chronic renal failure (Ccr 15 to 55 mL/min) not yet on dialysis. In children, the creatinine clearance value must be corrected for a surface area of 1.73 square meters. A serum iPTH level of ≥100 pg/mL is strongly suggestive of secondary hyperparathyroidism.

Dialysis Patients
Calcitriol Capsules are indicated in the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis. In these patients, calcitriol administration enhances calcium absorption, reduces serum alkaline phosphatase levels, and may reduce elevated parathyroid hormone levels and the histological manifestations of osteitis fibrosa cystica and defective mineralization.

Hypoparathyroidism Patients
Calcitriol Capsules are also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.

CONTRAINDICATIONS
Calcitriol Capsules should not be given to patients with hypercalcemia or evidence of vitamin D toxicity. Use of Calcitriol Capsules in patients with known hypersensitivity to Calcitriol Capsules (or drugs of the same class) or any of the inactive ingredients is contraindicated.

PHARMACODYNAMICS / KINETICS
Onset of action: ~2-6 hours.
Duration: 3-5 days.
Absorption: Oral: Rapid.
Protein binding: 99.9%.
Metabolism: Primarily to 1,24,25-trihydroxycholecalciferol and 1,24,25-trihydroxy ergocalciferol.
Half-life elimination: 3-8 hours.

Dosing (Adults):
Individualize dosage to maintain calcium levels of 9-10 mg/dL.

Renal failure:
Oral: 0.25 mcg/day or every other day (may require 0.5-1 mcg/day).
I.V.: 0.5 mcg (0.01 mcg/kg) 3 times/week; most doses in the range of 0.5-3 mcg (0.01-0.05 mcg/kg) 3 times/week.
Hypoparathyroidism/pseudohypoparathyroidism:
Oral: 0.5 to 2 mcg/day.

Vitamin D-dependent rickets: Oral: 1 mcg once daily.
Vitamin D-resistant rickets (familial hypophosphatemia): Oral: Initial: 0.015 to 0.02 mcg/kg once daily; maintenance: 0.03-0.06 mcg/kg once daily; maximum dose: 2 mcg once daily.

1 IU of Vitamin D is equal to 0.025 micrograms of cholecalciferol.

[Supplied: Tablet: 1000 IU, 400 IU]

CLINICAL PHARMACOLOGY
The in vivo synthesis of the major biologically active metabolites of vitamin D occurs in two steps. The first hydroxylation of ergocalciferol takes place in the liver (to 25-hydroxyvitamin D) and the second in the kidneys (to 1,25-dihydroxyvitamin D). Vitamin D metabolites promote the active absorption of calcium and phosphorus by the small intestine, thus elevating serum calcium and phosphate levels sufficiently to permit bone mineralization. Vitamin D metabolites also mobilize calcium and phosphate from bone and probably increase the reabsorption of calcium and perhaps also of phosphate by the renal tubules.

There is a time lag of 10 to 24 hours between the administration of vitamin D and the initiation of its action in the body due to the necessity of synthesis of the active metabolites in the liver and kidneys. Parathyroid hormone is responsible for the regulation of this metabolism in the kidneys.

INDICATIONS AND USAGE
DRISDOL is indicated for use in the treatment of hypoparathyroidism, refractory rickets, also known as vitamin D resistant rickets, and familial hypophosphatemia.

CONTRAINDICATIONS
DRISDOL is contraindicated in patients with hypercalcemia, malabsorption syndrome, abnormal sensitivity to the toxic effects of vitamin D, and hypervitaminosis D.

WARNINGS
Hypersensitivity to vitamin D may be one etiologic factor in infants with idiopathic hypercalcemia. In these cases vitamin D must be strictly restricted.

Keep out of the reach of children.

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 DOSING: ADULTS
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Oral dosing is preferred; I.M. therapy is required with GI, liver, or biliary disease associated with malabsorption.

Dietary supplementation (each 1 mcg = 40 I.U.):
Oral: 10 mcg/day (400 int. units/day)

Adequate intake: Oral:
18-50 years: 5 mcg/day (200 int. units/day)
51-70 years: 10 mcg/day (400 int. units/day)
Elderly >70 years: 15 mcg/day (600 int. units/day)

Vitamin D deficiency/insufficiency in patients with CKD stages 3-4 (K/DOQI guidelines): Note: Dose is based on 25-hydroxyvitamin D serum level [25(OH) D]:
Oral (treatment duration should be a total of 6 months):
Serum 25(OH)D <5 ng/mL:
50,000 int. units/week for 12 weeks, then 50,000 int. units/month
Serum 25(OH)D 5-15 ng/mL:
50,000 int. units/week for 4 weeks, then 50,000 int. units/month
Serum 25(OH)D 16-30 ng/mL:
50,000 int. units/month

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Familial phosphatemia: 10,000-80,000 I.U./day and phosphorus 1-2 g/day.
Renal failure: Oral: 500 mcg/day (20,000 I.U.).
Hypoparathyroidism: Oral: 625 mcg to 5 mg/day (25,000-200,000 I.U.) and calcium supplements.

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Nutritional rickets and osteomalacia: Oral:
Adults with normal absorption: 25-125 mcg/day (1000 - 5000 int. units)
Adults with malabsorption: 250-7500 mcg (10,000 - 300,000 int. units)

Vitamin D-dependent rickets: Oral: 250 mcg to 1.5 mg/day (10,000-60,000 int. units)

Vitamin D-resistant rickets: Oral: 12,000 - 500,000 int. units/day
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Supplied:
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Capsule: 50,000 I.U. [1.25 mg]. ]
Liquid, drops: Calciferol™, Drisdol®: 8000 I.U./mL [200 mcg/mL] (60 mL)

Several nutrition scientists recently challenged these ULs, first published in 1997. They point to newer clinical trials conducted in healthy adults and conclude that the data support a UL as high as 10,000 IU/day. Although vitamin D supplements above recommended levels given in clinical trials have not shown harm, most trials were not adequately designed to assess harm. Evidence is not sufficient to determine the potential risks of excess vitamin D in infants, children, and women of reproductive age.

Source:
https://ods.od.nih.gov/factsheets/vitamind.asp

*IUs = International Units.
**DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin D is 400 IU for adults and children age 5 and older. Food labels, however, are not required to list vitamin D content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.

Source:
https://ods.od.nih.gov/factsheets/vitamind.asp

Serum concentration of 25(OH)D is the best indicator of vitamin D status. It reflects vitamin D produced cutaneously and that obtained from food and supplements [5] and has a fairly long circulating half-life of 15 days [15]. However, serum 25(OH)D levels do not indicate the amount of vitamin D stored in other body tissues. Circulating 1,25(OH)2D is generally not a good indicator of vitamin D status because it has a short half-life of 15 hours and serum concentrations are closely regulated by parathyroid hormone, calcium, and phosphate [15]. Levels of 1,25(OH)2D do not typically decrease until vitamin D deficiency is severe.

There is considerable discussion of the serum concentrations of 25(OH)D associated with deficiency (e.g., rickets), adequacy for bone health, and optimal overall health (Table 1). A concentration of <20 nanograms per milliliter (ng/mL) (or <50 nanomoles per liter [nmol/L]) is generally considered inadequate.

Table 1: Serum 25-Hydroxyvitamin D [25(OH)D] Concentrations and Health*

* Serum concentrations of 25(OH)D are reported in both nanograms per milliliter (ng/mL) and nanomoles per liter (nmol/L).
** 1 ng/mL = 2.5 nmol/L.

Source:
https://ods.od.nih.gov/factsheets/vitamind.asp