Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1.2.1) MOLECULAR FORMULA
1) VITAMIN D2: C28H44O

Available Forms Sources

A)

1) VITAMIN D SUPPLEMENTS

a) SUMMARY

1) Vitamin D2 (ergocalciferol) is the synthetic form of vitamin D (Budavari, 1996).
2) Vitamin D2 crystals have a potency of 40 Units of vitamin D per microgram (Budavari, 1996).
3) Vitamin D is available in many formulations including capsules, tablets, and injectables.
4) One mg of cholecalciferol is equivalent to 40,000 International Units of vitamin D. One USP or International Unit is equal to 25 ng of cholecalciferol or ergocalciferol.
5) Cod liver oil contains approximately 2 mcg/mL of vitamin D3 (80 International Units) (Rice, 1983).

2) CHOLECALCIFEROL (D3)

a) Oral Capsule: 5000 IU
b) Oral Capsule, Liquid Filled: 1000 IU, 2000 IU
c) Oral Tablet: 400 IU, 1000 IU, 2000 IU, 3000 IU, 5000 IU
d) Oral Tablet, Chewable: 400 IU
e) Powder: 100,000 IU/GM
f) Solution: 1 Million IU/GM, 2400 U/mL

3) ERGOCALCIFEROL (D2)

a) Oral Capsule: 50000 IU
b) Oral Capsule, Liquid Filled: 50000 IU
c) Oral Solution: 8000 IU/mL
d) Oral Tablet: 400 IU, 2000 IU

4) CHEMICAL FORMULATION

a) White, odorless crystals (Lewis, 1993)
b) Commercial solutions are usually made with propylene glycol or sesame oil (Budavari, 1996).

B)

1) Vitamin D2 is found in fish and oils and fortified foods such as milk and margarine. It undergoes biotransformation similar to that of cholecalciferol (vitamin D3). The 2 compounds are equally potent in man (HSDB, 1993).
2) DERIVATION: From ergosterol by irradiation with UV light (Lewis, 1993).
3) RICKET THERAPY/INTERNATIONAL ADOPTION: Vitamin D intoxication was reported in an infant with apparent failure-to-thrive following an international adoption in which the infant was given formula fortified with vitamin D. It was determined that massive quantities of vitamin D were likely given based on the elevated laboratory findings and physical symptoms. The patient gradually improved with supportive care (Chan et al, 2006).
4) SPECIFIC PRODUCTS

a) ADULTERATED DIETARY FISH SUPPLEMENT: Seven children (between the ages of 0.7 and 4.2 years) developed vitamin D intoxication after being given a fish oil supplement that contained a high level of vitamin D3 due to a manufacturing error. The supplement was analyzed and found to contain 3.6 mg (144,000 International Units) per gram of fish oil (each 5 mL of fish oil was calculated to contain approximately 20 mg (800,000 International Units) of vitamin D3). The estimated daily doses that these children received varied between 266,000 and 800,000 International Units or 177 to 320 times the recommended tolerable upper limits for infants and children. Each child recovered with supportive care (Kara et al, 2014).
b) SOLADEK is a prescription vitamin supplement (each 5 mL contains 120,000 International Units of vitamin A, 600,000 International Units of vitamin D and 5 mg of vitamin E) sold in the Dominican Republic, but it can be found in United States as an over-the-counter supplement without dosing instructions in some independent grocery stores. It purportedly is used to control pain, prevent colds and viruses, and enhances general conditioning and muscle strength. It has also been used as a performance-enhancing drug by athletes. An adult female developed symptomatic vitamin D toxicity following use, but recovered with supportive care (Leu et al, 2008).

C)

1) Vitamin D (represents D2 {ergocalciferol} or D3 {cholecalciferol} is a fat soluble vitamin (Office of Dietary Supplements, National Institutes of Health, 2011; Ginsburg, 2011). It is used for the prevention and treatment of rickets, osteomalacia, and osteoporosis, and the treatment of hypoparathyroidism (Office of Dietary Supplements, National Institutes of Health, 2011; Ginsburg, 2011). More recently, evidence suggests that it may also have a role in the prevention of cardiovascular disease, and colon, prostate, and breast cancers (Office of Dietary Supplements, National Institutes of Health, 2011; O'Keefe et al, 2011). Vitamin D is found in many dietary supplements (multivitamins, combined with calcium) or as a single dietary supplement and also commonly found in fortified foods (ie, milk, cereal, and bread) (Ginsburg, 2011).
2) Vitamin D is metabolized into 25-hydroxyvitamin D [25(OH)D] by vitamin D-25-hydroxylase. It regulates calcium homeostasis via interactions with the intestines and bones. Vitamin D it thought to act as a hormone, because it is synthesized in the body, circulates in the blood, and binds to receptors in order to evoke its biologic action. It promotes calcium absorption in the gut and aids adequate serum calcium and phosphate concentrations (Ginsburg, 2011; Office of Dietary Supplements, National Institutes of Health, 2011).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Vitamin D (represents D2 {ergocalciferol} or D3 {cholecalciferol} is a fat soluble vitamin. It is used for the prevention and treatment of rickets, osteomalacia, and osteoporosis, and the treatment of hypoparathyroidism. More recently, evidence suggests that it may also have a role in the prevention of cardiovascular disease, and colon, prostate, and breast cancers. Vitamin D is found in many dietary supplements (multivitamins, combined with calcium) or as a single dietary supplement, and also commonly found in fortified foods (ie, milk, cereal, and bread).
B) PHARMACOLOGY: Vitamin D is metabolized into 25-hydroxyvitamin D [25(OH)D] by vitamin D-25-hydroxylase. It regulates calcium homeostasis via interactions with the intestines and bones. Vitamin D is thought to act as a hormone, because it is synthesized in the body, circulates in the blood, and binds to receptors in order to evoke its biologic action. It promotes calcium absorption in the gut and aids adequate serum calcium and phosphate concentrations.
C) EPIDEMIOLOGY: Overdose is rare. Toxicity is mild after acute overdose, but more severe toxicity occasionally develops after chronic ingestion of large amounts. In some cases, exposure has occurred due to excessive fortification of foods or overuse of supplements.
D) TOXICOLOGY: Hypercalcemia is characteristic of vitamin D toxicity.
E) WITH THERAPEUTIC USE

1) Adverse events are not typically reported with normal use.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Nausea, vomiting and abdominal cramps are likely to occur with an acute ingestion. Other symptoms include: anorexia, constipation or diarrhea, weakness, fatigue, irritability, drowsiness, headache and dizziness.
2) SEVERE TOXICITY: Generally, only seen after chronic ingestion of large amounts of vitamin D. Seizures, confusion, ataxia, psychotic disturbances, coma, or renal failure can occur. Cardiac dysrhythmias can develop. Polyuria and polydipsia may be present.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Mild persistent hypertension has been reported in children with vitamin D intoxication.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Cardiac arrhythmias and myocardial infarction may be seen with chronically high ingestion.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Anorexia, nausea, vomiting, constipation and/or diarrhea may develop.

0.2.9)

A) WITH POISONING/EXPOSURE

1) Hepatomegaly has been reported in one case.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Chronic exposures may produce metastatic calcification of the renal tubules resulting in albuminuria, nocturia, polydipsia, and polyuria.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Hypercalcemia is frequently reported following chronic ingestion of excessive doses or following chronic occupational exposure.

0.2.13)

A) WITH POISONING/EXPOSURE

1) Normocytic, normochromic anemia has been described after chronic intoxication.

0.2.15)

A) WITH POISONING/EXPOSURE

1) Widespread joint, periarticular, and nephro-calcinosis has been reported in one case. Demineralization of bone may result in multiple fractures from very slight trauma.

0.2.18)

A) WITH POISONING/EXPOSURE

1) Extreme depression, apathy, confusion, and fatigue may be associated with chronic excessive intake of vitamin D.

0.2.20)

A) Vitamin D if used in doses above the recommended daily allowance is classified as FDA pregnancy category D. Calcipotriene is classified as FDA pregnancy category C, while Vitamin D (as vitamin D2, ergocalciferol) is classified as FDA pregnancy category A. In humans, aortic stenosis was associated with high doses of vitamin D in pregnancy. However, conflicting results have been observed. In animal studies, toxic effects including fetotoxicity, spontaneous abortion and specific developmental abnormalities were observed.

0.2.21)

A) At the time of this review, some studies suggest that vitamin D may have some protective effects against various cancers (eg, colon, prostate, ovarian). However, the results have been inconsistent.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Monitor serum calcium and phosphorus concentrations. Discontinue all vitamin D and calcium supplements; start a low-calcium diet. Increase oral fluids or IV fluids, if patient is unable to tolerate fluids, to increase renal calcium clearance. Forced diuresis with IV 0.9% normal saline and furosemide can be used to promote calcium excretion.

B) MANAGEMENT OF SEVERE TOXICITY

1) HYPERCALCEMIA: Monitor serum calcium and phosphorus concentrations until levels have stabilized, discontinue all supplements, and continue forced diuresis as indicated. Corticosteroids: Hydrocortisone: 100 mg/day OR Prednisone: 20 mg/day can improve hypercalcemia and hypercalcuria. Bisphosphonates (eg, pamidronate 90 mg IV; alendronate) have been used successfully to treat severe hypercalcemia. Calcitonin has also been used. Hemodialysis may be indicated in patients with severe hypercalcemia that is unresponsive to other treatment. Cardiac dysrhythmias may develop, obtain a baseline ECG and continuous cardiac monitoring. SEIZURES: Treat initially with benzodiazepines, followed by barbiturates as needed. OTHER: Monitor CNS and renal function.

C) DECONTAMINATION

1) PREHOSPITAL: Decontamination is unlikely to be necessary following an acute ingestion, unless a very large amount has been ingested (more than 100 times the RDA).
2) HOSPITAL: Decontamination is unlikely to be necessary following an acute ingestion, unless a very large amount has been ingested or coingestants are suspected.

D) AIRWAY MANAGEMENT

1) Airway management is unlikely to be necessary following a mild to moderate exposure. Patients with severe toxicity (ie, altered mental status, confusion, seizures, coma, or cardiac dysrhythmias) may require airway protection and mechanical ventilation.

E) ANTIDOTE

1) None.

F) ENHANCED ELIMINATION

1) Hemodialysis or peritoneal dialysis against a calcium-free dialysate may be useful if the patient has persistent severe hypercalcemia unresponsive to other treatment measures.

G) PATIENT DISPOSITION

1) HOME CRITERIA: An asymptomatic adult or child with an inadvertent minor exposure (eg, a single dietary supplement ingested by a child) may be monitored at home.
2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with seizure activity or CNS depression should be monitored until symptoms resolve and neurologic exam is normal. Patients may be discharged to home once symptoms have resolved and laboratory studies are within normal limits.
3) ADMISSION CRITERIA: Patients with evidence of severe hypercalcemia or persistent seizures should be admitted for further treatment.
4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.

H) PHARMACOKINETICS

1) Vitamin D is metabolized into 25-hydroxyvitamin D [25(OH)D] by vitamin D-25-hydroxylase. It regulates calcium homeostasis via interactions with the intestines and bones. Vitamin D is thought to act as a hormone, because it is synthesized in the body, circulates in the blood and binds to receptors in order to evoke its biologic action. It promotes calcium absorption in the gut and aids adequate serum calcium and phosphate concentrations.

I) PITFALLS

1) Discharge too early prior to laboratory and CNS stability.

J) DIFFERENTIAL DIAGNOSIS

1) Other agents (ie,) or conditions that may cause hypercalcemia (eg, aluminum, antacids (calcium-containing), lithium, thiazide diuretics, vitamin A).

Range Of Toxicity

A)

B)

C)

D)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) Adverse events are not typically reported with normal use.

F)

1) MILD TO MODERATE TOXICITY: Nausea, vomiting and abdominal cramps are likely to occur with an acute ingestion. Other symptoms include: anorexia, constipation or diarrhea, weakness, fatigue, irritability, drowsiness, headache and dizziness.
2) SEVERE TOXICITY: Generally, only seen after chronic ingestion of large amounts of vitamin D. Seizures, confusion, ataxia, psychotic disturbances, coma, or renal failure can occur. Cardiac dysrhythmias can develop. Polyuria and polydipsia may be present.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Mild persistent hypertension has been reported in children with vitamin D intoxication.

3.3.4)

A) WITH POISONING/EXPOSURE

1) Mild persistent hypertension was reported in a 2-year-old boy who also developed hypercalcemia following vitamin D intoxication. Over a 4-day period, the child received 1 ampule of a vitamin D supplement per day (each ampule containing 600,000 International Units of vitamin D). The recommended dosage was 2 drops from an ampule per day (each drop containing approximately 2500 International Units of vitamin D) (Barrueto et al, 2005).
2) A 6-month-old infant developed hypertension (130/70 mmHg) after inadvertently receiving 300,000 units of vitamin D orally daily for 10 days (Gurkan et al, 2004).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) CONJUNCTIVITIS: A 7-month-old infant developed conjunctivitis associated with chronic over-supplementation of cholecalciferol (Lukaszkiewicz et al, 1987).
2) ANIMAL STUDIES: Excessive vitamin D in experimental animals has produced band keratopathy, elevated lens calcium, and inhibited human retinoblastoma growth (Grant, 1986; Srivastava et al, 1986; Albert et al, 1988; HSDB, 2001).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Cardiac arrhythmias and myocardial infarction may be seen with chronically high ingestion.

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) ECG changes may include shortening of the QT interval in patients with hypercalcemia secondary to vitamin D intoxication (Nordt et al, 2002).
b) Premature beats were seen on ECG in a 3-month-old infant with hypercalcemia following vitamin D intoxication (Ezgu et al, 2004).

B) HYPERTENSIVE DISORDER

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Mild persistent hypertension was reported in a 2-year-old boy who also developed hypercalcemia following vitamin D intoxication. Over a 4-day period, the child received 1 ampule of a vitamin D supplement per day (each ampule containing 600,000 International Units of vitamin D). The recommended dosage was 2 drops from an ampule per day (each drop containing approximately 2500 International Units of vitamin D) (Barrueto et al, 2005).
b) CASE REPORT: A 6-month-old infant developed hypertension (130/70 mmHg) after inadvertently receiving 300,000 units of vitamin D orally daily for 10 days (Gurkan et al, 2004).

C) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) The average daily intake of vitamin D was higher for patients with myocardial infarction (31.28 mcg/d) than for matched controls (20.68 mcg/d) in one study (Linden, 1974).

D) ARTERITIS

1) WITH POISONING/EXPOSURE

a) ARTERIAL LESIONS: Degeneration of smooth muscle cells and coronary arterial abnormalities have been seen with chronic hypervitaminosis D (Chesney, 1989).

E) HYPERCHOLESTEROLEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 11-month-old infant developed severe hypercalcemia (serum calcium 5.5 mmol/L [22 mg/dL]) and hyperlipidemia (total cholesterol 246 mg/dL, HDL-C 30 mg/dL, VLDL 54 mg/dL, LDL-C 162 mg/dL, triglyceride 271 mg/dL) after receiving bolus vitamin D at a dose of 600,000 International Units in 2 doses, 15 days apart. Treatment consisted of intravenous fluids with furosemide, steroid, calcitonin, magnesium sulfate, and phosphorus. Serum calcium level declined below 3 mmol/L (12 mg/dL) on the 16th day of therapy and the hyperlipidemia resolved gradually (Evliyaoglu et al, 2001).

3.5.3)

A) ANIMAL STUDIES

1) ARTERIOSCLEROSIS

a) SOFT TISSUE MINERALIZATION: Horses given large doses of ergocalciferol developed mineralization of various soft tissues, particularly the endocardium and wall of large blood vessels (Harrington, 1982).
b) CORONARY ARTERIES: A large dose of vitamin D induced changes in rat coronary arteries (Mohtai & Yamamoto, 1987).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) Toxicity is similar to that seen with hypercalcemia from many sources.

1) Symptoms include confusion, fatigue, lethargy, headache, drowsiness, sluggishness, and weakness (Gurkan et al, 2004; Pundzien et al, 2001). Fatigue and confusion are common presenting signs after vitamin D poisoning, occurring in 9 of 21 patients in one series (Paterson, 1980).

B) NEUROPATHY

1) WITH POISONING/EXPOSURE

a) Acute polyneuropathy with marked weakness and sensory loss was reported in a 24-year-old woman after acute vitamin D3 intoxication (Down et al, 1979).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A single seizure was reported in a 52-year-old woman who presented to the ED after inadvertently taking 50,000 International Units of vitamin D 3 times a day for 7 days instead of the same dose 3 times weekly. Her family reported decreased mentation 2 days prior to admission. Hypercalcemia (17.1 mg/dL) was found. The patient was hydrated, given intravenous furosemide and released 3 days later with no further seizure activity noted (Nordt et al, 2002).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Anorexia, nausea, vomiting, constipation and/or diarrhea may develop.

3.8.2)

A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE

1) WITH POISONING/EXPOSURE

a) Symptoms include anorexia, nausea, vomiting, abdominal pain, constipation and/or diarrhea (Barrueto et al, 2005; Gurkan et al, 2004; Ezgu et al, 2004; Pundzien et al, 2001; HSDB, 2001; Paterson, 1980).

3.8.3)

A) ANIMAL STUDIES

1) GASTRITIS HEMORRHAGIC

a) DOGS: Hemorrhagic gastritis was observed in dogs given lethal doses of cholecalciferol (Gunther et al, 1988).

Hepatic

3.9.1)

A) WITH POISONING/EXPOSURE

1) Hepatomegaly has been reported in one case.

3.9.2)

A) LARGE LIVER

1) WITH POISONING/EXPOSURE

a) A 7-month-old infant had moderate hepatomegaly associated with chronic over-supplementation of cholecalciferol (Lukaszkiewicz et al, 1987).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Chronic exposures may produce metastatic calcification of the renal tubules resulting in albuminuria, nocturia, polydipsia, and polyuria.

3.10.2)

A) RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) SUMMARY: Acute renal failure has developed due to compounding errors and inadvertent exposure to higher than reported amounts of Vitamin D due to improper reporting of the amount declared in over-the-counter dietary supplements or misunderstanding by consumers regarding dosage (eg, milliliters vs drops) (Smollin & Srisansanee, 2014; Conti et al, 2014; Marins et al, 2014).
b) CASE REPORT: A 53-year-old man with a history of diabetes and non-dialysis chronic renal failure developed hypercalcemia and acute renal failure associated with a compounding error resulting in vitamin D intoxication. Symptoms included pruritus, muscle weakness, decreased appetite and weight loss. Laboratory studies revealed an elevated calcium (13.4 mg/dL, range 8.4 to 10.4) and creatinine (4.67 mg/dL, range 0.6 to 1.2). An ultrasound showed a renal calculi and the patient underwent ureterolithotripsy. Despite supportive therapy and ruling out other conditions, hypercalcemia persisted. An initial vitamin D (25(OH)D) level was 226 ng/mL (range, 30 to 100). Upon analysis the capsules were found to contain 4,000,000 International Units instead of 2,000 International Units; an estimated 40-fold higher dose than recommended (Marins et al, 2014).
c) CASE REPORT: A 22-year-old male athlete developed hypercalcemia and acute renal failure associated with hypercalcemia after starting a conditioning program and injecting himself with anabolic hormones and intramuscular injections of vitamins A, D, and E. Initial labs included: an ionized calcium of 1.99 mmol/L (range: 1.11 to 140 ) and total calcium 14.8 mg/dL (range: 8.6 to 10.3), serum creatinine of 3.0 (0.7 to 1.3 mg/dL), potassium 2.9 (3.5 to 4.5 mEq/L) and a BUN of 61 (range: 10 to 50 mg/dL). Hypercalcemia persisted despite saline hydration and diuretics, the patient was treated with pamidronate (a single 60 mg dose) with complete resolution of his symptoms and normalization of renal function (Titan et al, 2009).
d) CASE REPORTS: Renal insufficiency associated with hypercalcemia was observed in 5 patients undergoing long-term dihydrotachysterol (DHT) or calcitriol therapy (mean duration of 29 years) for hypoparathyroidism after thyroid surgery. All patients presented with elevated serum creatinine (mean of 247 micromoles/liter) and serum calcium (mean of 3.05 millimoles/liter). Three of the 5 patients exhibited mild hypertension, and 2 presented with epigastric tenderness. Following withdrawal of DHT and substitution with shorter-acting vitamin D derivatives, creatinine and calcium levels declined toward normal range, accompanied by resolution of associated symptoms (Jehle et al, 1999).
e) Chronic toxicity can present with metastatic calcification with renal tubular injury, resulting in albuminuria, nocturia, polydipsia, and polyuria (Paunier et al, 1968).

B) NEPHRITIS

1) WITH THERAPEUTIC USE

a) Abnormal renal histology (tubulo-interstitial nephritis or calcium deposits) was observed in 14 of 22 patients on chronic vitamin D therapy.

1) The incidence of lesions correlated with the yearly incidence of hypercalcemia, mean plasma 25-OHD level, and diagnosis (hypoparathyroidism or hypophosphatemic rickets) (Curtis, 1982).
2) CASE SERIES: Nephrocalcinosis was reported in 2 infants after receiving 1 mL of a multivitamin product twice daily and 1 mL of a vitamin D solution for 17 days (total dose approximately 1.5 million units per child) (Pundzien et al, 2001).

2) WITH POISONING/EXPOSURE

a) In 12 of 27 episodes of chronic vitamin D poisoning, renal impairment was present; persisting impairment was noted on follow-up in 3 of 9 patients evaluated (Paterson, 1980).

C) POLYURIA

1) WITH POISONING/EXPOSURE

a) Symptoms of vitamin D intoxication in infants include polyuria, polydipsia, feeding difficulties, irritability, lassitude, and poor weight gain (Araki et al, 2011; Gurkan et al, 2004; Pundzien et al, 2001; Chesney, 1989).

D) RENAL COLIC

1) WITH POISONING/EXPOSURE

a) CHRONIC TOXICITY

1) CASE REPORTS: A 62-year-old man was admitted to the hospital for renal colic after receiving intramuscular injections of a slow-release multivitamin preparation containing vitamins D and A over a 3-month period. He reportedly excreted several small stones in the urine prior to hospitalization. Hypercalcemia (serum total calcium: 15.3 mg/100 mL), polyuria and renal failure (serum creatinine: 3.72 mg/100 mL; urea: 93 mg/100 mL; uric acid: 6.7 mg/100 mL) were present. Bilateral hydronephrosis was found on ultrasound exam. Renal failure improved with normalization of serum calcium levels (Chiricone et al, 2003).

a) The patient's 55-year-old wife also received the injections and although asymptomatic was found to have hypercalcemia (11.3 mg/100 mL) and mild renal failure. Both patients received hydration and supportive treatment for hypervitaminosis D for up to 6 months. The authors suggested that the unusual duration of toxicity was probably caused by the slow-release preparation in an oily vehicle for intramuscular injection (Chiricone et al, 2003).

E) HYPERCALCIURIA

1) WITH THERAPEUTIC USE

a) CASE SERIES: Calciuria (33.8 and 23 mg/kg/day) was reported in 2 infants after receiving 1 mL of a multivitamin product twice daily and 1 mL of a vitamin D solution for 17 days (total dose approximately 1.5 million units per child) (Pundzien et al, 2001).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 73-year-old man with a history of chronic plaque psoriasis developed hypercalcemia and hypercalciuria after topical application of excessive amounts of calcipotriol (calcipotriene; Dovonex(R)) ointment (420 g/week for 2 weeks). He was prescribed calcipotriol ointment 50 mcg/g twice daily. These effects resolved one week after discontinuation of the ointment (Georgiou & Tsambaos, 1999).

3.10.3)

A) ANIMAL STUDIES

1) NEPHROPATHY TOXIC

a) Hypercalcemic nephropathy developed in experimental animals after repeated injections of vitamin D2 for 2 to 8 weeks (Rosen et al, 1990).

2) URINE ABNORMAL

a) HYPOSTHENURIA: A horse given ergocalciferol 33,000 International Units/kg daily developed a moderate decrease in urine specific gravity after 3 weeks of treatment (Harrington & Page, 1983).

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

1) Normocytic, normochromic anemia has been described after chronic intoxication.

3.13.2)

A) ANEMIA

1) WITH POISONING/EXPOSURE

a) Normocytic normochromic anemia has been described in patients with chronic vitamin D toxicity, presumably due to hypercalcemia-induced kidney or bone marrow damage (Gabriel et al, 1970) (Keddie, 1987).
b) CASE REPORT: A 66-year-old woman developed hypercalcemia and anemia following vitamin D intoxication (200 mcg or 8000 IU). Although she was taking an extemporaneous formulation (200 IU of vitamin D and 1 g of calcium glucobionate twice daily) for osteoporosis, her symptoms began when a new bottle of pills was started (Puig et al, 1998).

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) Widespread joint, periarticular, and nephro-calcinosis has been reported in one case. Demineralization of bone may result in multiple fractures from very slight trauma.

3.15.2)

A) ARTHROPATHY

1) WITH POISONING/EXPOSURE

a) JOINT CALCINOSIS: Widespread joint, periarticular, and nephro-calcinosis were described in a 67-year-old woman who had taken several tablespoonfuls of cod liver oil daily for 18 months. The total daily vitamin intake was estimated to be greater than 5500 International Units (Butler et al, 1985).

B) PATHOLOGICAL FRACTURE

1) WITH THERAPEUTIC USE

a) FRACTURES: Excessive vitamin D intake can cause demineralization of bone resulting in multiple fractures from very slight trauma (Ginsburg, 2011; HSDB, 2001).

3.15.3)

A) ANIMAL STUDIES

1) MUSCLE WEAKNESS

a) Horses given large doses of ergocalciferol developed weakness and limb stiffness with impaired mobility (Harrington, 1982).

Endocrine

3.16.2)

A) ABNORMAL GLUCOSE LEVEL

1) WITH THERAPEUTIC USE

a) Vitamin D replacement in well-controlled non-insulin-dependent diabetic patients may result in an increase in insulin resistance and a deterioration of glycemic control. The fasting glucose levels and insulin resistance of 3 vitamin D deficient Asian patients with non-insulin-dependent diabetes mellitus ranged from 8 to 11.4 mmol/L and 1.18 to 2.79, respectively, before vitamin D replacement. After vitamin D replacement, the fasting glucose levels and insulin resistance ranged from 10.4 to 15.5 mmol/L and 1.54 to 9.8, respectively (Taylor & Wise, 1998).

Reproductive

3.20.1)

A) Vitamin D if used in doses above the recommended daily allowance is classified as FDA pregnancy category D. Calcipotriene is classified as FDA pregnancy category C, while Vitamin D (as vitamin D2, ergocalciferol) is classified as FDA pregnancy category A. In humans, aortic stenosis was associated with high doses of vitamin D in pregnancy. However, conflicting results have been observed. In animal studies, toxic effects including fetotoxicity, spontaneous abortion and specific developmental abnormalities were observed.

3.20.2)

A) LACK OF INFORMATION

1) CALCIPOTRIENE

a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info Calcipotriene .005% topical ointment, 2010; Prod Info SORILUX(TM) topical foam, 2010; Prod Info Dovonex(R) topical scalp solution, 2007; Prod Info Dovonex(R) topical cream, 2007).

B) HUMANS

1) AORTIC STENOSIS

a) Aortic stenosis was associated with high doses of vitamin D in pregnancy (Friedman, 1968). However, other studies have shown conflicting results.
b) No excessive maternal vitamin D intake was described in 15 children with aortic stenosis (Anita et al, 1967).
c) In another study, ingestion averaging 107,000 International Units/day during pregnancy resulted in 27 normal offspring (Goodenday & Gordon, 1971).
d) In 1 case of a mother with hereditary insensitivity to 1,25-dihydroxyvitamin D who required very large doses of vitamin D throughout pregnancy, a normal infant was delivered (Marx et al, 1980).

C) ANIMAL STUDIES

1) RATS, RABBITS, MICE: Very large doses of vitamin D have been associated with aortic lesions in rabbits (Friedman & Roberts, 1966), micromelia in rats (Yukioka et al, 1959), and microcephaly and skeletal defects in mice (Zane, 1976).
2) RATS: Toxic effects such as fetotoxicity, changes in the weaning or lactation index, growth statistics and viability index, specific developmental abnormalities in the endocrine and musculoskeletal systems, and extra embryonic structures were observed in rats (RTECS , 2001).
3) MICE: In the mouse, specific developmental abnormalities in the central nervous system, craniofacial (including the nose and tongue) area, and musculoskeletal system were observed (RTECS , 2001).
4) In experimental animals, ossification of the sternebrae was moderately retarded and ossification of proximal phalanges in the forepaw was severely retarded following administration of ergocalciferol. Combined treatments of fasting and ergocalciferol produced even more deleterious effects on growth and induced facial anomalies (Ariyuki, 1987).
5) RABBITS: Specific cardiovascular developmental abnormalities (circulatory system), changes in weaning or lactation index and growth statistics, and delayed effects on the newborn were also detected in the rabbit (RTECS , 2001).
6) RATS: Ergocalciferol and cholesterol were given to pregnant rats daily. In mothers killed on day 22 of pregnancy, findings included significant fetal placental growth retardation, fetal bone lesions associated with a generalized retardation of ossification, placental edema, or calcification accompanied by a loss of the normal structure of the placenta and degenerative manifestations, and a striking alteration of the fetal face (Tshibangu et al, 1975).
7) The effects of maternal hypercortisonism and the concomitant administration of vitamin D2 were investigated. Further bone shortening and hypomineralization were noted with the concomitant administration of vitamin D2 (Ornoy, 1971).
8) RABBITS: Pregnant rabbits given a minimum of 2.5 million international units of vitamin D2, a lethal dose, aborted or delivered macerated fetuses. Pathological changes were present in the aortas of the fetuses (Friedman & Roberts, 1966). Vitamin D2 given IM every other day from day 2 through termination of gestation (total dose of 750,000 International Units) produced craniofacial defects in rabbits (Friedman & Mills, 1969).
9) RABBITS: Cardiovascular defects similar to those reported in humans have also been produced in rabbits receiving 10,000 or 100,000 International Units vitamin D2 every 2 days for 14 doses. Abortions were increased in the high dose group (Chan et al, 1979).
10) MICE: Facial, skeletal and CNS defects (microcephaly) occurred in mice exposed to 50,000 International Units of vitamin D2 from day 4 to 7 of gestation (Zane, 1976).
11) RATS: Delayed ossification, facial defects, and metastatic calcinosis (calcified tissue) were present in rats receiving high doses of vitamin D2 from day 9 of gestation (Ariyuki, 1987; Tshibangu et al, 1975). A daily dose of 40,000 International Units of vitamin D2 starting on day 9 of gestation produced lower fetal weight, lighter fetal bones, and impairment of ossification in rats (Ornoy et al, 1969). Sixty percent of rats receiving 40,000 International Units from day 10 to 21 of gestation died shortly after birth, and the survivors had impaired development of the long bones (Ornoy, 1971).
12) CALCIFEDIOL

a) During animal studies, teratogenic effects were observed with administration of calcifediol at doses 8 to 16 times the human dose (Prod Info RAYALDEE(R) oral extended-release capsules, 2016).

13) CALCIPOTRIENE

a) RATS, RABBITS: Studies conducted in rats and rabbits were performed by the oral route and resulted in teratogenic effects. Rabbits exhibited maternal and fetal toxicity at doses of 12 mcg/kg/day. Higher doses of 36 mcg/kg/day caused an increased incidence of incomplete ossification of pubic bones and forelimb phalanges in fetuses. Rats given oral doses of 54 mcg/kg/day had a higher incidence of skeletal abnormalities, especially enlarged fontanelles and extra ribs (Prod Info Calcipotriene .005% topical ointment, 2010; Prod Info SORILUX(TM) topical foam, 2010; Prod Info Dovonex(R) topical scalp solution, 2007; Prod Info Dovonex(R) topical cream, 2007).

3.20.3)

A) LACK OF INFORMATION

1) CALCIPOTRIENE

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info Calcipotriene .005% topical ointment, 2010; Prod Info SORILUX(TM) topical foam, 2010; Prod Info Dovonex(R) topical scalp solution, 2007; Prod Info Dovonex(R) topical cream, 2007).

B) HUMANS

1) PREGNANCY CATEGORY

a) Vitamin D is classified as FDA pregnancy category D if used in doses above the recommended daily allowance. Calcitriol, cholecalciferol, dihydrotachysterol, and ergocalciferol are also classified as FDA pregnancy category D, if used in doses above the recommended daily allowance, and as FDA pregnancy category A, if used within the recommended daily allowance (Briggs et al, 1994).
b) Calcipotriene is classified as FDA pregnancy category C (Prod Info SORILUX(TM) topical foam, 2010).
c) Vitamin D (as vitamin D2 ergocalciferol) is classified as FDA pregnancy category A (Schardein, 1993).
d) CALCIFEDIOL

1) The manufacturer has classified calcifediol as FDA pregnancy category C (Prod Info RAYALDEE(R) oral extended-release capsules, 2016).
2) Use during pregnancy only if the potential maternal benefit outweighs the potential risk to the fetus (Prod Info RAYALDEE(R) oral extended-release capsules, 2016).

2) ABORTION

a) Spontaneous abortion of a 10-week fetus occurred 5 weeks after ingestion of a massive amount of vitamin D (Down et al, 1979).

3) HYPOPARATHYROIDISM

a) Parathyroid function can be suppressed in newborns of mothers with hypercalcemia due to excess vitamin D (HSDB, 2001).

C) ANIMAL STUDIES

1) ABORTION

a) RABBITS: Cardiovascular defects similar to those reported in humans have also been produced in rabbits receiving 10,000 or 100,000 International Units vitamin D2 every 2 days for 14 doses. Abortions were increased in the high dose group (Chan et al, 1979).

2) CALCINOSIS

a) RATS: Ergocalciferol and cholesterol were given to pregnant rats daily. Disseminated lesions of metastatic calcinosis were noted in various tissues: the coronary arteries and myocardium, the media of the abdominal aorta, the lung and pleura, the kidney, and the gastrointestinal tract (Tshibangu et al, 1975).

3.20.4)

A) LACK OF INFORMATION

1) Cholecalciferol

a) Both a monthly dose of 150,000 IU and a daily dose of 5000 IU of cholecalciferol administered to nursing mothers provided sufficient vitamin D supplementation for their infants, and increased infant mean serum 25-hydroxyvitamin D concentrations from 17 +/- 13 to 39 +/- 6 ng/mL (single dose) and 16 +/- 12 to 39 +/- 12 (daily dose). A 25-hydroxyvitamin D serum level of more than 20 ng/mL was achieved in all infants. At the time of this study, there were no data to assess the potential effects of exposure to cholecalciferol during lactation in humans. More studies are needed before adopting this vitamin D supplementation strategy in infants (Oberhelman et al, 2013).

B) HUMANS

1) BREAST MILK

a) Vitamin D is excreted into breast milk in small amounts. The American Academy of Pediatrics considers maternal consumption of vitamin D to be compatible with breast feeding. However, serum calcium levels should be obtained if the mother is receiving pharmacologic doses (Briggs et al, 1998).
b) Breast milk may contain enough vitamin D to be harmful to the nursing infant if the mother is taking large doses (Chesney, 1989; Briggs et al, 1994a). Whether or not vitamin D supplementation is advantageous to nursing infants is a matter of debate.
c) CALCIFEDIOL

1) Calcifediol is poorly excreted into human milk (Prod Info RAYALDEE(R) oral extended-release capsules, 2016).
2) Caution is advised if calcifediol is administered to woman that is breastfeeding (Prod Info RAYALDEE(R) oral extended-release capsules, 2016).

d) CALCIPOTRIENE

1) Evidence shows that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter fetal circulation; it is unknown whether calcitrol is excreted in human milk. The systemic disposition of calcipotriene is expected to be similar to vitamin D3. Maternal use of topical preparations generally carries less risk than a systemically administered drug; risk to the infant should be considered relative to the inherent toxicity of the drug (Prod Info Calcipotriene .005% topical ointment, 2010; Prod Info SORILUX(TM) topical foam, 2010; Prod Info Dovonex(R) topical scalp solution, 2007; Prod Info Dovonex(R) topical cream, 2007).

3.20.5)

A) LACK OF INFORMATION

1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info Calcipotriene .005% topical ointment, 2010; Prod Info SORILUX(TM) topical foam, 2010; Prod Info Dovonex(R) topical scalp solution, 2007; Prod Info Dovonex(R) topical cream, 2007).

B) ANIMAL STUDIES

1) DOGS, RATS: Atrophy of the testes and prostate has occurred in dogs receiving vitamin D (Hayes & Laws, 1991). However, vitamin D is required for adequate testicular function and spermatogenesis in rats (Sood et al, 1995).
2) RATS, RABBITS: Vitamin D given to female rats prior to mating caused changes and disorders in the menstrual cycle. A change in the female rat fertility index was also observed. In the rabbit, abortion and toxic effects on fertility were observed (RTECS , 2001).
3) CALCIFEDIOL

a) No significant effects on animal fertility have been reported (Prod Info RAYALDEE(R) oral extended-release capsules, 2016).

4) CALCIPOTRIENE

a) RATS: Studies in rats given calcipotriene in doses up to 54 mcg/kg/day (318 mcg/m(2)/day) showed no impairment of fertility (Prod Info SORILUX(TM) topical foam, 2010).

Carcinogenicity

3.21.2)

A) At the time of this review, some studies suggest that vitamin D may have some protective effects against various cancers (eg, colon, prostate, ovarian). However, the results have been inconsistent.

3.21.3)

A) PROTECTIVE EFFECT

1) Vitamin D at normal levels may afford some protection against cancer. In a prospective study on 47,935 male US health professionals, intake of calcium and vitamin D were inversely associated with risk for colon cancer, but the trends were not statistically significant (Kearney et al, 1996).
2) Epidemiologic studies examining the possible link between vitamin D/calcium and protection against colon cancer have been inconclusive. A questionnaire from 89,448 female nurses followed since 1980 showed lower relative risk for colon cancer among women in the highest quintile of calcium or vitamin D intake, versus those in the lowest quintile (RR = 0.70 for dietary calcium and 0.33 for total vitamin D). While neither was statistically significant, they are suggestive and point to the need for further study (Martinez et al, 1996).
3) In a case-control study on 569 cases of colon and rectal cancer in Stockholm, Sweden, levels of dietary vitamin D were inversely associated with risk for colorectal cancer, and dietary calcium was not a factor in the risk (Pritchard et al, 1996).
4) High levels of serum 1,25-dihydroxyvitamin D may be associated with protection from prostate cancer (Corder et al, 1995). In another study, incidence of fatal ovarian cancer in American women was shown to be inversely proportional to mean annual intensity of local sunlight; this result is consistent with, but does not prove, the conclusion that vitamin D offers protection from ovarian cancer (Lefkowitz & Garland, 1994).
5) 1,25-Dihydroxycholecaliferol, a vitamin D metabolite, can regulate cell proliferation and differentiation; it and other vitamin D derivatives may be useful in cancer chemotherapy. One study showed that many cell lines derived from small-cell lung cancer and non-small-cell lung cancer expressed the vitamin D receptor, and were thus potential targets for vitamin D therapy (Kaiser et al, 1996). 1,25-Dihydroxyvitamin D-3 was effective in reducing proliferation only in breast cancer cells which contained the vitamin D receptor (Buras et al, 1994).

3.21.4)

A) BENIGN ADENOMAS

1) CALCIPOTRIENE: An increase in benign c-cell adenomas were observed in the thyroid of female rats given oral calcipotriene doses of 15 mcg/kg/day (approximately 90 mcg/m(2)/day) until week 71 and then 10 mcg/kg/day (approximately 60 mcg/m(2)/day) until week 104 (Prod Info TACLONEX(R) topical ointment, 2014).

B) BENIGN PHEOCHROMOCYTOMAS

1) CALCIPOTRIENE: An increase in benign pheochromocytomas were observed in the adrenal glands of male rats given oral calcipotriene doses of 15 mcg/kg/day (approximately 90 mcg/m(2)/day) until week 71 and then 10 mcg/kg/day (approximately 60 mcg/m(2)/day) until week 104 (Prod Info TACLONEX(R) topical ointment, 2014).

C) SKIN TUMORS

1) CALCIPOTRIENE: Skin tumors formed quicker than normal in mice applied with topical calcipotriene and exposed to ultra-violet radiation (statistically significant in male mice only) (Prod Info TACLONEX(R) topical ointment, 2014).

D) LACK OF EFFECT

1) CALCIPOTRIENE

a) No carcinogenesis was observed when calcipotriene was applied to mice for up to 24 months in topical doses of 3, 10, and 30 mcg/kg/day (9, 30, and 90 mcg/m(2)/day) (Prod Info TACLONEX(R) topical ointment, 2014).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Institute continuous cardiac monitoring and obtain an ECG (evaluate for prolonged PR interval and QRS widening, shortened QT interval and flattened T waves).
C) Serum calcium and phosphate concentrations should be monitored closely.
D) Monitor renal function. Obtain a baseline urinalysis; monitor for hypercalcuria and polydipsia.
E) Monitor fluid status, if significant dehydration, polyuria or vomiting occurs.
F) Plasma concentrations of 25-hydroxyvitamin [25(OH)D] are generally be elevated with vitamin D toxicity and can confirm the diagnosis but are not useful to guide therapy.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Serum calcium and phosphate levels should be monitored closely.

a) Serum calcium should be measured at least every 3 months in patients receiving large doses of vitamin D (Davies & Adams, 1978).

2) Monitor renal function tests.

B) HEMATOLOGIC

1) Monitor CBC in patients with signs or symptoms of hypercalcemia.

4.1.3)

A) Obtain a baseline urinalysis. Hypercalcuria and polydipsia may occur. Children may be more likely to develop hypercalcuria even when serum calcium and phosphorus concentrations are normal (Ginsburg, 2011).

4.1.4)

A) OTHER

1) ECG

a) Obtain an ECG. Manifestations of severe hypercalcemia secondary to vitamin D toxicity may include prolonged PR interval and QRS widening, shortened QT interval and flattened T waves (Ginsburg, 2011).

Radiographic Studies

A)

1) Chronic vitamin D intoxication may result in periosteal thickening and increased mineralization on bone x-ray.

Methods

A)

1) Estimation of vitamin D levels is usually restricted to specialized laboratories engaged in research.
2) May be analyzed by high pressure liquid chromatography. AOAC Method 43.079 (Lukaszkiewicz et al, 1989; HSDB, 2001).
3) The majority of methods used for quantitation of vitamin D and its metabolites in human body fluids, particularly in clinical situations, use protein binding methods. Gas chromatography-mass spectrometry is not widely used, but is available for many of the metabolites of vitamin D (Porteous et al, 1987).
4) The alizarin-red-S method provides a rapid and easily reproducible method for detection of extensive calcium deposition in kidneys of wildlife casualties involving the rodenticide calciferol (Tarrant & Westlake, 1984).
5) A sensitive and stable colorimetric method for spectrophotometric determination of ergocalciferol following reaction with trifluoroacetic acid has been described (Gharbo & Gosser, 1974).
6) In one study, radioreceptor assays were used to measure the serum total 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels. Centrifugal ultrafiltration isodialysis was used to measure the percentage of free 1,25-dihydroxyvitamin D (Pettifor et al, 1995). It was found that patients with vitamin D toxicity had elevated free 1,25-dihydroxyvitamin D levels despite normal or only marginally elevated total 1,25-dihydroxyvitamin D levels. The elevated free levels of 1,25-dihydroxyvitamin D might contribute to the pathogenesis of hypercalcemia in vitamin D toxicity.

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with evidence of severe hypercalcemia or persistent seizures should be admitted for further treatment.

6.3.1.2) HOME CRITERIA/ORAL

A) An asymptomatic adult or child with an inadvertent minor exposure (eg, a single dietary supplement ingested by a child) may be monitored at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with CNS depression or seizure activity should be monitored until symptoms resolve and neurologic exam is normal. Patients may be discharged to home once symptoms have resolved and laboratory studies are within normal limits.

Monitoring

A)

B)

C)

D)

E)

F)

Oral Exposure

6.5.1)

A) SUMMARY

1) Gastric decontamination is rarely necessary with an acute ingestion unless extremely large amounts have been ingested (more than 100 times the RDA) (Brin M, 1976). This is equivalent to 100 multiple vitamin tablets or 17 pellets of rodenticide bait.

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) SUMMARY

1) Gastric decontamination is seldom necessary with acute ingestion unless extremely large amounts have been ingested (more than 100 times the RDA) (Brin M, 1976). This is equivalent to 100 multiple vitamin tablets or 17 pellets of rodenticide bait.

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) Treatment is symptomatic and supportive. Increase oral fluids or IV fluids, if patient is unable to tolerate fluids, to increase renal calcium clearance. Forced diuresis with IV 0.9% NaCl and furosemide may be used to promote calcium excretion (Ginsburg, 2011).
2) URINE: Measure urine volumes, sodium, and potassium as pooled samples at least once per day. Replace lost fluids, sodium, and potassium by intravenous infusions.

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Institute continuous cardiac monitoring and obtain an ECG (evaluate for prolonged PR interval and QRS widening, shortened QT interval and flattened T waves).
3) Serum calcium and phosphate concentrations should be monitored closely.
4) Monitor renal function. Obtain a baseline urinalysis; monitor for hypercalcuria and polydipsia.
5) Monitor fluid status, if significant dehydration, polyuria or vomiting occurs.
6) Plasma concentrations of 25-hydroxyvitamin [25(OH)D] are generally elevated with vitamin D toxicity and can confirm the diagnosis but are not useful to guide therapy.

C) CHRONIC POISONING

1) Discontinue all vitamin D supplementation.
2) A LOW calcium diet should be initiated with consultation of a nutritionist.

D) HYPERCALCEMIA

1) Most patients will do well with intravenous hydration with 0.9% saline and standard doses of furosemide to promote calcium excretion in the urine. Patients with severe hypercalcemia may require other therapies.
2) CORTICOSTEROIDS

a) SUMMARY: Corticosteroid therapy can improve hypercalcemia and hypercalcuria associated with vitamin D poisoning (Ginsburg, 2011).
b) PREDNISONE: A dose of 1 mg/kg/day to a maximum of 20 mg/day should be administered for a short 1 to 2 week course, thereby decreasing plasma calcium. Rebound elevations in plasma calcium may occur upon discontinuation of prednisone.
c) HYDROCORTISONE: 100 mg/day (Ginsburg, 2011).

3) BISPHOSPHONATES

a) Bisphosphonates have been used to treat severe hypercalcemia secondary to vitamin D toxicity.
b) ALENDRONATE

1) Alendronate, either orally or via a nasogastric tube, has been used successfully in a small number of infants and children to treat hypercalcemia secondary to vitamin D toxicity (Doneray et al, 2008; Orbak et al, 2006; Hatun & Cizmecioglu, 2005; Hatun & Cizmecioglu, 2005).
2) CASE REPORTS

a) CASE REPORTS/NASOGASTRIC ADMINISTRATION: An 8-month-old girl with delayed sitting and walking skills was treated with vitamin D for presumed hypotonia secondary to rickets and was given a total dose of 1,200,000 International Units. She was admitted with restlessness and vomiting with an initial serum calcium concentration of 14.2 mg/dL. The infant was treated with 5 mg daily of alendronate crushed and mixed with water and administered via a nasogastric tube (NGT) for 3 days with no side effects. Her calcium level normalized and she was discharged on hospital day 10; follow-up at 3 months showed normal growth. The second patient was a 35-day-old male infant with growth retardation with reported muscle weakness by his family. A single 600,000 International Units of vitamin D was given for suspected vitamin D deficiency. He was admitted with increasing restlessness and poor feeding with evidence of dehydration and hypercalcemia (14.5 mg/dL). The patient was treated with alendronate (5 mg/day for 2 days and 10 mg/day for one day) via an NGT for hypercalcemia after failing to respond to furosemide and saline therapies. Calcium serum concentration on day 8 and 9 were 10.1 and 9.5 mg/dL, respectively. The patient was discharged on day 11 with normal growth and development at 3 month follow-up (Doneray et al, 2008).
b) CASE REPORT: A 7-year-old child developed symptoms of anorexia, nausea, vomiting, polydipsia, polyuria, and constipation following the administration of 300,000 units of oral vitamin D daily for 15 days for suspected vitamin D deficiency. Laboratory studies on admission included serum calcium of 12.1 mg/dL and a vitamin D level of greater than 400 ng/mL. Initial therapy included IV hydration, calcium and vitamin D restriction, with 5 mg/day of oral alendronate added on day 2, which was increased to 10 mg/day. The calcium level gradually declined to 10.3 mg/dL following 16 days of alendronate therapy. Alendronate was well tolerated with no adverse events observed, including no laboratory evidence of nephrocalcinosis or radiographic evidence of metaphyseal sclerosis up to 2 months after exposure (Orbak et al, 2006).
c) CASE REPORT: An 11-month-old infant developed hypercalcemia after receiving 3 doses of cholecalciferol 300,000 International Units (at 5, 5.5, and 9 months of age) and daily doses of vitamin D (400 International Units). Laboratory results showed serum calcium of 18 mg/dL (4.5 mmol/L), serum 25 (OH) vitamin D level of 200 ng/mL, parathyroid hormone (PTH) of 1.84 pg/mL, and urinary calcium excretion of 10 mg/kg/day. Bilateral metastatic calcification was observed on the x-ray of the left hand and wrist. A renal ultrasound examination showed bilateral peripheral nephrocalcinosis. After treatment with calcitonin, glucocorticoid and oral phosphates for one month, the patient's serum calcium levels declined to 14.4 mg/dL. Alendronate sodium (5 mg/day) was then added to the treatment and she became normocalcemic with normal urinary calcium excretion on the 21st day of treatment (Hatun & Cizmecioglu, 2005).
d) CASE REPORT: A 4-month-old infant who had been misdiagnosed with rickets developed hypercalcemia after receiving cholecalciferol (300,000 International Units IM) twice in 3 weeks. Laboratory results showed serum calcium 14.9 mg/dL; alkaline phosphatase 166 Units/L, calcium/creatinine ratio in spot urine 2.06, serum 25 (OH) vitamin D level greater than 160 ng/mL, and PTH 4.1 pg/mL. The infant was treated with intravenous hydration, diuretics, glucocorticoids, calcitonin, and phosphate solution. Since the serum calcium remained elevated, she was treated with pamidronate (1 mg/kg/day) for 10 days without a satisfactory response. Abdominal ultrasound showed bilateral medullary nephrocalcinosis. She was then treated with alendronate (10 mg/day) for 6 weeks in addition to intravenous hydration and calcitonin; alendronate was discontinued gradually until serum calcium levels decreased to normal levels (Hatun & Cizmecioglu, 2005).

c) PAMIDRONATE

1) CASE REPORTS/INFANTS: Pamidronate was used successfully in three infants (ages 4 months to 25 months) that developed vitamin D toxicity secondary to inadvertent overdoses of vitamin D. Signs and symptoms of overdose developed about 2 weeks after exposure. In the first case, standard treatment including furosemide, IV hydration and prednisolone were given to treat elevated calcium levels; however, the levels remained elevated and the patient was treated with pamidronate (1 mg/kg in 250 mL saline over 4 hours and a second dose was given 20 hours later). After 3 days, all therapies were stopped. Prior to discharge, ECG, hearing, and ophthalmology studies were found to be normal. At one month follow-up, laboratory studies remained normal. In the other 2 cases, the infants were initially treated with conventional therapies and pamidronate was added due to excessive levels of calcium and failure to respond to initial therapies. In both cases, calcium levels returned to normal following the administration of pamidronate. Its suggested that serum phosphorus and parathyroid hormone levels should also be monitored during follow-up of patients who received pamidronate therapy (Sagsak et al, 2015).
2) A 3-month-old male infant developed vitamin D intoxication following a cumulative dose of 2,560,000 IU vitamin D within 8 days. Serum calcium levels were measured as high as 18.1 mg/dL. Hydration, furosemide, potassium and prednisolone were initiated, bringing the serum calcium level down to 15.9 mg/dL approximately 36 hours after hospitalization. An intravenous solution of 0.5 mg/dL sodium pamidronate in 40 mL isotonic saline was infused over 4 hours. Serum calcium levels at 12, 24 and 36 hours post-infusion were 13.3, 12.1 and 10.6 mg/dL, respectively. On outpatient follow-up, a total of 3 more infusions were given at 21, 30 and 59 days post discharge for recurring mild serum calcium elevations. The patient had no sequelae other than metaphyseal sclerosis which was expected to resolve (Ezgu et al, 2004).
3) A 6-month-old infant developed hypercalcemia (serum calcium level 16.8 mg/dL {normal range 9 to 11 mg/dL}) after inadvertently receiving 300,000 units of oral vitamin D daily for 10 days. The prescribed amount was a total dose of 300,000 units of vitamin D for treatment of suspected rickets. The patient was also lethargic with anorexia, nausea, vomiting, polydipsia, polyuria, and constipation. Despite treatment with fluids, furosemide, and calcitonin, the patient's serum calcium remained elevated at 15.8 mg/dL. Pamidronate was then infused on two consecutive days at 1 mg/kg/day, resulting in a steady decline of her serum calcium level to 10.3 mg/dL. The patient became asymptomatic and was discharged on hospital day 5 (Gurkan et al, 2004).

4) CALCITONIN

a) DOSE: 4 MRC units/kg body weight intramuscularly every 12 hours has been used in one case of vitamin D intoxication with some success (Counts, 1975).
b) CASE REPORTS: Intravenous porcine calcitonin was used to treat 3 adult patients with vitamin D intoxication. All 3 patients received porcine calcitonin 40 MRC units intravenously twice daily and a continuous infusion of 120 MRC units every 12 hours. Normocalcemia was achieved in 3 days in 2 patients and 8 days in the third patient (Buckle et al, 1982).

5) CHOLESTYRAMINE

a) CASE REPORT: The administration of 8 g twice a day to a man with acute vitamin D intoxication appeared to produce a more sustained decrease in serum calcium than high dose corticosteroids (Jibani & Hodges, 1985).
b) CASE REPORT: Cholestyramine 12 grams/day was given to a woman with acute vitamin D intoxication. Despite similar initial vitamin D serum levels to her husband, who was not treated with cholestyramine, there was a more rapid fall in vitamin D levels after 10 weeks of therapy (221 vs 412 nanomoles/liter) in the woman (Thomson & Johnson, 1986).
c) ANIMAL DATA: Oral cholestyramine is effective in the treatment of vitamin D toxicity in experimental animals (Queen & Bell, 1976).

6) MITHRAMYCIN

a) MITHRAMYCIN/EDTA: Severe hypercalcemia not responding to other therapies has been treated with sodium EDTA or mithramycin. These agents should be used with great caution (Buckle et al, 1982; Potts, 1987).

E) VENTRICULAR ARRHYTHMIA

1) POTASSIUM

a) Cardiac dysrhythmias due to hypercalcemia may be treated with potassium in cautious doses, under continuous ECG monitoring.

F) SEIZURE

1) SUMMARY: Severe hypercalcemia may produce confusion, psychosis, seizures and coma (Ginsburg, 2011)
2) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

3) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

4) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

5) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

6) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

7) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

G) DIPHOSPHONATE

1) LACK OF EFFECT

a) CASE REPORTS: The diphosphonate, disodium etidronate, was used for 24 days in 3 male children with acute vitamin D intoxication, with no apparent evidence of decreased urine calcium excretion (Thompson & Johnson, 1986).

H) PHOSPHATE

1) LACK OF EFFICACY

a) The administration of oral phosphates in attempts to lower serum calcium levels has been associated with the development of ectopic calcification, including permanent renal calcinosis (Butler et al, 1985).

I) EXPERIMENTAL THERAPY

1) SUMMARY: Additional studies are needed before any of these experimental treatments can be recommended for the symptomatic treatment of patients with acute vitamin D3 poisoning.
2) Na4EDTA: Mortality was decreased to 50% by administering saline solution containing Na4EDTA (380.2 mg/kg subQ) once daily for 7 days, beginning 2 days after exposure. This treatment regimen was tested in mice acutely poisoned with cholecalciferol (vitamin D3) 300 milligrams/kilogram intraperitoneally (Hatch & Laflamme, 1989).
3) METYRAPONE: Mortality was decreased to 25% and mean survival time was lengthened over control by administering metyrapone (100 mg/kg subQ) twice daily in saline solution for 7 days, beginning 2 days after exposure. This treatment regimen was tested in mice acutely poisoned with cholecalciferol (vitamin D3) 300 mg/kg intraperitoneally (Hatch & Laflamme, 1989).
4) CIMETIDINE: Mean survival time was lengthened by administration of cimetidine (200 mg/kg subQ) twice daily for 7 days, beginning 2 days after exposure in mice acutely poisoned with calciferol. Mortality was not significantly decreased by this intervention (Hatch & Laflamme, 1989).
5) CHLORAMPHENICOL: Mean survival time was lengthened by administering chloramphenicol (50 mg/kg subQ) twice daily for 7 days, beginning 2 days after exposure in mice acutely poisoned with calciferol. Mortality was not significantly decreased by this intervention (Hatch & Laflamme, 1989).
6) AMINO BISPHOSPHONATE IBANDRONATE: In rats, amino bisphosphonate ibandronate prevented vitamin D toxicity and inhibited vitamin D-induced calcification of arteries, cartilage, lungs and kidneys (Price et al, 2001).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) PULMONARY ABSORPTION

1) No reports of significant systemic poisoning from inhalation exposure have been reported in humans.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

6.8.2)

A) OCULAR ABSORPTION

1) No reports of significant systemic poisoning from eye exposure have been reported in humans.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) SKIN ABSORPTION

1) No reports of significant systemic poisoning from dermal exposure have been reported in humans.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) Rehydrate the patient with a 0.9% NaCl. The patient should have a urine flow in excess of 3 mL/kg/hour.

B)

1) Increase calcium excretion by forced saline diuresis with intravenous furosemide (20 to 40 mg IV every 4 to 6 hours as needed to maintain urine flow of 3 mL/kg/hour).

C)

1) Hemodialysis or peritoneal dialysis against a calcium-free dialysate may be useful (Counts, 1975).

D)

1) GLUTETHIMIDE: 500 mg at night, is a known inducer of hepatic microsomal enzymes. Induction of these enzymes appears to enhance the elimination of vitamin D-2.

a) Glutethimide has been used for this purpose in one patient resulting in normalization of serum calcium levels in 12 days and improvement in renal function and level of confusion (Iqbal & Taylor, 1982).

2) PHENYTOIN/PHENOBARBITAL: A 7-month-old with a 25-hydroxyvitamin D concentration of 410.7 ng/mL (1025 nanomoles/liter) was treated with a low calcium diet, furosemide 1 mg/kg/day for 1 week, and enzyme induction with phenytoin and phenobarbital (Lukaszkiewicz et al, 1987).

a) DOSE: Phenytoin 5 mg/kg/day for 17 days plus phenobarbital 5 mg/kg/day for 133 days. Phenobarbital was discontinued for 14 days beginning on the 44th day of treatment.
b) Serum 25-hydroxyvitamin D decreased from 410.7 ng/mL to about 85 ng/mL, over 29 days. The elimination half-life in this child was estimated to be about 13 days (Lukaszkiewicz et al, 1987). More case studies are needed to assess the safety and efficacy of enzyme induction therapy before it can be routinely recommended. At this time, it is not routinely recommended in the management of vitamin D intoxication.

Abstracts

Case Reports

A)

1) ADULT

a) A 32-year-old laboratory technician who had worked in manufacture of vitamin D3 for 22 days developed polydipsia, anorexia, nausea, and malaise 2 days later. The initial serum calcium level was 14 mg/dL (3.5 mmol/L). Despite treatment with intravenous saline, furosemide, and hydrocortisone, the serum calcium was again elevated one week after discharge. After the addition of cholestyramine 8 g twice daily, the serum calcium normalized after 8 weeks (Jibani & Hodges, 1985).

2) PEDIATRIC

a) RICKET THERAPY/INTERNATIONAL ADOPTION: A 10 month-old girl (adopted from an international agency) with a history of rickets and constipation was fed a formula fortified with vitamin D. She was examined shortly after adoption for apparent failure-to-thrive. The infant refused all solid food. Her weight was 5.2 kg, length 66.4 cm, and head circumference 41 cm (well below the 3rd percentile for American children) with significant developmental delays (ie, gross and fine motor, cognitive and expressive language). Initial laboratory studies included a serum calcium of 14.2 mg/dL (normal 8.7 to 9.8 mg/dL), phosphorus 5.8 mg/dL (normal 3.8 to 6.5 mg/dL) , alkaline phosphatase 11 I/L (normal 145 to 320 IU/L) and 1,25-dihydroxycholecalciferol was greater than 240 pmol/L (or greater than 100 pg/mL, normal 20 to 100). Following supportive care, her appetite, constipation and growth rate improved, and serum calcium was normal at 15 weeks. It was thought that the infants immediate physical condition was due to vitamin D intoxication. At 21 months, the child had made some improvements in physical growth and was developmentally age-appropriate with only minimal delays (Chan et al, 2006).

B)

1) Few cases of acute vitamin D toxicity have been described. A family of 3 developed hypercalcemia after ingesting a meal cooked with an oil containing 5 million International Units of vitamin D3/mL. Plasma vitamin D levels were elevated in the 2 adults 6 months after the overdose (Down et al, 1979).
2) Six members of a family became ill after consuming a meal presumably contaminated with vitamin D. Hypercalcemia and elevated vitamin D serum levels were present (Thomson & Johnson, 1986).

Range Of Toxicity

Summary

A)

B)

C)

D)

Therapeutic Dose

7.2.1)

A) SUMMARY

1) RECOMMENDED DIETARY ALLOWANCE: ADULT: 19 to 70 years of age or Pregnant/Lactating women: 600 International Units/day; ELDERLY: Greater than 70 years: 800 International Units/day. No dosing adjustment is required based on gender (Office of Dietary Supplements, National Institutes of Health, 2011).
2) CLINICAL PRACTICE GUIDELINES: Doses of 1000 to 2000 International Units of vitamin D3 have been recommended by the Endocrine Society to raise a low 25-hydroxyvitamin D level to at least 30 ng/mL (Holick et al,null). However, other clinicians do not support prescribing vitamin D supplementation beyond the recommended daily needs to prevent cardiovascular disease or improve overall health. The Institute of Medicine currently supports a daily intake of 600 International Units/day for individuals 1 to 70 years of age and 800 International Units/day for individuals older than 70 years (Shapses & Manson, 2011; O'Keefe et al, 2011).
3) TOLERABLE UPPER INTAKE LEVELS: ADULT: Greater or equal to 9 years of age: 4000 International Units/day (Office of Dietary Supplements, National Institutes of Health, 2011)

B) SPECIFIC SUBSTANCE

1) CALCIPOTRIENE/BETAMETHASONE

a) USUAL DOSE: Apply to affected area(s) topically once daily for up to 4 weeks. Discontinue use once control is achieved in the treatment of plaque psoriasis (Prod Info ENSTILAR(R) topical foam, 2015).
b) MAXIMUM DOSE: 60 g every 4 days (Prod Info ENSTILAR(R) topical foam, 2015)

2) CALCITRIOL CAPSULES AND ORAL SOLUTION

a) ADULT and ADOLESCENT: INITIAL DOSE: ORAL: 0.25 mcg daily, may be increased in increments of 0.25 mcg at 4 to 8 week intervals as necessary (Prod Info calcitriol oral solution, 2005).

3) CALCITRIOL INJECTION

a) INITIAL DOSE: 1 mcg (0.0 mcg/kg) to 2 mcg administered 3 times weeks. Doses as small as 0.5 mcg and a large as 4 mcg 3 times weeks have been used as an initial dose depending on the degree of hypocalcemia and/or secondary hyperparathyroidism (Prod Info CALCIJEX(R) injection, 2004).

4) DIHYDROTACHYSTEROL CAPSULES, TABLETS, ORAL SOLUTIONS

a) TABLETS or ORAL SOLUTION: Individualize dose to establish serum calcium of 9 to 10 mg/100 mL. DOSAGE GUIDE: INITIAL 0.8 to 2.4 mg orally daily for several days. MAINTENANCE: 0.2 to 1 mg orally daily; average dose 0.6 mg daily (Prod Info DHT(TM), 1994).
b) CAPSULES: Individualize dose to establish normal serum calcium. INITIAL: 0.75 to 2.5 mg orally daily for several days. MAINTENANCE: 0.25 to 1.75 mg orally weekly depending on serum calcium level (Prod Info HYTAKEROL(R) oral capsules, 1999).

5) ERGOCALCIFEROL CAPSULES

a) GENERAL: Treatment is individualized. Patients should be closely monitored because the range between therapeutic and toxic doses is narrow. Blood calcium and phosphorus levels should be obtained every 2 weeks or more frequently, if needed (Prod Info DRISDOL(R) oral capsules, 2007).
b) VITAMIN D RESISTANT RICKETS: ORAL: 12,000 to 150,000 International Units daily (Prod Info DRISDOL(R) oral capsules, 2007).
c) HYPOPARATHYROIDISM: ORAL: 50,000 to 200,000 International Units daily concomitantly with calcium lactate 4 g, 6 times per day (Prod Info DRISDOL(R) oral capsules, 2007).

7.2.2)

A) RECOMMENDED DIETARY ALLOWANCE

1) 0 to 12 months: 400 International Units/day (Office of Dietary Supplements, National Institutes of Health, 2011)
2) 1 to 18 years: 600 International Units/day (Office of Dietary Supplements, National Institutes of Health, 2011)

B) GENERAL

1) ERGOCALCIFEROL OR CHOLECALCIFEROL

a) CYSTIC FIBROSIS - VITAMIN D DEFICIENCY (25-OH-D level less than 75 nanomoles (nmol/L) (Hall et al, 2010):

1) 0 to 12 months of age: 8000 units orally per week
2) 1 to 5 years of age: 12,000 units orally per week
3) 5 years of age and older: 50,000 units per week

1) If 25-OH-D level is greater than 75 nmol/L: Continue dose or adjust dose to keep level less than 200 nmol/L. If patients do not respond adequately and compliance has been confirmed, increase dose as follows and reassess at 12 weeks (Hall et al, 2010):

1) 1 to 5 years of age: 12,000 units orally biweekly
2) 5 years of age and older: 50,000 units biweekly

a) NOTE: Vitamin D3 (cholecalciferol) may be preferred over vitamin D2 (ergocalciferol) in this population (Hall et al, 2010).

b) HIV INFECTED CHILDREN WITH VITAMIN D DEFICIENCY (25-OH-D level less than 75 nanomoles (nmol/L): 3 YEARS OF AGE AND OLDER: 11,200 units orally per week. In a randomized, controlled trial of HIV-infected children with vitamin D deficiency receiving supplementation with 11,200 units/week of vitamin D (equivalent to 1600 units/day) for 6 months, 67% achieved sufficiency (25-OH-D levesof 75 nmol/L or greater). For children receiving 5600 units/week (equivalent to 800 units/day) only 39% achieved sufficiency. Man increases in serum 25-OH-D levels from baseline were 49 +/- 6.5 nmol/L and 27 +/- 6.5 nmol/L for the 1600 units/day and 800 units/day groups, respectively. Achieving vitamin D sufficiency was not associated with an increase in CD4 percent or CD4 cell count (Kakalia et al, 2011).
c) VITAMIN D DEFICIENT RICKETS: 2000 to 10,000 units/day orally for 4 to 8 weeks, or Stosstherapy regimen of 600,000 units orally of ergocalciferol or cholecalciferol in 6 divided doses in a single day (10,000 units/dose every 2 hours). Give in conjunction with elemental calcium 500 to 1000 mg/day orally once daily until serum calcium normalizes. For patients on Stosstherapy regimen, begin a maintenance dose of vitamin D 400 units/day orally after 12 weeks (Bellazzini & Howes, 2005; Umpaichitra et al, 2001).

2) CALCIPOTRIENE/BETAMETHASONE

a) Safety and effectiveness have not been established in pediatric patients (Prod Info ENSTILAR(R) topical foam, 2015).

Minimum Lethal Exposure

A)

1) CASE REPORT: A 43-year-old man receiving 130 mg of vitamin D3 over 4 weeks (5.2 million units) (approximately 185,000 units/day) was exposed extensively to sunlight 2 weeks later and developed an acute hypercalcemic crisis. He died 5 weeks later of cardiac failure (Laubenthal et al, 1975).

B)

1) Lethal dose of vitamin D2 in dogs is said to be 13 mg/kg (530,000 International Units/kg) (HSDB, 2001).
2) Acute ingestion of as little as 10 mg/kg (400,000 International Units/kg) (1000 times the human RDA/kg) of vitamin D3 was lethal in dogs (Gunther et al, 1988).
3) In experimental studies in dogs, the minimum lethal dose given as a single large dose was 4 to 5 mg/kg orally, 5 mg/kg intramuscularly, 5 mg/kg intravenously, and 10 mg/kg intraperitoneally (Schettler, 1950).

Maximum Tolerated Exposure

A)

1) A specific toxic dose has not been established and the literature varies widely. The current "no observed adverse effect level" or tolerable upper intake dose was conservatively set at 2000 International Units/day. Toxicity has been reported after Vitamin D intake of 50,000 to 150,000 International Units daily for prolonged periods (Ginsburg, 2011).
2) CLINICAL PRACTICE GUIDELINES: Doses of 1000 to 2000 International Units of vitamin D3 daily have been recommended by the Endocrine Society to raise a low 25-hydroxyvitamin D level to at least 30 ng/mL (Holick et al,null). However, other clinicians do not support prescribing vitamin D supplementation beyond the recommended daily needs to prevent cardiovascular disease or improve overall health. The Institute of Medicine currently supports a daily intake of 600 International Units/day for individuals 1 to 70 years of age and 800 International Units/day for individuals older than 70 years (Shapses & Manson, 2011; O'Keefe et al, 2011).
3) TOLERABLE UPPER INTAKE LEVELS: PEDIATRIC: 0 to 6 months: 1000 International Units/day; 7 to 12 months: 1500 International Units/day; 1 to 3 years of age: 2500 International Units/day; 4 to 8 years of age: 3000 International Units/day; ADULT: Greater or equal to 9 years of age: 4000 International Units/day (Office of Dietary Supplements, National Institutes of Health, 2011).
4) Individual variation may occur. However, based on reports of vitamin D toxicity evidence suggests that hypercalcemia occurs at serum 25-hydroxyvitamin D [25(OH)D] concentrations over 200 nmol/L, this would equate to an estimated daily intake of equal to or greater than 1000 mcg (40,000 International Units) (Vieth, 1999).
5) The following information is for vitamin D in general (Brin M, 1976):

a) Chronic ingestion of vitamin D in excess of 1600 units may cause toxicity.
b) Daily ingestion in excess of 75,000 units/day in adults will produce the toxic symptoms associated with hypervitaminosis D.
c) Decreased renal function may prevent excretion thereby resulting in elevated serum levels and enhance the possibility of toxicity.

6) INFANT: Daily ingestion of 2000 to 6300 units/day may inhibit the growth of a normal child, while as little as 1000 units/day can produce the infantile hypercalcemia syndrome in hypersensitive infants (Brin M, 1976).

B)

1) ADULT

a) A 42-year-old man presented with a serum 25-hydroxyvitamin D concentration of 487.3 ng/mL (normal range: 8.9 to 46.7) and hypercalcemia (15.0 mg/dL) following chronic use of a vitamin D3 supplement. Three different lot numbers of the supplement were analyzed by HPLC and found to have a much higher concentration of vitamin D3 than listed by the manufacturer. The patient had been receiving 156,000 to 2,604,000 International Units of vitamin D3 daily (78 to 1302 times the recommended safe upper limit of 2000 International Units/day) (Koutkia et al, 2001).
b) A 70-year-old woman ingested 50,000 International Units of Vitamin D2 daily for 78 days due to a dispensing error and developed hypercalcemia and acute renal injury. She was admitted with confusion, slurred speech and gait disturbances. An initial 25-hydroxyvitamin D level was 194 ng/mL. Treatment included IV hydration and pamidronate. The patient improved within 4 days and was discharged to home (Jacobsen et al, 2011).
c) A 58-year-old man was admitted obtunded with a serum calcium of 15 mg/dL after ingesting a dietary supplement for approximately 2 months that contained 186,400 International Units (instead of 1600 IU) per capsule of vitamin D3 and the bottle was mislabelled to suggest a recommended dose of 10 capsules/day (estimated dose consumed was 1,864,000 International Units (46,600 mcg) of vitamin D3 daily for 2 months). At presentation, the patient had a 25 hydroxyvitamin D (25(OH)D) level of 1220 ng/mL (normal: 30 to 80 ng/mL). His calcium level decreased with supportive care and eventually normalized once the 25(OH)D level fell below 400 ng/mL. The 25(OH)D level did not normalize completely until 13 months after exposure. No permanent sequelae occurred (Araki et al, 2011).
d) In a similar case, a 40 year-old-man became hypercalcemic after ingesting a dietary supplement that contained 970,000 International Units (approximately 1000 times more than the label reported) of vitamin D3. The patient was treated with IV hydration and calcium levels normalized over one month once the 25(OH)D level fell below 400 ng/mL. It took approximately 10 months for the 25(OH)D level to normalize (Araki et al, 2011).
e) A 53-year-old man with a history of diabetes and non-dialysis chronic renal failure developed hypercalcemia and acute renal failure associated with a compounding error resulting in vitamin D intoxication. Symptoms included pruritus, muscle weakness, decreased appetite and weight loss. Laboratory studies revealed an elevated calcium (13.4 mg/dL, range 8.4 to 10.4) and creatinine (4.67 mg/dL, range 0.6 to 1.2). An ultrasound showed a renal calculi and the patient underwent ureterolithotripsy. Despite supportive therapy and ruling out other conditions, hypercalcemia persisted. An initial vitamin D (25 hydroxyvitamin D (25(OH)D) level was 226 ng/mL (range, 30 to 100). Upon analysis the capsules were found to contain 4,000,000 International Units instead of 2,000 International Units; an estimated 40-fold higher dose than recommended (Marins et al, 2014).
f) LACK OF EFFECT

1) ADULT: A 42-year-old woman with vitamin D deficiency (serum 25-hydroxyvitamin D 12.5 ng/mL) developed a high serum Vitamin D level (serum 25-hydroxyvitamin D level of 746 ng/mL) following an inadvertent medication error (ie, took 60,000 IU of vitamin D3 once weekly for 4 months instead of 6 weeks); however, she developed no symptoms and her serum calcium level remained normal. Magnesium and phosphate levels also remained normal (Chakraborty et al, 2015).
2) ELDERLY PATIENTS: Two elderly patients (a 90-year-old man and a 95-year-old woman) inadvertently received 2,000,000 International Units of vitamin D3 from a concentrated solution (40 mL vitamin D3 aquosum FNA 50,000 International Units/mL) instead of a single dose of 100,000 International Units (or 2 mL vitamin D3). The error was noted a short time after ingestion and biochemical and clinical monitoring was started. Peak blood 25(OH) D3 concentrations (527 and 422 nmol/L, respectively; normal, 50 to 200 nmol/L) occurred on day 8. Calcium levels increased only slightly up to 2.68 and 2.73 mmol/L, respectively (normal, 2.2 to 2.65 mmol/L) in both patients. The patients were monitored for up to 3 months after exposure and neither patient developed any clinical effects (van den Ouweland et al, 2014).

2) PEDIATRIC

a) LACK OF EFFECT: A 3-month-old breastfed infant was receiving vitamin D supplements and inadvertently received a 30-fold (12,000 International Units daily) overdose of vitamin D for approximately 20 days after receiving a new formulation. The original formulation was 400 International Units/mL and the new formulation was 400 International Units/drop (1 mL contains 30 drops and the mother had continued to administer 1 mL/day with the new formulation). At the time of presentation, the infant was alert and doing well. Physical exam was essentially normal. Serum 25-hydroxyvitamin D [25(OH)D] was 422 ng/mL (reference range: 30 to 100 ng/mL); 1-25-dihydroxyvitamin D was normal and the parathyroid hormone was decreased (less than 3 pg/mL; range: 15 to 65 pg/mL). Laboratory testing of the product was consistent with the concentration listed on the bottle (approximately 400 International Units/drop). Infant and maternal vitamin D supplementation were stopped. The infant was closely monitored for the next 6 months and laboratory levels gradually declined with no increase in calcium or phosphorus concentrations (Rajakumar et al, 2013).
b) In a similar case, a healthy 2-month-old female had received 12,000 International Units/day of vitamin D (approximately 30 times the intended daily dose) for approximately 1 month. She was admitted due to a recent history of poor feeding and decreased activity. The only findings on physical exam were a slight decrease in muscle tone and a decreased sucking reflex. Her 25-hydroxyvitamin D level was measured at 750 ng/mL (normal, 25 to 80 ng/mL) and her parathyroid hormone (PTH) level was less than 3 pg/mL (consistent with expected PTH suppression). The patient was admitted and treated with normal saline, calcitonin, pamidronate and methylprednisolone and her calcium levels gradually declined from an initial level on admission of 19.1 mg/dL (normal, 8.8 to 11.3 mg/dL) to 9.6 mg/dL. She was discharged to home one week after admission in her normal state of health (Smollin & Srisansanee, 2014).
c) ADULTERATED DIETARY FISH SUPPLEMENT: Seven children (between the ages of 0.7 and 4.2 years) developed vitamin D intoxication after being given a fish oil supplement that contained a high level of vitamin D3 due to a manufacturing error. The supplement was analyzed and found to contain 3.6 mg (144,000 International Units) per gram of fish oil (each 5 mL of fish oil was calculated to contain approximately 20 mg (800,000 International Units) of vitamin D3). The estimated daily doses that these children received varied between 266,000 and 800,000 International Units or 177 to 320 times the recommended tolerable upper limits for infants and children. Each child recovered with IV hydration, furosemide and pamidronate infusions. Two patients initially developed evidence of nephrocalcinosis; however repeat imaging at 6 and 12 months were normal. At 1-year follow-up, no permanent sequelae occurred in any child (Kara et al, 2014).
d) A 2-year-old boy developed constipation, mild hypertension, abdominal pain and hypercalcemia after receiving 600,000 International Units of vitamin D daily for 4 days. He recovered with supportive care (Barrueto et al, 2005).
e) Severe vitamin D overdose, with sluggishness, drowsiness, hypotonia, constipation, decreasing weight, polyuria (6-11 mL/kg/h) and calciuria (33.8 and 23 mg/kg/d) was reported in two 6-month-old twins after their mother gave them 1 mL of a multivitamin product twice daily and 1 mL of a vitamin D solution for 17 days (total dose approximately 1.5 million units per child). In both infants, ultrasonography revealed nephrocalcinosis. On admission, the following total calcium, ionized calcium and phosphate levels were obtained, respectively: 3.8 and 3.9 mmol/L, 1.7 and 1.8 mmol/L, phosphate 0.8 and 1.5 mmol/L; parathyroid hormone levels were less than 0.1 pmol/L (Pundzien et al, 2001).
f) A 6-month-old developed anorexia, vomiting, polydipsia, polyuria, constipation, lethargy, hypertension, and hypercalcemia after receiving 300,000 International Units of vitamin D orally daily for 10 days (Gurkan et al, 2004).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) NORMAL TOTAL SERUM CALCIUM LEVELS - 8.8 to 10.3 milligrams/deciliter (4.4 to 5.1 milliequivalents/liter)

2) SPECIFIC SUBSTANCE

a) Normal vitamin D levels (Ellenhorn & Barceloux, 1988)
b) Vitamin D - 10 to 50 nanograms/milliliter
c) 25-OHD3 - 10 to 50 nanograms/milliliter
d) CALCITRIOL - 10 to 20 picograms/milliliter

3) CASE REPORTS

a) A 7-month-old male had a vitamin D serum concentration of 161.2 nanograms/milliliter (419 nanomoles/liter) measured by high performance liquid chromatography (HPLC) following chronic over-supplementation (7,680,000 international units over 89 days).
b) Serum concentration of 25-hydroxyvitamin D was 410.7 nanograms/milliliter (1025 nanomoles/liter) by a radiocompetitive test. Serum and urine calcium concentrations were 7.5 milliequivalents/liter (3.75 millimoles/liter) (Lukaszkiewicz et al, 1987).
c) A 42-year-old male presented with a serum 25-hydroxyvitamin D concentration of 487.3 ng/mL (normal range: 8.9 to 46.7) and hypercalcemia (15.0 mg/dL) following chronic use of a vitamin D3 supplement. Three different lot numbers of the supplement were analyzed by HPLC and found to have a much higher concentration of vitamin D3 than listed by the manufacturer. The patient had been receiving 156,000 to 2,604,000 IU of vitamin D3 daily (78 to 1302 times the recommended safe upper limit of 2000 IU/day) (Koutkia et al, 2001).

4) CASE SERIES - A series of 4 patients, who were taking 1000 mg of supplemental calcium and a multivitamin preparation daily (up to 1200 international units of vitamin D) as well as other dietary supplements, developed hypercalciuria and elevated serum levels of 25-hydroxyvitamin D. The mean serum 25-hydroxyvitamin D level of the 4 patients was 177 +/- 41 nmol/L (normal range 22 to 125 nmol/L). The 25-hydroxyvitamin D levels normalized following discontinuation of all dietary supplements (Adams & Lee, 1997). Further investigation of the dietary supplements ingested found that some of the supplements contained as much as 3,600 international units of vitamin D(3) per daily dosage.

Toxicity Information

7.7.1)

A) References: Lewis, 1992 RTECS, 1994)

1) LD50- (ORAL)MOUSE:

a) 23,700 mcg/kg

2) LD50- (ORAL)RAT:

a) 10 mg/kg
b) 56 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) The daily requirement of vitamin D in adults is small and normally met in part by exposure to sunlight (Fraser, 1983). There are increased requirements during infancy and during pregnancy and lactation. Approximately 100 units is considered adequate in adults.
2) Calciferol takes slightly longer to act than dihydrotachysterol and its effects last longer. Due to its cumulative action, dosing should be carefully controlled.

Physicochemical

Physical Characteristics

A)

B)

Molecular Weight

A)

B)

Animal Toxicology

Clinical Effects

11.1.3)

A) Acute ingestion of a cholecalciferol-containing rodenticide bait resulted in decreased activity 30 hours postingestion, followed by lethargy, weakness, and anorexia 48 hours postingestion.

1) Within 60 to 70 hours dogs were recumbent, with hematemesis and bloody diarrhea. Shock occurred prior to death. Serum calcium levels were elevated at 24 hours and were still rising at 70 hours when death ensued.
2) Necropsy revealed diffuse gastric hemorrhage (Gunther et al, 1988).

B) Other clinical signs include dehydration, polyuria, polydipsia, and EKG findings of prolonged P-R interval, shortened Q-T interval, and ventricular arrythmias.

1) Neurologic signs that may occur include muscle twitching, seizures, depression, and coma (El Bahri, 1990). Dogs may be febrile and may have abnormal pulmonary signs (Talcott et al, 1990).

11.1.5)

A) Common signs are depression, decreased appetite, weight loss, limb stiffness, painful flexor tendons, cardiac murmurs, tachycardia, polyuria, and hyposthenuria (Harrington & Page, 1983).

11.1.6)

A) Clinical signs resulting from hypercalcemia include azotemia, twitching, nausea, abdominal pain, tachypnea, hematemesis, melena, dehydration, and EKG changes (Anon, 1989).
B) In 3 cats who ingested a cholecalciferol-containing rodenticide, lethargy, vomiting, polydipsia, and anorexia were the only clinical signs noted, despite elevated serum calcium levels.

1) All recovered with fluid therapy alone or in combination with furosemide. The benign outcome compared to experience with poisoned dogs was presumed to be related to a lesser amount ingested (Moore et al, 1988).

C) A 2.5 kg cat ingested an unknown amount of cholecalciferol rodenticide. Vomiting started in less than 24 hours. Biochemistry results showed hypercalcemia, hyperkalemia and acidosis (pH >7.18).

1) Treatment consisted of IV normal saline, 1 mg/kg furosemide, 3 mcg/kg/min dopamine, 4 International Units/kilogram calcitonin every 12 hours. Furosemide and dopamine were later discontinued.
2) Acidosis worsened; sodium bicarbonate was given and the acidosis improved. The cat continued to fail, developing tachycardia, hypothermia, and depression. The animal died 36-48 hours after ingestion (Peterson et al, 1991).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Sample vomitus, blood, urine, and feces for analysis.

2) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 3 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

2) RUMINANTS/HORSES/SWINE

a) EMESIS

1) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).

b) ACTIVATED CHARCOAL

1) Adult horses: administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube.
2) Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
3) Adult cattle: administer 2 to 9 grams/ kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube.
4) Sheep may be given 0.5 kilogram charcoal in slurry.

c) CATHARTIC

1) Administer an oral cathartic:

a) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
b) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram) or
c) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).

2) Give these solutions via stomach tube and monitor for aspiration.

11.2.5)

A) DOGS/CATS

1) MAINTAIN VITAL FUNCTIONS - as necessary.
2) FLUID THERAPY

a) Take a baseline blood sample and obtain chemistries (including calcium, creatinine, and BUN).
b) Begin fluid therapy with 0.9% NaCl at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive, dehydrated, or azotemic patients, at high doses (up to shock dose 60 milliliters/kilogram/hour).
c) Monitor for urine production and pulmonary edema. Add potassium chloride to fluids as necessary to prevent potassium depletion.

3) SEIZURES

a) DIAZEPAM - The dose of diazepam for DOGS & CATS is 0.5 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes.
b) PHENOBARBITAL - Pentobarbital may be used as adjunct treatment at 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously.
c) REFRACTORY SEIZURES - Consider anaesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.
d) FUROSEMIDE - Dose at 2 to 4 milligrams/kilogram every 12 hours, intravenously or subcutaneously (Dougherty et al, 1990).
e) CIMETIDINE - Cimetidine may be given to help prevent gastric mucosal irritation and damage, dosed at 10 milligrams/kilogram intravenously every 8 hours. If also administering gastric protectants, wait 2 hours between cimetidine and protectant doses.
f) PREDNISOLONE - Prednisolone inhibits intestinal absorption of Vitamin D. May be given parenterally or per os at 2 milligrams/kilogram every 12 hours. Corticosteroids may be more useful if the serum calcium level is less than 16 milligrams/deciliter (El Bahri, 1990).
g) ANTIBIOTICS are indicated in the presence of gastrointestinal mucosal damage.
h) CALCITONIN - Salmon calcitonin is indicated in initial treatment of severely poisoned cases; cases in which hypercalcemia is profound; and cases in which the calcium level multiplied by the phosphorus level is greater than 60 milligrams/deciliter (adults) or up to 104 milligrams/deciliter (neonates) (Dougherty et al, 1990).

1) Calcitonin administration will rapidly and effectively decrease blood calcium levels within approximately 6 hours (El Bahri, 1990).
2) DOSE - Experimental evidence to determine dose in animals is lacking; human dose is 4 to 8 units/kilogram every 12 hours.
3) Beasley et al (1989) recommend giving 4 to 6 units/kilogram subcutaneously every 2 to 3 hours initially until blood calcium levels stabilize, then continue doses as needed.
4) CASE REPORT - One report successfully used 4 to 7 units/kilogram subcutaneously every 6 to 8 hours in a puppy.

a) The puppy was discharged to the owner with instructions to give 5.5 units/kilogram calcitonin subcutaneously every 8 hours, and duration of calcitonin therapy was 27 days (Dougherty et al, 1990).

5) CASE REPORT - An adult dog was treated with 5 units/kilogram every 12 hours subcutaneously for 7 days, then calcitonin was discontinued due to adverse effects (anorexia).

a) However, the calcium level rose again 2 days later and calcitonin was reinstated for 5 more days (Fooshee & Forrester, 1990).

6) ADVERSE EFFECTS of calcitonin reported in dogs include anorexia and gastrointestinal irritation (Fooshee & Forrester, 1990); however, in another case calcitonin seemed to be protective against irritation and vomiting (Dougherty et al, 1990).
7) MONITORING - While calcitonin is being administered in hospital, check blood calcium levels every 24 to 48 hours at the end of a dosing period. Calcitonin given at home: check serum calcium 3 times during first week, twice during second, once in the third week (Dougherty et al, 1990).

i) DIET - Maintain the animal on a low-calcium diet for several months (Gunther et al, 1988). A commercial diet used in renal insufficiency works well. Also, avoid exposure of the animal to sunlight.
j) URINARY ACIDIFICATION may speed excretion of cholecalciferol derivatives; used in treatment of humans. Ascorbic acid or other acidifier may be used if necessary to keep the urine pH below 5.5.
k) Treatment usually needs to be continued for 2 to 4 weeks after ingestion. Patients may be sent home with owner-administered calcitonin, furosemide, or prednisolone.
l) FOLLOW-UP - Blood calcium levels must be checked, even in lightly affected animals, at 12, 24, and 48 hours post-ingestion, and at 24, 48, and 72 hours after the cessation of treatment.
m) CHOLESTYRAMINE was effective in treating vitamin D intoxication in the rat (Queen & Bell, 1976).

B) RUMINANTS/HORSES/SWINE

1) MAINTAIN VITAL FUNCTIONS

a) Secure airway, supply oxygen and begin supportive fluid therapy if necessary.

2) FLUIDS

a) HORSE - Administer electrolyte and fluid therapy as needed. MAINTENANCE DOSE of intravenous isotonic fluids: 10 to 20 milliliters/ kilogram per day.

1) HIGH DOSE FOR SHOCK is 20 to 45 milliliters/kilogram/hour. Monitor for packed cell volume, adequate urine output and pulmonary edema. Goal is to maintain a urinary flow of 0.1 milliliters/kilogram/minute (2.4 liters/ hour for an 880 pound horse).

b) CATTLE - Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 milliliters/kilogram/day. Dose for rehydration: 50 to 100 milliliters/kilogram given over 4 to 6 hours.

3) FUROSEMIDE

a) HORSES - 1 milligram/kilogram intravenously every 12 hours.
b) CATTLE - 2.2 to 4.4 milligrams/kilogram intravenously every 12 hours.

4) CORTICOSTEROIDS

a) Corticosteroids may be administered for both initial and prolonged treatment to decrease cholecalciferol absorption.

5) ANTIBIOTICS

a) ANTIBIOTICS are indicated in the presence of gastrointestinal mucosal damage.

6) CALCITONIN -

a) Salmon calcitonin is indicated in initial treatment of severely poisoned cases; cases in which hypercalcemia is profound. Calcitonin administration will rapidly and effectively decrease blood calcium levels within approximately 6 hours (El Bahri, 1990).

1) DOSE - Experimental evidence to determine dose in animals is lacking; human dose is 4 to 8 units/kilogram every 12 hours.

b) Beasley et al (1989) recommend giving 4 to 6 units/kilogram subcutaneously every 2 to 3 hours initially until blood calcium levels stabilize, then continue doses as needed. Dosing may need to be continued for several days to weeks.
c) Adverse effects of calcitonin reported in dogs include anorexia and gastrointestinal irritation (Fooshee & Forrester, 1990); however, in another case, calcitonin seemed to be protective against irritation and vomiting (Dougherty et al, 1990).
d) MONITORING - While calcitonin is being administered in hospital, check blood calcium levels every 24 to 48 hours at the end of a dosing period.

1) Calcitonin given at home: check serum calcium 3 times during first week, twice during second, once in the third week (Dougherty et al, 1990).

7) DIET

a) Maintain the animal on a low-calcium diet for several months (Gunther et al, 1988). Also, avoid exposure of the animal to sunlight.

8) FOLLOW-UP

a) Blood calcium levels must be checked, even in lightly affected animals, at 12, 24, and 48 hours post-ingestion, and at 24, 48, and 72 hours after the cessation of treatment.

Range Of Toxicity

11.3.1)

A) HORSE

1) The recommended daily allowance of vitamin D in horses is 6.6 International Units/kilogram.

11.3.2)

A) RODENT

1) Product information on cholecalciferol-containing rodenticides indicates an LD50 of 2.6 to 56 g/kilogram of bait (Prod Info, 1985).

B) HORSE

1) CASE REPORT - Two horses receiving cholecalciferol 12,000 to 13,000 International Units/kilogram/day for 30 days developed vitamin D intoxication; one horse died, while the other survived (Harrington & Page, 1983).
2) CHOLECALCIFEROL is more toxic than ergocalciferol in horses and swine (Harrington & Page, 1983; Long, 1984).

C) SWINE

1) Acute intoxication was reported in 35 pigs 1 to 2 days after consumption of feed containing large amounts of vitamin D (473,000 International Units/kilogram) (Long, 1984).

D) DOG

1) All of 4 dogs given 10 to 20 mg/kg of cholecalciferol (equivalent to 13.5 to 27 g/kg of bait) died (Gunther et al, 1988).

a) This compound has been listed by the manufacturer as having an LD50 of 88 milligrams/kilogram in dogs. Deaths have occurred with as little as 4.5 milligrams/kilogram (Talcott et al, 1991).
b) Toxicities have occurred at doses of 0.5 to 3 milligrams/kilogram (Beasley et al, 1989). Cats are even more sensitive (El Bahri, 1990).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Sample vomitus, blood, urine, and feces for analysis.

2) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 3 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary tracheal intubation.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

2) RUMINANTS/HORSES/SWINE

a) EMESIS

1) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).

b) ACTIVATED CHARCOAL

1) Adult horses: administer 0.5 to 1 kilogram of activated charcoal in up to 1 gallon warm water via nasogastric tube.
2) Neonates: administer 250 grams (one-half pound) activated charcoal in up to 2 quarts water.
3) Adult cattle: administer 2 to 9 grams/ kilogram of activated charcoal in a slurry of 1 gram charcoal/3 to 5 milliliters warm water via stomach tube.
4) Sheep may be given 0.5 kilogram charcoal in slurry.

c) CATHARTIC

1) Administer an oral cathartic:

a) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon) or
b) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram) or
c) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os).

2) Give these solutions via stomach tube and monitor for aspiration.

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Ongoing treatment is symptomatic and supportive.

11.4.3.6) OTHER

A) OTHER

1) GENERAL

a) PRE-MORTEM LABORATORY -

1) CHOLECALCIFEROL LEVELS - The best metabolite to measure in animals seems to be 25-hydroxycholecalciferol (25-OHD3).

a) Levels measured in acutely ill dogs range from 300 to over 600 nanograms/milliliter, while therapeutic or normal levels in humans, dogs, and cattle are around 30 to 40 nanograms/milliliter.
b) Normal levels for horses are around 2 nanograms/milliliter; sheep and goats are around 10 to 20 nanograms/milliliter (Scheftel et al, 1991).

2) MONITOR LEVELS - Exposed animals should receive a full blood chemistry including creatinine, BUN, and electrolytes. Blood calcium levels must be checked, even in lightly affected animals, at 12, 24, and 48 hours post-ingestion, and 2 weeks after the cessation of treatment.

b) POSTMORTEM FINDINGS

1) Postmortem findings include diffuse metastatic mineralization throughout the body and severe pulmonary congestion (Talcott et al, 1991).

Kinetics

11.5.1)

A) LACK OF INFORMATION

1) There was no specific information on absorption at the time of this review.

11.5.4)

A) DOG

1) Half-life of serum 25-OHD3 in dogs has been measured at 10.67 days (Dougherty et al, 1990).

Sources

A)

1) Cholecalciferol rodenticides are available containing 0.075%, under tradenames Rampage(R), Quintox(R), Ortho Mouse B Gone(R), and Ortho Rat B Gone(R).

Other

A)

1) GENERAL

a) CALCULATIONS -

1) One 30-gram pouch of rodenticide (0.075% cholecalciferol) is equivalent to 900,000 units cholecalciferol.
2) One unit of vitamin D equals the biologic activity of 25 nanograms cholecalciferol. The daily vitamin D requirement for a dog is 8 to 22 units/kilogram/day.
3) Therefore an average-sized dog who eats one packet of rodenticide has taken in approximately 10,000 times the therapeutic dose of vitamin D (Dougherty et al, 1990).

b) DIFFERENTIAL DIAGNOSES

1) Other causes of depression, polyuria, and polydipsia include diabetes mellitus and insipidus, hyperadrenocorticism, renal disease, pyometra, and psychogenic polydipsia.
2) Differentials for hypercalcemia include malignant lymphoma, multiple myeloma, metastatic bone tumors, and parathyroid tumors (El Bahri, 1990).

References

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FeedBack

VITAMIN D

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

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Neurologic

Gastrointestinal

Hepatic

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Hematologic

Musculoskeletal

Endocrine

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Carcinogenicity

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Monitoring Parameters Levels

Radiographic Studies

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Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

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Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Physical Characteristics

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

Sources

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General Bibliography