Vitamin D and Analogs (Systemic)

This monograph includes information on the following:

1) Alfacalcidol  *
2) Calcifediol  
3) Calcitriol
4) Dihydrotachysterol
5) Doxercalciferol
6) Ergocalciferol
7) Paricalcitol

VA CLASSIFICATION
Alfacalcidol
Primary: VT509

Calcifediol
Primary: VT501

Calcitriol
Primary: VT502

Dihydrotachysterol
Primary: VT503

Doxercalciferol
Primary: VT509

Ergocalciferol
Primary: VT504

Paricalcitol
Primary: VT509


Commonly used brand name(s): Calciferol6; Calciferol Drops6; Calcijex3; Calderol2; DHT4; DHT Intensol4; Drisdol6; Drisdol Drops6; Hectorol5; Hytakerol4; One-Alpha1; Ostoforte6; Radiostol Forte6; Rocaltrol3; Zemplar7.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:

Note: Vitamin D is a fat-soluble vitamin.



Antihypocalcemic— Alfacalcidol; Calcifediol; Calcitriol; Dihydrotachysterol ; Ergocalciferol;

Nutritional supplement (vitamin)— Calcifediol; Calcitriol; Ergocalciferol;

Antihypoparathyroid— Calcitriol; Dihydrotachysterol; Ergocalciferol;

Antihyperparathyroid—Doxercalciferol; Paricalcitol ;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Hypocalcemia, chronic (treatment) {08} {09} {10} {26} {38} {71} {72}
Hypophosphatemia (treatment) {01} {12} {16} {27} {36} {38}
Osteodystrophy (treatment) or {09} {26} {36} {37} {38}
Rickets (prophylaxis and treatment) {01} {12} {16} {27}—Therapeutic doses of specific vitamin D analogs are used in the treatment of chronic hypocalcemia, hypophosphatemia, rickets, and osteodystrophy associated with various medical conditions including chronic renal failure, familial hypophosphatemia, and hypoparathyroidism (postsurgical or idiopathic, or pseudohypoparathyroidism). Some analogs have been found to reduce elevated parathyroid hormone concentrations in patients with renal osteodystrophy associated with hyperparathyroidism. {37}
—Theoretically, any of the vitamin D analogs may be used for the above conditions. However, because of their pharmacologic properties, some may be more useful in certain situations than others. Alfacalcidol, {38} calcitriol, and dihydrotachysterol are usually preferred in patients with renal failure since these patients have impaired ability to synthesize calcitriol from cholecalciferol and ergocalciferol; therefore, the response is more predictable. In addition, their shorter half-lives may make toxicity easier to manage (hypercalcemia reverses more quickly). Ergocalciferol may not be the preferred agent in the treatment of familial hypophosphatemia or hypoparathyroidism because the large doses needed are associated with a risk of overdose and hypercalcemia; dihydrotachysterol and calcitriol may be preferred. {12}

Secondary hyperparathyroidism (prophylaxis and treatment)—Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure. {123}

—Doxercalciferol is indicated for the treatment of elevated intact parathyroid hormone (iPTH) levels in the management of secondary hyperparathyroidism in patients undergoing chronic renal dialysis. {124}

Tetany (prophylaxis and treatment)—Dihydrotachysterol is indicated [and ergocalciferol and calcitriol are used] {84} for treatment of chronic and latent forms of postoperative tetany and idiopathic tetany. {17} {18} {25}

Vitamin D deficiency (prophylaxis and treatment) {10}—Ergocalciferol is indicated for prevention and treatment of vitamin D deficiency states. Vitamin D deficiency may occur as a result of inadequate nutrition, intestinal malabsorption, or lack of exposure to sunlight, but does not occur in healthy individuals receiving an adequate balanced diet and exposure to sunlight. Vitamin D therapy, alone, as treatment for osteoporosis is not generally recommended; {78} {79} {80} {81} however, vitamin D supplements in doses of 400 to 800 Units may be used as part of the prevention and treatment of osteoporosis in patients with an inadequate vitamin D and/or calcium intake. {62} {63} {64} {65} {82} For prophylaxis of vitamin D deficiency, dietary improvement, rather than supplementation, is advisable. For treatment of vitamin D deficiency, supplementation is preferred. {120}
—Deficiency of vitamin D may lead to rickets and osteomalacia. {02}
—Recommended intakes may be increased and/or supplementation may be necessary in the following persons or conditions (based on documented vitamin D deficiency):

• Alcoholism {55}


• Dark-skinned individuals {11}


• Hepatic-biliary tract disease—hepatic function impairment, cirrhosis, obstructive jaundice {02} {12} {52}


• Infants, breast-fed, with inadequate exposure to sunlight {06} {20}


• Intestinal diseases—celiac, tropical sprue, regional enteritis, persistent diarrhea {02} {15}


• Lack of exposure to sunlight combined with reduced vitamin D intake {93}


• Renal function impairment {89}


• In general, vitamin D absorption will be impaired in any condition in which fat malabsorption (steatorrhea) occurs. {02}

—Some unusual diets (e.g., strict vegetarian diets with no milk intake such as vegan-vegetarian {15} {34} or macrobiotic, {35} or reducing diets that drastically restrict food selection) may not supply minimum daily requirements of vitamin D. Supplementation may be necessary in patients receiving total parenteral nutrition (TPN) or undergoing rapid weight loss or in those with malnutrition, because of inadequate dietary intake.
—Recommended intakes for all vitamins and most minerals are increased during pregnancy. Many physicians recommend that pregnant women receive multivitamin and mineral supplements, especially those pregnant women who do not consume an adequate diet and those in high-risk categories (i.e., women carrying more than one fetus, heavy cigarette smokers, and alcohol and drug abusers). {39} Taking excessive amounts of a multivitamin and mineral supplement may be harmful to the mother and/or fetus and should be avoided.
—Pregnant women who are strict vegetarians (vegan-vegetarians) and/or have minimal exposure to sunlight may need vitamin D supplementation. {39}
—Congenital rickets have been reported in newborns whose mothers had low serum levels of vitamin D. {56}
—Recommended intakes for all vitamins and most minerals are increased during breast-feeding. {06}
—Recommended intakes may be increased by the following medications: Barbiturates, cholestyramine, colestipol, hydantoin anticonvulsants, mineral oil, and primidone.

Acceptance not established
There are insufficient data to show that vitamin D supplementation is beneficial in the treatment of psoriasis. {67} {68} {69}

Unaccepted
Ergocalciferol has not been proven effective for treatment of lupus vulgaris or rheumatoid arthritis, or prevention of nearsightedness or nervousness.

Table 1. Indications


Note: Bracketed information in the Category/Indications section refers to uses that are not included in U.S. product labeling.



  Legend:
I=Alfacalcidol
II=Calcifediol
III =Calcitriol
IV=Dihydrotachysterol
V=Doxercalciferol
VI=Ergocalciferol
VII=Paricalcitol
I
 
II
 
III
 
IV
 
V
 
VI
 
VII 
Vitamin D deficiency (prophylaxis and treatment)
  []
     
 
Vitamin D–dependent rickets (prophylaxis and treatment)
    []
       
Familial hypophosphatemia (vitamin D–resistant rickets) (treatment)
  []
[]
[]
  {12} {16}
 
Hypocalcemia associated with hypoparathyroidism (treatment)

[]
{10}
{18}
  {12} {16}
 
Chronic renal failure (treatment adjunct)

  {10}
[]
{124}    {123} 
Chronic, and latent forms of postoperative tetany and idiopathic tetany (treatment)
      {17} {18}
  []
 



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Alfacalcidol: 400.64 {90}
    Calcifediol: 418.66 {90}
    Calcitriol: 416.64 {90}
    Dihydrotachysterol: 398.67 {90}
    Doxercalciferol: 412.66 {124}
    Ergocalciferol: 396.65 {90}
    Paricalcitol: 416.65{123}

Mechanism of action/Effect:

Vitamin D is essential for promoting absorption and utilization of calcium and phosphate and for normal calcification of bone. Along with parathyroid hormone and calcitonin, it regulates serum calcium concentrations by increasing serum calcium and phosphate concentrations as needed. Vitamin D stimulates calcium and phosphate absorption from the small intestine and mobilizes calcium from bone. {02}

Exposure of the skin to ultraviolet rays in sunlight results in formation of cholecalciferol (vitamin D 3). {66} Ergocalciferol (calciferol, vitamin D 2) is found in commercial vitamin preparations and is used as a food additive; {40} cholecalciferol is found in vitamin D–fortified milk. Cholecalciferol and ergocalciferol are transferred to the liver where they are converted to calcifediol (25-hydroxycholecalciferol), which is then transferred to the kidneys and converted to calcitriol (1,25-dihydroxycholecalciferol, thought to be the most active form) and 24,25-dihydroxycholecalciferol (physiologic role not determined). {40} Dihydrotachysterol is a synthetic reduction product of ergocalciferol; it has only weak antirachitic activity; it is metabolically activated by 25-hydroxylation in the liver. {18} Alfacalcidol is rapidly converted to 1,25-dihydroxycholecalciferol in the liver. {38}Doxercalciferol is activated by CYP 27 in the liver to form 1, 25–dihydroxyvitamin D 2(major metabolite); activation does not require involvement of the kidneys.{124}

Calcitriol appears to act by binding to a specific receptor in the cytoplasm of the intestinal mucosa and subsequently being incorporated into the nucleus, probably leading to formation of the calcium-binding protein that results in increased absorption of calcium from the intestine. {15} Also, calcitriol may regulate the transfer of calcium ion from bone and stimulate reabsorption of calcium in the distal renal tubule, thereby effecting calcium homeostasis in the extracellular fluid. {15} {91}

Vitamin D, doxercalciferol, and paricalcitol have been shown to reduce parathyroid hormone levels.{123}

Absorption:

Readily absorbed from small intestine (proximal or distal) {02} {05}; cholecalciferol may be absorbed more rapidly and completely than ergocalciferol. Ergocalciferol requires presence of bile salts. {02}

There is evidence that some metabolites of vitamin D are reabsorbed from bile; however, the benefit to overall vitamin D status is thought to be negligible. {47} {48} {54}

Protein binding:

Bound to specific alpha globulins for transport. {02}

In vitro plasma protein binding of paricalcitol is extensive (>99.8%). {123}


Storage

Stored mainly in liver and other fat depots.

Biotransformation:

Metabolic activation of cholecalciferol and ergocalciferol occurs in 2 steps, the first in the liver and the second in the kidneys. {40} Metabolic activation of calcifediol occurs in the kidneys; dihydrotachysterol, alfacalcidol and doxercalciferol are activated in the liver. {18} {38} Calcitriol does not require metabolic activation. Degradation also occurs partly in the kidney.

Unidentified metabolites of paricalcitol were detected in urine and feces, with no parent drug detected in the urine. {123}

Plasma half-life

Alfacalcidol— 3 hours{125}

Calcifediol—Approximately 16 days {08} (10 to 22 days).

Calcitriol—3 to 6 hours. {09}

Doxercalciferol—32 to 37 hours (range up to 96 hours, similar in end-stage renal disease patients on hemodialysis).{124}

Ergocalciferol—19 to 48 hours (however, stored in fat deposits in body for prolonged periods).

Paricalcitol—15 hours. {123}

Onset of action:


Hypercalcemic:

Alfacalcidol— 6 hours

Calcitriol: Oral—2 to 6 hours.

Dihydrotachysterol: Several hours (maximal after 1 to 2 weeks).

Ergocalciferol: 12 to 24 hours; therapeutic effect may take 10 to 14 days. {12}{125}


Time to peak serum concentration

Alfacalcidol—Approximately 12 hours after a single dose. {38}

Calcifediol—Approximately 4 hours. {08}

Calcitriol—Oral: Approximately 3 to 6 hours. {09}

Doxercalciferol—Oral: Approximately 11 to 12 hours, after repeated oral doses of 5 to 15 mcg. {124}

Duration of action:


Following oral administration:

Alfacalcidol: Up to 48 hours. {38}

Calcifediol: 15 to 20 days (increased 2 to 3 times in renal failure).

Calcitriol: 3 to 5 days. {09}

Dihydrotachysterol: Up to 9 weeks.

Ergocalciferol: Up to 6 months; repeated doses have a cumulative action.


Elimination:
    Biliary/renal. {02}{123}


Precautions to Consider

Mutagenicity

Studies with calcitriol, paricalcitol,{123} or doxercalciferol {124}have found no evidence of mutagenicity.

Doxercalciferol caused structural chromatid and chromosome aberrations in an in vitro human lymphocyte clastogenicity assay with metabolic activation. Doxercalciferol was not clastogenic in an in vivo mouse clastogenicity assay.{124}

Pregnancy/Reproduction
Fertility—
Paricalcitol had no effect on the fertility of rats at intravenous doses up to 20 micrograms/kg (mcg/kg) per dose (equivalent to 13 times the highest recommended human dose (0.24 mcg/kg) based on body surface area (mg/m2)).{123}

Doxercalciferol had no effect on the fertility of rats at doses up to 2.5 micrograms/kg/day (mcg/kg/day) (approximately 3 times and less than the maximum recommended human dose of 60 mcg/week based on mg/m 2 body surface area), .{124}

Pregnancy—
Problems in humans have not been documented with intake of normal daily recommended amounts. There are insufficient data on acute and chronic vitamin D toxicity in pregnant women. {121} Maternal hypercalcemia during pregnancy in humans may be associated with increased sensitivity to effects of vitamin D, suppression of parathyroid function, or a syndrome of peculiar (elfin) facies, mental retardation, and congenital aortic stenosis in infants. {02} {109}

Overdosage of vitamin D has been associated with fetal abnormalities in animals. Animal studies have shown calcitriol to be teratogenic when given in doses 4 and 15 times the dose recommended for human use. {10} Excessive doses of dihydrotachysterol are also teratogenic in animals. Animal studies have also shown calcifediol to be teratogenic when given in doses of 6 to 12 times the human dose. {08}

Adequate and well–controlled studies in pregnant women have not been conducted with paricalcitol or doxercalciferol. Paricalcitol or doxercalciferol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. {123}{124}Studies, using paricalcitol, in rabbits and rats have shown decreased fetal viability at doses 0.5 and 2 times the 0.24 mcg/kg human dose based on body surface area (mg/m2), respectively. A significant increase in the mortality of newborn rats was reported at maternally toxic doses of 20 mcg/kg given 3 times per week (13 times the 0.24 mcg/kg human dose) based on body surface area (mg/m2). Paricalcitol was not teratogenic at the doses tested.{123} Studies, using doxercalciferol, in rats and rabbits, at doses up 20 micrograms/kg/day (mcg/kg/day) and 0.1 mcg/kg/day (approximately 25 times and less than the maximum recommended human dose of 60 mcg/week based on mg/m 2 body surface area, respectively, revealed no teratogenic or fetotoxic effects due to doxercalciferol.{124}

FDA Pregnancy Category C. {10}{123}

FDA Pregnancy Category B. {124}

Note: Doxercalciferol only


Breast-feeding

Only small amounts of vitamin D metabolites appear in human milk. {12} {19} {21} {61} Infants who are totally breast-fed and have little exposure to the sun may require vitamin D supplementation.

It is not known whether paricalcitol or doxercalciferol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when paricalcitol or doxercalciferol is administered to a nursing woman. {123}{124}

Pediatrics

Some studies have shown that infants who are exclusively breast-fed, especially from dark-skinned mothers, and/or have little exposure to sunlight may be at risk for vitamin D deficiency. {06} {20} {104}

Because of varying sensitivity, some infants may be sensitive to even small doses. {15}

Also, growth may be arrested in children, especially after prolonged administration of 1800 Units of ergocalciferol a day.

Appropriate studies on the relationship of age to the effects of paricalcitol or doxercalciferol have not been performed in the pediatric population. Safety and efficacy have not been established.{123}{124}


Geriatrics


Studies have shown that the elderly may have an increased need for vitamin D due to a possible decrease in the capacity of the skin to produce previtamin D 3 or{41} {45}a decrease in exposure to the sun or{42} {43}impaired renal function {44} or impaired vitamin D absorption. {46}

Studies performed in 40 chronic renal patients, including 10 patients 65 years of age or older, have not demonstrated geriatrics-specific problems that would limit the usefulness of paricalcitol in the elderly.{123}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following, depending on the amount present, may also interact with vitamin D.

Antacids, aluminum-containing    (long-term use of aluminum-containing antacids as phosphate binders in hyperphosphatemia in conjunction with vitamin D has been found to increase blood levels for aluminum and may lead to aluminum bone toxicity, especially in patients with chronic renal failure {58} {59} {83})


» Antacids, magnesium-containing {10}    (concurrent use with vitamin D may result in hypermagnesemia, especially in patients with chronic renal failure {09} {10} {38})


Anticonvulsants, hydantoin or {02} {08} {15}
Barbiturates or {02} {15}
Primidone {02} {15}    (may reduce effect of vitamin D by accelerating metabolism by hepatic microsomal enzyme induction; patients on long-term anticonvulsant therapy may require vitamin D supplementation to prevent osteomalacia)


Calcitonin or
Etidronate or {84}
Gallium nitrate or {77}
Pamidronate or {105} {106}
Plicamycin {84}    (concurrent use with vitamin D may antagonize these medications in the treatment of hypercalcemia)


» Calcium-containing preparations, in high doses or {22}
» Diuretics, thiazide {28} {29}    (concurrent use with vitamin D may increase the risk of hypercalcemia; however, it may be therapeutically advantageous in elderly and high-risk groups when it is necessary to prescribe vitamin D or its derivatives together with calcium; careful monitoring of serum calcium concentrations is essential during long-term therapy {22} {23})


Cholestyramine or {03} {08} {15}
Colestipol or {04}
Mineral oil {12} {16}    (concurrent use may impair intestinal absorption of vitamin D since these medications have been reported to reduce intestinal absorption of fat-soluble vitamins; requirements for vitamin D may be increased in patients receiving these medications)


Corticosteroids    (vitamin D supplementation may be recommended by some clinicians for prolonged corticosteroids use, because corticosteroids may interfere with vitamin D action {02} {86} {92} {105})


Digitalis glycosides    (caution is recommended in patients being treated with these medications since the hypercalcemia that may be caused by vitamin D may potentiate the effects of digitalis glycosides, resulting in cardiac arrhythmias {02} {08})


Hepatic enzyme inhibitors (see Appendix II )    (May affect 25–hydroxylation and necessitate dosage adjustments of doxercalciferol)


Phosphorus-containing preparations, in high doses    (concurrent use with vitamin D may increase the potential for hyperphosphatemia, because of vitamin D enhancement of phosphate absorption {02} {06})


» Vitamin D and analogs, other    (concurrent use of one analog with another, especially calcifediol, is not recommended because of additive effects and increased potential for toxicity {08} {24})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase {08} {09} {108}{123}    (serum concentrations may be decreased prior to development of hypercalcemia in patients receiving excessive doses)


Alanine aminotransferase (ALT[SGPT]) or
Aspartate aminotransferase (AST[SGOT]) or
Blood urea nitrogen (BUN)    (serum concentrations may be increased in cases of vitamin D toxicity with hypercalcemia{123}{125})


Calcium concentrations, serum and {08}
Cholesterol concentrations, serum and {95}
Phosphate concentrations, serum {08}    (may be increased with high doses)


Albumin concentrations, urinary{125}
Calcium concentrations, urinary and
Phosphate concentrations, urinary    (may be increased with therapeutic doses, even when serum concentrations are still low)


Magnesium {50}    (serum concentrations may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hypercalcemia {08}
» Hypervitaminosis D {08}
» Renal osteodystrophy with hyperphosphatemia    (risk of metastatic calcification; however, vitamin D therapy can begin once serum phosphate levels have stabilized {96})


Risk-benefit should be considered when the following medical problems exist
» Arteriosclerosis or {12}
» Cardiac function impairment {12}    (conditions may be exacerbated due to possibility of hypercalcemia and elevated serum cholesterol concentrations)


» Hyperphosphatemia    (risk of metastatic calcification; dietary phosphate restriction or administration of intestinal phosphate binders is recommended to produce normal serum phosphorus concentrations {38})


» Hypersensitivity to effects of vitamin D    (may be involved in causing idiopathic hypercalcemia {12} in infants)


» Renal function impairment {12}    (toxicity may occur in patients receiving vitamin D for nonrenal problems, although toxicity is also possible during treatment of renal osteodystrophy because of increased requirements and decreased renal function)


Sarcoidosis, and possibly other granulomatous diseases {15} {51}    (increased sensitivity to effects of vitamin D {14})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood urea nitrogen (BUN) and {08} {38}
Creatinine, serum {09} {38}    (determinations recommended at periodic intervals in patients receiving therapeutic doses)


Alkaline phosphatase concentrations, serum and {08} {10}
Phosphorus concentrations, serum and {08} {10}
Calcium concentrations, urinary, 24-hour and {08} {10} {53}
Calcium/creatinine, urinary ratio    (determinations recommended every 1 to 3 months during therapy, as long as the patient remains stable {83})

    (serum phosphorus concentrations recommended twice weekly until stable, then once a month, while on paricalcitol therapy{123})

    (more frequent monitoring of these parameters should be conducted in patients with impaired hepatic function receiving doxercalciferol {124})

    (for dialysis patients receiving doxercalciferol, serum calcium, and phosphorus should be determined prior to initiation of therapy and then weekly during the early phases of treatment. {124})


» Calcium concentrations, serum {08} {10} or
Ionized calcium concentration, serum {30} {31}    (determinations recommended at least once weekly in early period of treatment to aid in dosage adjustment because of narrow therapeutic range, then at periodic intervals during therapy in patients receiving therapeutic doses; serum calcium concentrations should be maintained at 8.8 to 10.3 mg {96} {97} per 100 mL, depending on lab variability; serum ionized calcium concentrations are preferable to determine free and bound calcium, {31} but may not be readily available from a reliable lab {32})

    (serum calcium concentrations recommended twice weekly until stable, then once a month, while on paricalcitol therapy{123})


Ophthalmological examinations    (recommended periodically to promote early detection of ectopic calcifications )

{125}
Parathyroid hormone (PTH) concentration, serum or plasma    (recommended every 3 months{123})

    (for dialysis patients receiving doxercalciferol, serum or plasma iPTH should be determined prior to initiation of therapy and then weekly during the early phases of treatment. {124})


Protein, serum    (for correction of plasma calcium in instances of hypercalcemia)

{125}
X-rays of bones {12}    (recommended by some clinicians every 3 to 6 months until patient is stable, then yearly {84} to determine when treatment of familial hypophosphatemia or hypoparathyroidism is sufficient; serum calcium times serum phosphorus (Ca X P) prduct should not exceed 70 with doxercalciferol{124})




Side/Adverse Effects

Note: Ingestion of excessive doses of vitamin D over prolonged periods (20,000 to 60,000 Units a day or more for several weeks or months in adults and 2,000 to 4,000 Units a day for several months in children) {33} {121} can result in severe toxicity. {12} Acute excessive doses of vitamin D can also result in severe toxicity, but there are insufficient data to determine at what dose. {121}
Chronic vitamin D–induced hypercalcemia may result in generalized vascular calcification, nephrocalcinosis, and other soft tissue calcification that may lead to hypertension and renal failure. {12} {15} These effects are more likely to occur when the hypercalcemia is accompanied by hyperphosphatemia.
Growth may be arrested in children, especially after prolonged administration of 1800 Units of ergocalciferol per day.
Death may occur as a result of renal or cardiovascular failure caused by vitamin D toxicity.
Dosage necessary to cause toxicity varies with individual sensitivity, but in individuals without malabsorption problems, 10,000 Units a day for more than several weeks or months is the maximum dose. {111}
Toxicity may occur with therapeutic doses of calcitriol. {57}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Early symptoms of vitamin D toxicity associated with hypercalcemia {08} {38} {110}{123}
    
Bone pain
{123}    
constipation —usually more frequent in children and adolescents
    
diarrhea
    
drowsiness
{123}    
dryness of mouth
    
headache, continuing
    
increased thirst
    
increase in frequency of urination, especially at night, or in amount of urine
    
irregular heartbeat{125}
    
loss of appetite {110}
    
metallic taste
    
muscle pain
{123}    
nausea or vomiting —usually more frequent in children and adolescents{110}
    
pruritis{125}
    
unusual tiredness or weakness {110}

Late symptoms of vitamin D toxicity associated with hypercalcemia {08} {38} {110}{123}
    
bone pain
    
cloudy urine {33}
    
conjunctivitis (redness or discharge of the eye, eyelid, or lining of the eyelid )—calcific{123}
    
decreased libido (loss of sex drive)
{123}    
ectopic calcification (calcium deposits in tissues other than bone)
{123}    
high fever
{123}    
high blood pressure
    
increased sensitivity of eyes to light or irritation of eyes
    
irregular heartbeat
    
itching of skin
    
lethargy (drowsiness){84}
    
loss of appetite {123}
    
muscle pain
    
nausea or vomiting and pancreatitis (stomach pain, severe)
    
psychosis, overt {110}(mood or mental changes)—rare
    
rhinorrhea (runny nose)
{123}    
weight loss





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Vitamin D and Related Compounds (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use

For ergocalciferol
Description should include function in the body, signs of deficiency, and unproven uses

For doxercalciferol and paricalcitol
Description should include use in hyperparathyroidism associated with chronic renal failure


Importance of diet

For ergocalciferol
Importance of proper nutrition; supplement may be needed because of inadequate dietary intake

Food sources of vitamin D; importance of sunlight exposure; effects of processing

Recommended daily intake for vitamin D

» Importance of not exceeding recommended daily intake if self-medicating with vitamin supplements

Before using this dietary supplement
»   Conditions affecting use, especially:
Sensitivity to vitamin D or any vitamin D analog

Pregnancy—No problems documented with normal intake; overdose associated with increased sensitivity to vitamin D, suppression of parathyroid function, or syndrome of peculiar facies, mental retardation, and congenital aortic stenosis in infants

Studies with doxercalciferol and paricalcitol in pregnant women not done; problems in newborn animals reported





Breast-feeding—Possible vitamin D deficiency in totally breast-fed infants





Use in children—Possible vitamin D deficiency in breast-fed infants especially of dark-skinned mothers; varying sensitivity in infants may make some children sensitive to small doses; children may show slowed growth when receiving high doses of vitamin D for long periods; studies with doxercalciferol and paricalcitol not done in pediatrics

Other medications, especially calcium-containing preparations, magnesium-containing antacids, thiazide diuretics, or other vitamin D analogs
Other medical problems, especially hypercalcemia, hypervitaminosis D, renal or cardiac impairment, arteriosclerosis, or hyperphosphatemia

Proper use of this dietary supplement

» Proper storage

For the oral solution dosage form

Proper administration
Taking by mouth even though dietary supplement comes in a dropper bottle

May be dropped directly into the mouth or mixed with cereal, fruit juice, or other food

For use as an antihypocalcemic
» Importance of not taking more medication than the amount prescribed

Carefully following instructions for special diet or calcium supplementation, if prescribed

Making sure physician knows if calcium supplement or any calcium-containing preparation is already being taken

» Proper dosing

For use in hyperparathyroidism
» Proper dosing

Missed dose: If dosing schedule is—
Every other day: Taking as soon as possible if remembered same day; if remembered later, not taking until next day, then skipping a day; not doubling doses

Once a day: Taking as soon as possible; taking next day if not remembered until then; not doubling doses

Several times a day: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

For use as a dietary supplement
» Importance of not taking more dietary supplement than the amount recommended; risk of toxicity with chronic overdose

Missed dose: No cause for concern because of length of time necessary for depletion; remembering to take as directed

Precautions while using this dietary supplement
Avoiding concurrent use of nonprescription medications or dietary supplements containing calcium, phosphorus, or vitamin D, unless otherwise directed by health care professional

» Avoiding concurrent use of magnesium-containing antacids

For use as a dietary supplement
Risk of toxicity with overdose; upper limits for vitamin D toxicity

For use as an antihypocalcemic
» Regular visits to physician to check progress during therapy


Side/adverse effects
Signs of potential side effects, especially bone pain, constipation, diarrhea, drowsiness, dry mouth, headache (continuing), increased thirst, increase in frequency of urination (especially at night) or in the amount of urine, loss of appetite, metallic taste, muscle pain, nausea or vomiting, unusual tiredness or weakness, cloudy urine, conjunctivitis (calcific), decreased libido, ectopic calcification, high fever, high blood pressure, increased sensitivity of eyes to light or irritation of eyes, irregular heartbeat, itching of skin, lethargy, loss of appetite, pancreatitis, psychosis (overt), rhinorrhea, and weight loss


General Dosing Information

For use as an antihypocalcemic
Before vitamin D therapy is begun, elevated serum phosphate concentrations must be controlled. {38}

Clinical response to vitamin D depends on adequate dietary calcium.

Because of individual variation in sensitivity to its effects, dosage of vitamin D must be adjusted on the basis of clinical response. Some infants are hyperreactive to even small doses. Careful titration is necessary to avoid overdosage, which induces hypercalcemia and can cause hypercalciuria and hyperphosphatemia.

Dosage of vitamin D from dietary and other sources should be evaluated in determining the therapeutic dosage. {24}

The serum calcium times phosphorus (Ca × P, in mg/dL) product should not exceed 60. {09} {98}

To control elevated serum phosphate concentrations in patients undergoing dialysis, a phosphate binding agent should be used. The dosage of the binding agent may need to be increased during vitamin D therapy since phosphate absorption is enhanced. {38}

For use as a dietary supplement
Because of the infrequency of vitamin D deficiency alone, combinations of several vitamins are commonly administered. Many commercial vitamin complexes are available.

Diet/Nutrition
Recommended dietary intakes for vitamin D are defined differently worldwide:


For U.S.:
The Recommended Dietary Allowances (RDAs) for vitamins and minerals are determined by the Food and Nutrition Board of the National Research Council and are intended to provide adequate nutrition in most healthy persons under usual environmental stresses. In addition, a different designation may be used by the FDA for food and dietary supplement labeling purposes, as with Daily Value (DV). DVs replace the previous labeling terminology United States Recommended Daily Allowances (USRDAs).



For Canada:
Recommended Nutrient Intakes (RNIs) for vitamins, minerals, and protein are determined by Health and Welfare Canada and provide recommended amounts of a specific nutrient while minimizing the risk of chronic diseases.

The expression of vitamin D activity has changed from Units to micrograms (mcg), with 1 Unit of vitamin D equal to the activity of 0.025 mcg of cholecalciferol (vitamin D 3). This change was made to reflect a broader activity for vitamin D 3 compared to vitamin D 2. {06} {07}

Normal daily recommended intakes in mcg and Units are generally defined as follows:

Persons
U.S.
Canada
(mcg)
Units
(mcg)
Units
Infants and children
       
Birth to 3 years of age
7.5–10
300–400
5–10
200–400
4 to 6 years of age
10
400
5
200
7 to 10 years of age
10
400
2.5–5
100–200
Adolescents and adults
5–10
200–400
2.5–5
100–200
Pregnant and breast-feeding females
10
400
5–7.5
200–300


These are usually provided by adequate diets and adequate exposure to sunlight (1.5 to 2 hours of exposure per week is sufficient for most people) {107}.

Best dietary sources of vitamin D (as cholecalciferol) include some fish and fish liver oils {05} and vitamin D–fortified milk {05}. The vitamin D content of foods is not affected by cooking. {06}


For parenteral dosage forms only
Parenteral administration may be indicated in patients with malabsorption problems.

Intravenous administration may be indicated in patients undergoing hemodialysis. {123}

For treatment of adverse effects
Recommended treatment includes the following:

   • Hypervitaminosis D is treated by withdrawal of the vitamin, low-calcium diet, {15} and generous fluid intake {15} {33} {86}.
   • If hypercalcemia persists, prednisone may be started. Severe hypercalcemia may be treated with calcitonin, etidronate, pamidronate {105} {106}, or gallium nitrate. {33}
   • Hypercalcemic crisis requires vigorous hydration with intravenous saline to increase calcium excretion, with or without a loop diuretic. {15}
   • Cardiac arrhythmias may be treated with small doses of potassium with continuous cardiac monitoring. {33}
   • Therapy may be reinstituted at a lower dose when serum calcium concentrations return to normal. {38} Serum or urinary {101} calcium levels should be obtained twice weekly after dosage changes. {87}

ALFACALCIDOL


Oral Dosage Forms

ALFACALCIDOL CAPSULES

Usual adult and adolescent dose
For pre-dialysis patients—
Initial: Oral, 0.25 mcg a day as a single dose taken with food for two months, the dosage being increased in increments of 0.25 mcg a day every two months as necessary.{125}
Maintenance: Oral, 0.5 to 1 mcg a day.{125}

Note: Serum calcium and phosphate levels should be monitored every month. Calcium supplements should not exceed 500 mg of elemental calcium a day. If hypercalcemia develops, the dosage should be reduced by 50% and all calcium supplements should be stopped until serum calcium levels return to normal.{125}


For dialysis patients—
Initial: Oral, 1 mcg a day for four weeks, the dosage being increased in increments of 0.5 mcg a day every two to four weeks as necessary, up to 1 to 2 mcg a day. In rare cases, a maximum dose of 3 mcg a day may be needed.{125}
Maintenance: Oral, 0.25 to 1 mcg a day.{125}

Note: Serum calcium levels should be monitored on a weekly basis and at least twice a week during the initial dosage adjustment period. If hypercalcemia develops, alfacalcidol should be stopped immediately until serum calcium levels return to normal.{125}



Strength(s) usually available
U.S.—
Not commercially available.

Canada—


0.25 mcg (Rx) [One-Alpha (sesame oil) (alpha-tocopherol)]


0.5 mcg (Rx) [One-Alpha (sesame oil) ( alpha-tocopherol)]


1 mcg (Rx) [One-Alpha (sesame oil) ( alpha-tocopherol)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.


ALFACALCIDOL ORAL SOLUTION

Usual adult and adolescent dose
See Alfacalcidol Capsules.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


0.2 mcg per mL (Rx) [One-Alpha (citric acid monohydrate) (ethanol) (methyl parahydroxybenzoate ) (polyoxyl 40 hydrogenated castor oil) (sodium citrate) (sorbitol) (alpha tocopherol)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.


ALFACALCIDOL ORAL DROPS

Usual adult and adolescent dose
See Alfacalcidol Capsules.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


2 mcg per mL (Rx) [One-Alpha (citric acid monohydrate) (ethanol) (methyl parahydroxybenzoate ) (polyoxyl 40 hydrogenated castor oil) (purified water) (sodium citrate) (sorbitol) (alpha tocopherol)]

Packaging and storage:
Store at 2 to 8° C, unless otherwise specified by manufacturer. Store in a tight, light-resistant container.



Parenteral Dosage Forms

ALFACALCIDOL INJECTION

Usual adult and adolescent dose—
Initial: Intravenous, 1 mcg per dialysis two to three times a week, the dosage being increased in increments of 1 mcg per dialysis every week as necessary, up to 12 mcg a week. The total dose titration period should not exceed six weeks.{125}
Maintenance: Intravenous, 6 mcg a week. Doses may range from 1.5 to 12 mcg a week.{125}

Note: Serum calcium and phosphate levels should be monitored every other week. If hypercalcemia develops, alfacalcidol should be stopped immediately until serum calcium levels return to normal.{125}


Strength(s) usually available
U.S.—
Not commercially available

Canada—


2 mcg per mL (Rx) [One-Alpha (citric acid monohydrate 0.16 mg per mL) (ethanol 80 mg per mL) (propylene glycol 415 mg per mL) ( purified water 1 mL) (sodium citrate 6.8 mg per mL)]

Packaging and storage:
Store at 2 to 8° C, unless otherwise specified by manufacturer. Store in a tight, light-resistant container.


CALCIFEDIOL


Oral Dosage Forms

CALCIFEDIOL CAPSULES USP

Usual adult and adolescent dose
Oral, initially 300 to 350 mcg (0.3 to 0.35 mg) per week administered on a once-a-day or alternate-day schedule, the dosage being increased, if necessary, at four-week intervals.{08}

Note: Most patients respond to doses of 50 to 100 mcg (0.05 to 0.1 mg) per day or 100 to 200 mcg (0.1 to 0.2 mg) on alternate days; as low as 20 mcg (0.02 mg) every other day may be sufficient in patients with normal serum calcium concentrations.{08}


Usual pediatric dose {100} {103}
Children up to 2 years of age—Oral, 20 to 50 mcg (0.02 to 0.05 mg) per day.
Children 2 to 10 years of age—Oral, 50 mcg (0.05 mg) per day.

Note: For use of calcifediol in hypoparathyroidism, a dose of 3 to 6 mcg per kilogram of body weight a day in children less than 10 years of age may be necessary. {94} {95}

Children 10 years of age and over—See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


20 mcg (0.02 mg) (Rx) [Calderol]


50 mcg (0.05 mg) (Rx) [Calderol]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.


CALCITRIOL


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CALCITRIOL CAPSULES

Usual adult and adolescent dose
Initial—Oral, 0.25 mcg per day, the dosage being increased in increments of 0.25 mcg every two to four weeks as necessary, {09} up to the following usual doses:
[Familial hypophosphatemia ]
Oral, 2 mcg per day. {09}

Hypocalcemia in chronic dialysis
Oral, 0.5 to 3 mcg or more per day.

Hypoparathyroidism
Oral, 0.25 to 2.7 mcg per day. {08}

Renal osteodystrophy
Oral, 0.25 mcg every other day to 3 mcg or more per day.


Note: Some clinicians believe that in order for calcitriol to be most effective, it should be given in divided doses, at least two or three times a day.


Usual pediatric dose {100}
Oral, 0.25 mcg per day, the dosage being increased in increments of 0.25 mcg every two to four weeks as necessary up to the following usual doses:
[Vitamin D–dependent rickets]
Oral, 1 mcg per day.

Hypocalcemia in chronic dialysis
Oral, 0.25 to 2 mcg per day.

Hypoparathyroidism
Oral, 0.04 to 0.08 mcg per kg of body weight per day.

Renal osteodystrophy
Oral, 0.014 to 0.041 mcg per kg of body weight per day.


Note: Pediatric patients with liver disease may need initial doses of up to 0.1 to 0.2 mcg per kilogram of body weight per day. {95}


Strength(s) usually available
U.S.—


0.25 mcg (Rx) [Rocaltrol]


0.5 mcg (Rx) [Rocaltrol]

Canada—


0.25 mcg (Rx) [Rocaltrol]


0.5 mcg (Rx) [Rocaltrol]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer. Protect from light.


CALCITRIOL ORAL SOLUTION

Usual adult and adolescent dose
See Calcitriol Capsules.

Usual pediatric dose
See Calcitriol Capsules.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mcg per mL (Rx) [Rocaltrol{112}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.



Parenteral Dosage Forms

CALCITRIOL INJECTION

Usual adult and adolescent dose
Antihypocalcemic
Initial: Intravenous (rapid), 0.5 mcg (or 0.01 mcg per kg of body weight) three times a week, the dosage being increased in increments of 0.25 to 0.5 mcg every two to four weeks as necessary. {10}

Initial: Intravenous, 1 mcg (or 0.02 mcg per kg) to 2 mcg three times a week, approximately every other day. Dosage may be increased in increments of 0.5 to 1 mcg at two to four week intervals or as necessary. {*}
Maintenance: Intravenous (rapid), 0.5 to 3.0 mcg (or 0.01 to 0.05 mcg per kg of body weight) three times a week. {10}


Usual pediatric dose
Dosage has not been established. {10}

Strength(s) usually available
U.S.—


1 mcg per mL (Rx) [Calcijex]


2 mcg per mL (Rx) [Calcijex]

Canada—


1 mcg per mL (Rx) [Calcijex]


2 mcg per mL (Rx) [Calcijex]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light.


DIHYDROTACHYSTEROL


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

DIHYDROTACHYSTEROL CAPSULES USP

Usual adult and adolescent dose
Oral, 125 mcg (0.125 mg) to 2 mg per day.
[Familial hypophosphatemia ]
Initial: Oral, 500 mcg (0.5 mg) to 2 mg per day.
Maintenance: Oral, 200 mcg (0.2 mg) to 1.5 mg per day.

Hypocalcemic tetany
Initial: Acute—Oral, 750 mcg (0.75 mg) to 2.5 mg per day for three days. {17}

Less acute—Oral, 250 to 500 mcg (0.25 to 0.5 mg) per day for three days.
Maintenance:Oral, 250 mcg (0.25 mg) per week to 1 mg per day, as necessary.

Hypoparathyroidism
Initial: Oral, 750 mcg (0.75 mg) to 2.5 mg per day for several days.
Maintenance: Oral, 200 mcg (0.2 mg) to 1 mg per day.

[Renal osteodystrophy]
Initial: Oral, 100 to 250 mcg (0.1 to 0.25 mg) per day.
Maintenance: Oral, 200 mcg (0.2 mg) to 1 mg per day.


Usual pediatric dose {100}
[Familial hypophosphatemia ]
See Usual adult and adolescent dose.

Hypoparathyroidism
Initial: Oral, 1 to 5 mg per day for four days, then continued or decreased to one-fourth the dose.
Maintenance: Oral, 500 mcg (0.5 mg) to 1.5 mg per day.


Strength(s) usually available
U.S.—


125 mcg (0.125 mg) (Rx) [Hytakerol]

Canada—


125 mcg (0.125 mg) (Rx) [Hytakerol{113}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.


DIHYDROTACHYSTEROL ORAL SOLUTION USP

Usual adult and adolescent dose
Oral, 125 mcg (0.125 mg) to 2 mg per day.
[Familial hypophosphatemia ]
Initial: Oral, 500 mcg (0.5 mg) to 2 mg per day.
Maintenance: Oral, 200 mcg (0.2 mg) to 1.5 mg per day.

Hypocalcemic tetany
Initial: Acute—Oral, 750 mcg (0.75 mg) to 2.5 mg per day for three days. {17}

Less acute—Oral, 250 to 500 mcg (0.25 to 0.5 mg) per day for three days.
Maintenance: Oral, 250 mcg (0.25 mg) per week to 1 mg per day, as necessary.

Hypoparathyroidism
Initial: Oral, 750 mcg (0.75 mg) to 2.5 mg per day for several days.
Maintenance: Oral, 200 mcg (0.2 mg) to 1 mg per day.

[Renal osteodystrophy]
Initial: Oral, 100 to 250 mcg (0.1 to 0.25 mg) per day.
Maintenance: Oral, 200 mcg (0.2 mg) to 1 mg per day.


Usual pediatric dose {100}
[Familial hypophosphatemia ]
See Usual adult and adolescent dose.

Hypoparathyroidism
Initial: Oral, 1 to 5 mg per day for four days, then continued or decreased to one-fourth the dose.
Maintenance: Oral, 500 mcg (0.5 mg) to 1.5 mg per day.


Strength(s) usually available
U.S.—


200 mcg (0.2 mg) per mL (Rx) [DHT Intensol (alcohol 20% )]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant glass container. Protect from freezing.


DIHYDROTACHYSTEROL TABLETS USP

Usual adult and adolescent dose
Oral, 125 mcg (0.125 mg) to 2 mg per day.
[Familial hypophosphatemia ]
Initial: Oral, 500 mcg (0.5 mg) to 2 mg per day.
Maintenance: Oral, 200 mcg (0.2 mg) to 1.5 mg per day.

Hypocalcemic tetany
Initial: Acute—Oral, 750 mcg (0.75 mg) to 2.5 mg per day for three days.

Less acute—Oral, 250 to 500 mcg (0.25 to 0.5 mg) per day for three days.
Maintenance: Oral, 250 mcg (0.25 mg) per week to 1 mg per day, as necessary.

Hypoparathyroidism
Initial: Oral, 750 mcg (0.75 mg) to 2.5 mg per day for several days.
Maintenance: Oral, 200 mcg (0.2 mg) to 1 mg per day.

[Renal osteodystrophy]
Initial: Oral, 100 to 250 mcg (0.1 to 0.25 mg) per day.
Maintenance: Oral, 200 mcg (0.2 mg) to 1 mg per day.


Usual pediatric dose {100}
[Familial hypophosphatemia ]
See Usual adult and adolescent dose.

Hypoparathyroidism
Initial: Oral, 1 to 5 mg per day for four days, then continued or decreased to one-fourth the dose.
Maintenance: Oral, 500 mcg (0.5 mg) to 1.5 mg per day.


Strength(s) usually available
U.S.—


125 mcg (0.125 mg) (Rx) [DHT]


200 mcg (0.2 mg) (Rx) [DHT]


400 mcg (0.4 mg) (Rx) [DHT]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.


DOXERCALCIFEROL


Oral Dosage Forms

DOXERCALCIFEROL CAPSULES

Usual adult dose

Usual adult dose

Note: The initial dose should be adjusted in order to lower blood iPTH into the range of 150 to 300 pg/mL.

Antihyperparathyroid
Initial: Oral, 10 micrograms (mcg) three times weekly at dialysis, approximately every other day.{124}
Maintenance: Oral, if iPTH is not lowered by 50% and fails to meet the target range, the dose may be increased by 2.5 mcg at 8 week intervals. Therapy should be suspended if iPTH falls below 100 pg/mL and restarted one week later at a dose at least 2.5 mcg lower than the last administered dose. If an elevated calcium (Ca) or phosphorus (P) level, or a calcium-phosphorus (Ca × P) product is greater than 70 is noted, drug dosage should be immediately suspended until levels are normalized, and reinitiated at a dose that is at least 2.5 mcg lower.{124}

Note: Doxercalciferol doses may need to be decreased as the iPTH levels decrease in response to therapy. Incremental dosing must be individualized. {124}

Suggested Dosing Guidelines



iPTH Level  Doxercalciferol Dose 
decreased by < 50% and above 300 pg/mL   increase by 2.5 mcg at eight week intervals as necessary  
150 to 300 pg/mL  maintain 
< 100 pg/mL  suspend for one week, then resume at a dose that is at least 2.5 mcg lower 




Usual adult prescribing limits
The maximum recommended dose is 20 mcg administered 3 times weekly for a total of 60 mcg per week. {124}

Usual pediatric dose
Safety and efficacy have not been established. {124}

Strength(s) usually available
U.S.—


2.5 mcg capsules (Rx) [Hectorol]

Packaging and storage:
Store at controlled room temperature 20 to 25 °C (68 to 77 °F).{124}


ERGOCALCIFEROL


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ERGOCALCIFEROL CAPSULES USP

Usual adult and adolescent dose
Deficiency (prophylaxis)
Oral, amount based on normal daily recommended intakes:

Persons
U.S.
Canada
(mcg)
Units
(mcg)
Units
Adolescents and adults
5–10
200–400
2.5–5
100–200
Pregnant and breast-feeding females
10
400
5–7.5
200–300


Deficiency (treatment)
Treatment dose is individualized by prescriber based on severity of deficiency.

Vitamin D–resistant rickets
Oral, 12,000 to 150,000 Units per day. {16} {102}

Vitamin D–dependent rickets
Oral, 10,000 to 60,000 Units per day (up to 150,000 Units per day). {102}

Osteomalacia due to prolonged use of anticonvulsants
Oral, 1000 to 4000 Units per day.

Familial hypophosphatemia
Oral, 50,000 to 100,000 Units per day.

Hypoparathyroidism
Oral, 50,000 to 150,000 Units per day. {16}

[Renal function impairment ]
Oral, 40,000 to 100,000 Units per day.

[Renal osteodystrophy]
Initial: Oral, 20,000 Units per day.
Maintenance: Oral, 10,000 to 300,000 Units per day.


Usual pediatric dose {99} {100}
Deficiency (prophylaxis)
Oral, amount based on normal daily recommended intakes:

Persons
U.S.
Canada
(mcg)
Units
(mcg)
Units
Infants and children
       
Birth to 3 years of age
7.5–10
300–400
5–10
200–400
4 to 6 years of age
10
400
5
200
7 to 10 years of age
10
400
2.5–5
100–200


Deficiency (treatment)
Treatment dose in individualized by prescriber based on severity of deficiency.

Vitamin D–dependent rickets
Oral, 3000 to 10,000 Units per day (up to 50,000 Units per day).

Osteomalacia due to prolonged use of anticonvulsants
Oral, 1000 Units per day.

Hypoparathyroidism
Oral, 50,000 to 200,000 Units per day.

[Renal osteodystrophy]
Oral, 4000 to 40,000 Units per day.


Strength(s) usually available
U.S.—


50 Units (OTC)[Generic]{116}


400 Units (0.01 mg) (OTC)[Generic]{116}


25,000 Units (0.625 mg) (Rx)[Generic]{116}


50,000 Units (1.25 mg) (Rx) [Drisdol (tartrazine){115}][Generic]

Canada—


50,000 Units (1.25 mg) (Rx) [Ostoforte]

Note: Lower strengths are also available as over-the-counter dietary supplements.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.


ERGOCALCIFEROL ORAL SOLUTION USP

Usual adult and adolescent dose
Deficiency (prophylaxis or treatment)
See Ergocalciferol Capsules USP.

Vitamin D–resistant rickets
Oral, 12,000 to 500,000 Units per day.

Vitamin D–dependent rickets
Oral, 10,000 to 60,000 Units per day (up to 500,000 Units per day).

Osteomalacia due to prolonged use of anticonvulsants
Oral, 1000 to 4000 Units per day.

Familial hypophosphatemia
Oral, 50,000 to 100,000 Units per day.

Hypoparathyroidism
Oral, 50,000 to 150,000 Units per day.

[Renal function impairment ]
Oral, 40,000 to 100,000 Units per day.

[Renal osteodystrophy]
Initial: Oral, 20,000 Units per day.
Maintenance: Oral, 10,000 to 300,000 Units per day.


Usual pediatric dose {99} {100}
See Ergocalciferol Capsules USP.

Strength(s) usually available
U.S.—


8000 Units (0.2 mg) per mL (OTC) [Calciferol Drops{115}] [Drisdol Drops{115}]

Canada—


8000 Units (0.2 mg) per mL (OTC) [Drisdol{117}]


300,000 Units (7.5 mg) per mL (Rx) [Radiostol Forte (alcohol )]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.


ERGOCALCIFEROL TABLETS USP

Usual adult and adolescent dose
See Ergocalciferol Oral Solution USP.

Usual pediatric dose {99} {100}
See Ergocalciferol Capsules USP.

Strength(s) usually available
U.S.—


400 Units (0.01 mg) (OTC)[Generic]{116}


50,000 Units (1.25 mg)[Generic]{116}

Canada—


1,000 Units (0.025 mg) (OTC)[Generic]{118}{119}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container.



Parenteral Dosage Forms

ERGOCALCIFEROL INJECTION

Usual adult and adolescent dose
Deficiency (prophylaxis or treatment)
Intravenous infusion, as part of total parenteral nutrition solutions, the specific amount determined by individual patient need. {76}

Malabsorption
Intramuscular, 10,000 Units per day.


Usual pediatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


500,000 Units (12.5 mg) per mL (Rx) [Calciferol]

Canada—


500,000 Units (12.5 mg) per mL (Rx) [Calciferol]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.


PARICALCITOL


Parenteral Dosage Forms

PARICALCITOL INJECTION

Usual adult dose

Usual adult dose

Note: The currently accepted target range for iPTH levels in chronic renal failure patients is no more than 1.5 to 3 times the non-uremic upper limit of normal. {123}

Antihyperparathyroid
Initial: Intravenous (rapid), 0.04 mcg/kg to 0.1 mcg/kg (2.8 mcg to 7 mcg) administered no more frequently than every other day at anytime during dialysis.{123}
Maintenance: Intravenous (rapid), if a satisfactory response is not observed, the dose may be increased by 2 mcg to 4 mcg at 2 to 4 week intervals. If an elevated calcium (Ca) level, or a calcium-phosphorus (Ca × P) product is greater than 75 is noted, drug dosage should be immediately reduced or interrupted until levels are normalized, and reinitiated at a lower dose.{123}

Note: Paricalcitol doses may need to be decreased as the PTH levels decrease in response to therapy. Incremental dosing must be individualized. {123}

Suggested Dosing Guidelines



PTH Level  Paricalcitol Dose 
the same or increasing  increase 
decreasing by <30%  increase 
decreasing by >30%, <60%   maintain 
decreasing by >60%  decrease 
1.5 to 3.0 times the upper limit of normal   maintain 




Usual adult prescribing limits
Doses as high as 0.24 mcg/kg (16.8 mcg) have been safely administered. {123}

Usual pediatric dose
Safety and efficacy have not been established. {123}

Strength(s) usually available
U.S.—


5 mcg per mL (Rx) [Zemplar (propylene glycol, 30%) (alcohol, 20%)]

Packaging and storage:
Store at 25 °C (77 °F), excursions permitted to 15 °C to 30 °C (59 °F to 86 °F).{123}



Revised: 03/28/2001



References
  1. Calciferol tablets product information. Kremers Urban, rec 3/90, rev 3/88, U.S.
  1. Goodman and Gilman"s Pharmacological Basis of Therapeutics. 1985.
  1. Questran Light product information. Bristol Labs, rev 3/89, rec 8/89, U.S.
  1. Colestid product information. Upjohn, rec 3/89, rev 9/88, U.S.
  1. Manual of Clinical Nutrition. 1985, Nutrition Publications Inc.
  1. Recommended Dietary Allowances. National Research Council, 10th Edition.
  1. Bieri J and M McKenna. Expressing dietary values for fat-soluble vitamins: changes in concepts and terminology. Am J Clin Nutr 1981, 34: 289-95.
  1. Calderol product information. 1990 PDR, Organon, p 1544.
  1. Rocaltrol product information. Roche, PDR, 1990, p 1804-5.
  1. Calcijex product information. Abbott, 1990 PDR, p 509-10.
  1. Clemens T, et al. Increased skin pigment reduces the capacity of skin to synthesize Vitamin D 3. The Lancet 1/9/82, p 74-6.
  1. Calciferol product information. Kremers Urban, U.S., rec 1/89, rev 3/88.
  1. AHFS, 1990.
  1. Reichel H, et al. The role of the vitamin D endrocrine system in health and disease. NEJM 320[15]: pp 980-91.
  1. Cecil"s Textbook of Medicine. Saunders, 18th Edition, 1988.
  1. Deltalin Vitamin D Ergocalciferol capsules product information. Lilly, rec 1/88, rev 8/86, U.S.
  1. Hytakerol product information. CPS 1990, p 485.
  1. Hytakerol product information. U.S., rec 2/89, rev 6/88.
  1. Takeuchi A, et al. Effects of ergocalciferol supplementation on the concentration of vitamin D and its metabolites in human milk. J Nutr 1989, 119[11]: 1639-46.
  1. Edidin D, et al. Resurgence of nutritional rickets associated with breast-feeding and special dietary practices. Pediatr 1980, 65[2]: 232-5.
  1. Greer F, et al. Lack of 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D in human milk. J of Pediatr 1981, 99 [2]: 233-5.
  1. Gramacol product information. CPS, 1990.
  1. Panelist comment from Calcium Supplements monograph.
  1. Calcijex product information. Abbott, CPS, 1991.
  1. DHT product information. Roxane, PDR, 1991.
  1. Rocaltrol product information. Roche, CPS, 1991.
  1. Ostoforte product information. Frosst, CPS, 1991.
  1. Drug information facts. 1990.
  1. Parfitt A. Thiazide-induced hypercalcemia in vitamin D-treated hypothyroidism. Annals of Int Med 1972, 77: 557-63.
  1. Panelist comment, 1990 revision cycle.
  1. Forster J, et al. A comparative study of serum ultrafiltrable, ionized, and total calcium in the diagnosis of primary hyperparathyroidism in patients with intermittent or no elevation in total calcium. Surgery 1988, 104: 1137-42.
  1. Panel consensus from Calcium Supplements monograph, 1990 revision.
  1. Ellenhorn M and Barcelaux D. Medical Toxicology, 1988 Edition.
  1. Hellebostad M, Markestad T, Halvorsen S. Vitamin D deficiency rickets and vitamin B 1 2 deficiency in vegetarian children. Acta Paediatr Scand 1985, 74: 191-5.
  1. Dwyer J, Dietz W, Haas G, Suskind R, Risk of nutritional rickets among vegetarian children. Am J Dis Child 1979, 133: 134-40.
  1. Hodson E, Evans A, Dunstan C, Hills E, Wong Y, Rosenberg, et al. Treatment of childhood renal osteodystrophy with calcitriol or ergocalciferol. Clin Nephr 1985, 24[4]: 192-200.
  1. Trachtman H, Gauthier B. Parenteral calcitriol for treatment of severe renal osteodystrophy in children with chronic renal insufficiency. J Pediatr 1987, 110: 966-70.
  1. One-Alpha product information. Leo, CPS, 1991.
  1. Committee on Nutritional Status during Pregnancy and Lactation. National Academy of Sciences. 1990, National Academy Press.
  1. Pierides A. Pharmacology and therapeutic use of vitamin D and its analogues. Drugs 1981, 21: 241-56.
  1. MacLaughlin J, Holick M. Aging decreases the capacity of human skin to produce vitamin D 3. J Clin Invest 1985, 76: 1536-8.
  1. Omdahl J, Garry P, Hunsaker L, Hunt W, Goodwin J. Nutritional status in a healthy elderly population: vitamin D. Am J Clin Nutr 1982, 36: 1125-233.
  1. Gloth F, Tobin J, Sherman S, Hollis B. Is the recommended daily allowance for vitamin D too low for the homebound elderly? J Am Geriatr Soc 1991, 39[2]: 137-41.
  1. Halloran B, Portale A, Lonergan E, Morris R. Production and metabolic clearance of 1, 25-dihydroxyvitamin D in men—effect of advancing age. J Clin Endocrinol Metab 1990, 70[2]: 318-23.
  1. Holick M, Matsisoha L, Wortsman J. Age, vitamin D, and solar ultraviolet. The Lancet 11/4/89, pp 1104-5.
  1. Panelist comment, 1990 revision.
  1. Bell N. Vitamin D-endocrine system. J Clin Invest 1985, 76: 1-6.
  1. Wiesner R, Kumar R, Seeman E, Co V. Enterohepatic physiology of 1,25-dihydroxyvitamin D 3 metabolites in normal man. J Lab Clin Med 1980, 96[6]: 1094-100.
  1. Panelist comment, 1990 revision.
  1. Krejs G, Nicar M, Zerwekh J, Norman D, Kane M, Pak C. Effect of 1,25-dihydroxyvitamin D 3 on calcium and magnesium absorption in the healthy human jejunum and ileum. Am J Med 1983, 75: 973-6.
  1. Panelist comment, 1990 revision cycle.
  1. Dibble J, Sheridan P, Losowsky M. A survey of vitamin D deficiency in gastrointestinal and liver disorders. Quart J Med 1984, 209: 119-34.
  1. Santos F, Smith V, Chan J. Hypercalciuria associated with long-term administration of calcitriol (1,25-dihydroxyvitamin D 3). Am J Dis Child 1986, 140: 139-42.
  1. The enterohepatic circulation of vitamin D is negligible. Nutr Rev, 1985, 43[3]: 76-8.
  1. Lieber C. The influence of alcohol on nutritional status. Nutr Rev 1988, 46[7]: 241-54.
  1. Moncrieff M, Fadahunsi T. Congenital rickets due to maternal vitamin D deficiency. Arch Dis Child 1974, 49: 810.
  1. Chan J, Young R, Alon U, Mamunes P. Hypercalcemia in children with disorders of calcium and phosphate metabolism during long-term treatment with 1,25-dihydroxyvitamin D 3. Pediatr 1983, 7[2]: 225-33.
  1. Colussi G, Rombola G, DeFerrari M, Minola E, Minetti L. Vitamin D treatment: a hidden risk factor for aluminum bone toxicity? Nephron 1987, 47: 78-80.
  1. Demontis R, Reissi D, Noel C, Boudailliez N, Westeel, Leflon P. Indirect clinical evidence that 1-alpha OH vitamin D 3 increases the intestinal absorption of aluminum. Clin Nephrol 1989, 31[3]: 123-7.
  1. Ala-Houhala M. 25-hydroxyvitamin D levels during breast-feeding with or without maternal or infantile supplementation of vitamin D. J Pediatr Gastroenterol Nutr 1985, 4: 220-6.
  1. Greer F, Hollis B, Napoli J. High concentrations of vitamin D 2 in human milk associated with pharmacologic doses of vitamin D 2. J Pediatr 1984, 105[1]: 61-4.
  1. Parfitt A. Use of calciferol and its metabolites and analogues in osteoporosis. Drugs 1988, 36: 513-20.
  1. Villareal D, Civitelli R, Chines A, Avioli L. Subclinical vitamin D deficiency in postmenopausal women with low vertebral bone mass. J Clin Endocrinol Metab 1991, 72: 628-34.
  1. Riggs B, Nelson K. Effect of long term treatment with calcitriol on calcium absorption and mineral metabolism in postmenopausal osteoporosis. J Clin Endocrinol Metab 1985, 61: 457-61.
  1. Aloia J, Vaswani A, Yeh J. Calcitriol in the treatment of postmenopausal osteoporosis. Am J Med 1988, 84: 401-8.
  1. Holick M, Smith E, Pincus S. Skin as the site of vitamin D synthesis and target tissue for 1, 25 dihydroxyvitamin D 3. Arch Dermatol 1987, 123: 1676-83.
  1. Ararrjo O, Flowers F, Brown K. Vitamin D therapy in psoriasis. DICP 1991, 25: 835-9.
  1. Smith E, Pincus S, Donovon L, Holick M. A novel approach for the evaluation and treatment of psoriasis. J Am Acad Dermatol 1988, 19: 516-28.
  1. Morimoto S, Yoshikawa K, Kozuka T, Kitano Y, Imanada S, Fukuo K, et al. An open study of vitamin D 3 treatment in psoriasis vulgaris. Br J Dermatol 1986, 115: 421-9.
  1. Radiostol product information. Glaxo, rec 8/91, Canada.
  1. Baker L, Abrams S, Roe C, Faugere M, Fanti P, Subayti Y, et al. 1, 25 (OH) 2 D 3 administration in moderate renal failure: a prospective double-blind trial. Kidney Internat 1989, 35: 661-9.
  1. Naik R, Cundy T, Robinson B, Russell R, Kanis J. Effects of vitamin D metabolites and analogues on renal function. Nephron 1981, 28: 17-25.
  1. Cushner H, Adams N. Review: renal osteodystrophy-pathogenesis and treatment. Am J Med Sci 1986, 29[4]: 264-75.
  1. Okano K, Furukawa Y, Marii H, Fujita T. Comparative efficacy of various vitamin D metabolites in the treatment of various types of hypoparathyroidism. J Clin Endocrin Met 1982, 55: 238-42.
  1. Costa T, Marie P, Scriver C, Cole D, Reade T, Nogrady B, et al. X-linked hypophosphatemia: effect of calcitriol on renal handling of phosphate, serum phosphate, and bone mineralization. J Clin Endocrinol Met 1981, 5[3]: 463-72.
  1. Koo W, Tsang R, Steichen J, Succop P, Oestreich A, Noseworthy J, et al. Vitamin D requirement in infants receiving parenteral nutrition. JPEN 1987, 11[2]: 172-6.
  1. Panelist comment 1991 revision cycle.
  1. Jensen G, Meineche B, Boesen J, Transbol J. Does 1, 25 (OH) 2 D 3 accelerate spinal bone loss? Clin Ortho Rel Res 1985, 192: 215-21.
  1. Tjellesen L, Christiansen C, Rodbro P. Effect of 1, 25 dihydroxyvitamin D 3 on biochemical indices of bone turnover in postmenopausal women. Acta Med Scand 1984, 215: 411-5.
  1. Ott S, Chesnut C. Calcitriol treatment is not effective in postmenopausal osteoporosis. Annals of Int Med 1989, 110: 267-74.
  1. Schwartzman M, Frank W. Vitamin D toxicity complicating the treatment of senile, post-menopausal, and glucorticoid-induced osteoporosis. Am J Med 1987, 82: 224-30.
  1. Per panel consensus 1991 revision cycle.
  1. Panel consensus, 1991 revision cycle.
  1. Panel comment, 1991 revision cycle.
  1. Panelists comment, 1991 revision cycle.
  1. Panelist comment, 1991 revision cycle.
  1. Manufacturer comment, 1991 revision cycle.
  1. Panelist comment, 1991 revision cycle.
  1. Panelist comment, 1991 revision cycle.
  1. USAN, 1992 Edition.
  1. DeLuca H. Osteoporosis and the metabolites of vitamin D. Metabolism 1990, 39[4, suppl 1]: 3-9.
  1. Rickers H, Deding A, Christiansen C, Rodbro P, Naestoft J. Corticosteroid-induced osteopenia and vitamin D metabolism. Effect of vitamin D 2 calcium phosphate and sodium fluoride administration, Clin Endocrinol 1982, 16: 409-15.
  1. Webb A, Pilbeam C, Hanafin N, Holick M. An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr 1990; 51: 1075-81.
  1. Reviewer comment, 1992 revision.
  1. Tsang R, Noguchi A, Steichen J. Pediatric parathyroid disorders. Pediatr Clinic N Am 1979; 26[1]: 223-49.
  1. Panel consensus, 1992 revision.
  1. S.I. conversion chart, Ann Int Med 1987; 106[1]: 120.
  1. Panel consensus, 1992 revision.
  1. Reviewer comment, 1992 revision.
  1. Panelists comment, 1992 revision.
  1. Panelist comment, 1992 revision.
  1. Panelists comments, 1992 revision.
  1. Kaufman S, Murray N, Wood P, Shaw B, Vanderhoof J. Nutritional support for the infant with extrahepatic biliary atresia. J Pediatr 1987; 110[5]: 679-86.
  1. Specker B, Tsang R, Hollis B. Effect of race and diet on human-milk vitamin D and 25-hydroxyvitamin D. J Dis Child 1985; 139: 1134-7.
  1. Panelist comment. 1992 revision.
  1. Pamidronate product information (Aredia-Ciba), rec 11/91, U.S.
  1. Panelists comment, 1992 revision.
  1. Papapoulos S, Fraher L, Clemens T, Gleed J, O"Riordan J. Metabolites of vitamin D in human vitamin-D deficiency: effect of vitamin D 3 or 1,25 dihydroxycholecalciferol. The Lancet 9/20/80, pp 612-5.
  1. Panel consensus, 1992 reveision.
  1. Jacobus C, Holick M, Shao Q et al. Hypervitaminosis D associated with drinking milk. N Eng J Med 1992; 326[18]: 1172-7.
  1. Panelist comment, 1992 revision.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 1065.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 556.
  1. Olin BR, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc, December 1993 Index: 17.
  1. Olin BR, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc, July 1991: 4e.
  1. Red book 1993. Montvale, NJ: Medical Economics Data, 1993: 596.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 384.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 1357.
  1. Carruthers-Czyzewski P, editor. Self medication product information. Volume 2. 4th ed. Ottawa: Canadian Pharmaceutical Association, 1992: V25.
  1. Nutrition and Electrolytes Advisory Panel Meeting, 1/95.
  1. Reviewer comments, 1995.
  1. Reviewer consensus, 1995.
  1. Product Information: Zemplar™, paricalcitol, Abbott Laboratories, North Chicago, IL, (PI revised 04/98), reviewed 11/1999.
  1. Product Information: Hectorol™, doxercalciferol. Bone Care International, Madison, WI, (PI revised 6/1999), reviewed 01/2000.
  1. Product Information: One-Alpha, alfacalcidol. Leo Pharma Inc.,Ajax, Ontario(PI revised 07/2000), reviewed 02/2001.
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