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VITAMINS-MULTIPLE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This topic is limited to multiple vitamins and mineral products without iron (See Multivitamins-Iron as appropriate).

Specific Substances

    1) MULTIVITAMINS (WITHOUT IRON)
    2) MULTIPLE VITAMINS

Available Forms Sources

    A) USES
    1) Multivitamin and mineral supplements contain most of the vitamins and minerals associated with the Recommended Dietary Allowances (RDAs). In general, vitamin supplements contain similar vitamins and minerals, but are formulated for specific populations (ie, children, adults, men, women, pregnant women and older adults). However, no standard or regulatory definition is required to manufacturer a multivitamin.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USE: Multivitamin and mineral supplements contain most of the vitamins and minerals associated with the Recommended Dietary Allowances (RDAs). In general, vitamin supplements contain similar vitamins and minerals, but are formulated for specific populations (ie, children, adults, men, women, pregnant women and older adults). However, no standard or regulatory definition is required to manufacturer a multivitamin. This topic is limited to multiple vitamins and mineral products without iron (See Multivitamins-Iron as appropriate).
    B) TOXICOLOGY: The margin of safety for multivitamins is dependent on individual nutrients (eg, iron) and can vary by age group.
    C) EPIDEMIOLOGY: It is estimated that one-third of Americans take supplements. Women are more likely to take multivitamins/supplements than men. Inadvertent exposure is relatively common among children, but severe toxicity is not anticipated in multivitamin products without iron.
    D) WITH POISONING/EXPOSURE
    1) OVERDOSE: Toxicity following acute overdoses with multiple vitamin preparations is unlikely unless a massive amount has been ingested. Individuals may inadvertently exceed the Upper Limit of some vitamins/minerals if they take more than one supplement. Gastrointestinal irritation and diarrhea are the most frequently reported findings after ingestion.
    2) FAT SOLUBLE VITAMINS: Expected signs and symptoms of toxicity would be similar to individual vitamin preparations, especially fat soluble vitamins such as vitamin A and D. Hypercalcemia is characteristic of vitamin D toxicity. Excess vitamin A intake during pregnancy can lead to birth defects in infants. In severe toxicity, coagulopathies may develop in patients with a vitamin K-deficiency or those receiving warfarin following excess vitamin E intake. (SEE appropriate individual topics).
    3) WATER SOLUBLE VITAMINS: Most of the water soluble vitamins (ie, folic acid, thiamine (B1), riboflavin (B2), cyanocobalamin (B12), biotin, pantothenic acid) produce no acute toxic symptoms. Chronic ingestion of megadoses may be a more serious problem. An acute intravenous overdose of vitamin C has resulted in renal failure.
    0.2.4) HEENT
    A) Chronic administration of large doses of niacin has been associated with cystoid maculopathy.
    0.2.7) NEUROLOGIC
    A) Pure sensory axonal neuropathy, with symptoms of paresthesias, numbness, pain, and weakness may occur after chronic ingestion of pyridoxine.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, abdominal pain, and diarrhea are common, especially following ingestion of multiple vitamins with iron (see iron management).
    B) Vitamin C tablets may become lodged in the esophagus when swallowed with minimal fluids.
    0.2.9) HEPATIC
    A) Chronic high-dose niacin use has been associated with both cholestatic and hepatocellular liver injury, particularly with sustained-release preparations.
    0.2.10) GENITOURINARY
    A) Large intravenous doses of vitamin C may precipitate acute renal failure. Riboflavin may cause a bright yellow discoloration of urine.
    0.2.13) HEMATOLOGIC
    A) Vitamin C supplementation may cause hemolytic anemia in premature neonates.
    0.2.14) DERMATOLOGIC
    A) Niacin (vitamin B3) may cause intense cutaneous flushing lasting up to 2 to 3 hours with no other apparent toxicity. Nicotinamide lacks these effects. Topical vitamin E has rarely caused contact dermatitis and erythema multiforme.
    0.2.19) IMMUNOLOGIC
    A) Anaphylactoid reactions occur rarely after intravenous thiamine.
    0.2.20) REPRODUCTIVE
    A) There is a well-established association between some vitamin A congeners and a teratogenic outcome in infants whose mothers were exposed during pregnancy.

Laboratory Monitoring

    A) Routine laboratory studies are usually not indicated.
    B) Obtain iron levels as indicated following a significant exposure with a vitamin product that contains iron (see IRON Management).
    C) Serum calcium and phosphate levels should be monitored closely if vitamin D toxicity is suspected.
    D) Plasma vitamin A levels may be helpful in diagnosis, but are not clinically useful in treatment. Obtain serum aminotransferase levels, bilirubin, INR, and calcium levels in patients with chronic overdose of multivitamins which contain vitamin A.
    E) Plasma levels of the individual vitamins are not clinically useful.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD OR NO TOXIC SYMPTOMS
    1) Toxicity is unlikely following acute ingestion of a multiple vitamin preparation without iron. The majority of pediatric accidental ingestions of multivitamins can be safely managed at home with dilution.
    B) MANAGEMENT OF MODERATE TO SEVERE TOXICITY
    1) If the patient is symptomatic refer to the suspected toxin (ie, iron, vitamin A or D).
    C) DECONTAMINATION
    1) PREHOSPITAL: GI decontamination is NOT necessary in most cases. Dilution should be considered in children able to tolerate fluids.
    2) HOSPITAL: Gastrointestinal decontamination is not necessary in most cases. It should be considered if a potentially toxic dose of iron or iron salts, vitamin A or D has been ingested.
    D) PATIENT DISPOSITION
    1) HOME CRITERIA: An inadvertent ingestion by an asymptomatic child of a multivitamin without iron can be safely managed at home with dilution. Children displaying mild symptoms (ie, nausea, mild abdominal pain) only following a multivitamin ingestion without iron can be monitored at home with a responsible adult. Any progression of GI symptoms or alterations in mental status should be observed in a healthcare facility. Asymptomatic adults who ingest several extra doses or with chronic overuse can be managed 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 may be discharged to home once symptoms have resolved and laboratory studies are within normal limits.
    3) ADMISSION CRITERIA: Children who are symptomatic (eg, vitamin A or D toxicity, iron toxicity) should be admitted for observation and possible 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.
    E) PITFALLS
    1) Acute overdose rarely causes clinical toxicity; avoid over treatment for multivitamin overdose without iron.
    F) DIFFERENTIAL DIAGNOSIS
    1) Vitamin D: Other agents (ie,) or conditions that may cause hypercalcemia (eg, aluminum, antacids (calcium-containing), lithium, thiazide diuretics). Vitamin A: Other conditions causing increased intracranial pressure and papilledema (ie, intracranial tumor, malignant hypertension, optic neuropathy, cerebral venous sinus thrombosis). Other disorders causing elevations of liver enzymes (acetaminophen overdose, viral hepatitis). The differential diagnosis of an acute iron ingestion can be extremely broad and would include any process causing vomiting and abdominal pain. Hemorrhage may or may not be noted initially.

Range Of Toxicity

    A) TOXICITY: Toxicity following acute overdoses of multiple vitamin preparations is unlikely unless the preparation contains significant amounts of iron, vitamin A, or vitamin D. IRON: A potentially toxic oral dose of elemental iron is between 20 and 40 mg/kg. VITAMIN A: Oral ingestions of greater than 300,000 International Units by children have resulted in significant CNS toxicity; acute toxicity in adults is rare. VITAMIN D: Chronic ingestions of vitamin D in excess of 1600 units/day may cause toxicity. Daily ingestions in excess of 2000 units in children or 75,000 units in adults may produce toxic symptoms associated with hypervitaminosis D.

Clinical Effects

Summary Of Exposure

    A) USE: Multivitamin and mineral supplements contain most of the vitamins and minerals associated with the Recommended Dietary Allowances (RDAs). In general, vitamin supplements contain similar vitamins and minerals, but are formulated for specific populations (ie, children, adults, men, women, pregnant women and older adults). However, no standard or regulatory definition is required to manufacturer a multivitamin. This topic is limited to multiple vitamins and mineral products without iron (See Multivitamins-Iron as appropriate).
    B) TOXICOLOGY: The margin of safety for multivitamins is dependent on individual nutrients (eg, iron) and can vary by age group.
    C) EPIDEMIOLOGY: It is estimated that one-third of Americans take supplements. Women are more likely to take multivitamins/supplements than men. Inadvertent exposure is relatively common among children, but severe toxicity is not anticipated in multivitamin products without iron.
    D) WITH POISONING/EXPOSURE
    1) OVERDOSE: Toxicity following acute overdoses with multiple vitamin preparations is unlikely unless a massive amount has been ingested. Individuals may inadvertently exceed the Upper Limit of some vitamins/minerals if they take more than one supplement. Gastrointestinal irritation and diarrhea are the most frequently reported findings after ingestion.
    2) FAT SOLUBLE VITAMINS: Expected signs and symptoms of toxicity would be similar to individual vitamin preparations, especially fat soluble vitamins such as vitamin A and D. Hypercalcemia is characteristic of vitamin D toxicity. Excess vitamin A intake during pregnancy can lead to birth defects in infants. In severe toxicity, coagulopathies may develop in patients with a vitamin K-deficiency or those receiving warfarin following excess vitamin E intake. (SEE appropriate individual topics).
    3) WATER SOLUBLE VITAMINS: Most of the water soluble vitamins (ie, folic acid, thiamine (B1), riboflavin (B2), cyanocobalamin (B12), biotin, pantothenic acid) produce no acute toxic symptoms. Chronic ingestion of megadoses may be a more serious problem. An acute intravenous overdose of vitamin C has resulted in renal failure.

Heent

    3.4.1) SUMMARY
    A) Chronic administration of large doses of niacin has been associated with cystoid maculopathy.
    3.4.2) HEAD
    A) Dental Erosion: Chewable tablets of vitamin C were implicated in causing dental erosion in a patient ingesting 3 tablets/day (Giunta, 1983).
    3.4.3) EYES
    A) Cystoid Maculopathy: Chronic administration of niacin doses of 3 g/day or greater for 1.5 to 4 months resulted in blurred vision, striations, spokes, or radiations around lights in 4 patients and funduscopic findings of cystoid maculopathy in 2 patients (Millay et al, 1988).
    B) Gass (1973) described 3 cases of reversible maculopathy with niacin doses as low as 1.5 g/day. Symptoms resolved 4 to 8 weeks after discontinuation of the drug (Gass, 1973).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Asthma may be aggravated because of histamine release associated with ingestion of nicotinic acid (Alhadeff et al, 1984).

Neurologic

    3.7.1) SUMMARY
    A) Pure sensory axonal neuropathy, with symptoms of paresthesias, numbness, pain, and weakness may occur after chronic ingestion of pyridoxine.
    3.7.2) CLINICAL EFFECTS
    A) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) CHRONIC THERAPY
    1) PYRIDOXINE
    a) Pure sensory axonal neuropathy, with symptoms of numbness, burning, shooting, or tingling pain, clumsiness, and ataxia are alleged to occur after chronic daily ingestion of 75 to 300 mg pyridoxine (Dalton, 1985).
    b) Other neurologic symptoms may include depression, headache, tiredness, and irritability (Dalton, 1985).
    c) Central sensory neuropathy, with ataxia, Romberg's sign, and Lhermitte's symptoms, may also be present and may account for incomplete recovery in some patients (Schaumburg et al, 1983).
    d) Muscle weakness, fasciculations, and diminished reflexes may accompany the sensory changes (Dalton & Dalton, 1987).
    e) Uncontrolled studies allege that pyridoxine neuropathy may occur after daily intake of as little as 75 mg/day (Dalton, 1985), although more common doses in symptomatic patients would be from 500 mg/day (Berger & Schaumburg, 1984) to 2000 mg/day (Waterston & Gilligan, 1987; McLachlan & Brown, 1995).
    f) Sensory neuropathy, including paresthesias and reduced proprioception, occurred in 5 of 8 patients who ingested 600 to 1200 mg pyridoxine/day for years (Ludolph et al, 1993).
    g) Severe ataxia and peripheral sensory neuropathy were reported in 7 adults following chronic ingestion of pyridoxine 2 to 6 g daily for 2 to 40 months.
    h) A woman with a delusional disorder developed severe sensory and mild motor neuropathy after chronic high daily doses (approximately 10 g daily for 5 years) of pyridoxine. Symptoms included paresthesias, stocking-glove distributed sensory loss, the absence of deep tendon reflexes in all extremities and marked ataxia. The patient continued excessive pyridoxine therapy and refused further care (Morra et al, 1993).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, abdominal pain, and diarrhea are common, especially following ingestion of multiple vitamins with iron (see iron management).
    B) Vitamin C tablets may become lodged in the esophagus when swallowed with minimal fluids.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, abdominal pain, and diarrhea are common adverse effects (Mosher, 1970).
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, abdominal pain, and diarrhea are common adverse effects (Mosher, 1970).
    C) PEPTIC ULCER
    1) WITH THERAPEUTIC USE
    a) CHRONIC EXPOSURE: Because of the histamine release and acidity caused by nicotinic acid, patients with peptic ulcer disease may develop worsening symptoms while taking the drug. Thirteen percent of patients chronically taking 3 to 7.5 g of niacin developed ulcers (Mosher, 1970).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, abdominal pain, and diarrhea are common adverse effects (Mosher, 1970).
    E) ULCER OF ESOPHAGUS
    1) WITH THERAPEUTIC USE
    a) Esophageal injury and ulceration have been described after ingestion of vitamin C tablets. The typical setting is a patient with preexisting esophageal motility abnormalities and swallowing tablets with minimal or no concomitant fluids (Bonavina et al, 1987; Kikendall et al, 1986; Walta et al, 1976).

Hepatic

    3.9.1) SUMMARY
    A) Chronic high-dose niacin use has been associated with both cholestatic and hepatocellular liver injury, particularly with sustained-release preparations.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) NIACIN THERAPY
    1) High-dose niacin has been the cause of both cholestatic and hepatocellular liver toxicity (Alhadeff et al, 1984; DiPalma & Ritchie, 1977).
    a) Evidence indicates that sustained-release niacin may be more hepatotoxic than unmodified niacin (Knopp et al, 1985; Christensen et al, 1961; Henkin et al, 1990) and hepatotoxicity may develop with low daily doses (Henkin et al, 1990).
    b) Mullin et al (1989) reported a 44-year-old patient who developed fulminant hepatic failure shortly after switching to sustained-release nicotinic acid from ordinary nicotinic acid of over a year's duration without adverse effects (Mullin et al, 1989).
    c) Henkin et al (1990) reported 3 cases of sustained-release niacin-induced (500 milligrams daily) hepatitis that did not recur when the patients were rechallenged with crystalline niacin (Henkin et al, 1990).
    d) Patients may experience nausea, vomiting, and increased AST, sulfobromophthalein (SBP) retention, and alkaline phosphate. Jaundice, general malaise, anorexia, and cramping may also occur (Rader et al, 1992).
    b) VITAMIN A THERAPY
    1) CHRONIC EXPOSURE: Hepatic toxicity is most frequently associated with excessive long term ingestion of vitamin A. The range of doses associated with hepatotoxicity are daily doses of 15,000 to 1,400,000 IU with a mean daily dose of 120,000 IU (Cheruvattath et al, 2006; Sarles et al, 1990).
    2) Elevated levels of hepatic aminotransferases, alkaline phosphatase, and bilirubin and increased INR are common in chronic vitamin A intoxication (Sarles et al, 1990; Geubel et al, 1991; Minuk et al, 1988; Inkeles et al, 1986; Grubb, 1990; Nagai et al, 1999).

Genitourinary

    3.10.1) SUMMARY
    A) Large intravenous doses of vitamin C may precipitate acute renal failure. Riboflavin may cause a bright yellow discoloration of urine.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE
    1) WITH THERAPEUTIC USE
    a) Riboflavin may cause a bright yellow discoloration of urine.
    B) KIDNEY STONE
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Calcium oxalate kidney stone formation has been described after ingestion of vitamin C in doses of 1 to 4 g/day in susceptible individuals (Briggs et al, 1973). However, newer studies and epidemiological evidence suggests that consumption of vitamin C may be inversely correlated, or not correlated at all, with the formation of oxalate kidney stones (Hathcock, 1997).
    b) CASE REPORT/ADULT: Oxalate nephropathy was described after administration of a single IV 45 g dose of vitamin C to a 58-year-old woman with amyloidosis and a normal serum creatinine (Lawton et al, 1985).
    C) URETERIC STONE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT/CHILD: A 9-year-old child was admitted with left colic pain, hematuria, mild nausea and vomiting for 1 month. Plain x-rays of the kidneys, ureters and bladder found a left ureteral stone. It was reported by the parents that the child had been taking 3 g/day of Vitamin C effervescent tablets for approximately 6 years to avoid colds. Blood chemistry studies were all within normal limits. A urinalysis was positive for RBCs, WBCs and 2+ Vitamin C (normal range, negative). A 24-hour urine collection was extremely high for oxalate (278 mg/24 hr). Lithotripsy was successful in breaking up the ureteral stone. Vitamin C was discontinued and the child had no further symptoms (Chen et al, 2014).
    D) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Permanent renal failure with calcium oxalate crystal deposits was reported in a 70-year-old man following administration of 1.5 g of IV vitamin C (McAllister et al, 1984)

Hematologic

    3.13.1) SUMMARY
    A) Vitamin C supplementation may cause hemolytic anemia in premature neonates.
    3.13.2) CLINICAL EFFECTS
    A) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Heinz body hemolytic anemia has been associated with vitamin C supplementation in premature infants. Administration of vitamin C at 30 mg/day for 2 days resulted in anemia and jaundice in one case (Ballin et al, 1988).
    b) CASE REPORT: Acute hemolytic anemia developed in a 9 month-old boy with G6PD deficiency (diagnosed during admission) following high-dose ascorbic acid (2000 mg every 4 hours intravenously for 2 days) therapy for a presumed diagnosis of enterovirus infection. Clinical findings included deeply colored urine and a hemoglobin of 5.4 g/dL which had decreased from 11.1 g/dL 2 days prior. Direct and indirect Coombs tests were negative. Following supportive therapy, he was discharged to home (Huang et al, 2014).
    B) BLOOD COAGULATION DISORDER
    1) WITH THERAPEUTIC USE
    a) VITAMIN E THERAPY
    1) Prolonged prothrombin time, INR, and clotting time have been observed. Long-term use of doses greater than 800 Units/day have been associated with increased bleeding tendencies in patients deficient in vitamin K (HSDB , 2001).
    2) It is suggested that excessive use may antagonize vitamin K function and inhibit prothrombin production (HSDB , 2001). In one study, more deaths from hemorrhagic stroke and fewer from ischemic heart disease were observed among participants who received alpha-tocopherol than among those who did not (Liede et al, 1998).
    3) Alpha-tocopherol supplementation may increase the risk of gingival bleeding (Liede et al, 1998).
    4) Vitamin E, when used to treat retinopathy in low-birth-weight premature infants, has been associated with an increased incidence of retinal and intraventricular hemorrhages (Phelps et al, 1987).

Dermatologic

    3.14.1) SUMMARY
    A) Niacin (vitamin B3) may cause intense cutaneous flushing lasting up to 2 to 3 hours with no other apparent toxicity. Nicotinamide lacks these effects. Topical vitamin E has rarely caused contact dermatitis and erythema multiforme.
    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Niacin (B3) may cause intense cutaneous flushing lasting 2 to 3 hours with no other apparent toxicity. This is due to the release of the vasodilator histamine (Alhadeff et al, 1984). Flushing is more common on an empty stomach and with rapid absorption (Rader et al, 1992).
    b) Incidence: 92% to 100% of patients receiving niacin experience flushing of the face and trunk (Mosher, 1970; Knodel & Talbert, 1987).
    c) Nicotinamide lacks these effects.
    B) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Topical application of pure vitamin E oil was associated with the development of erythematous, pruritic, eczematous eruptions in a 63-year-old woman. Positive skin test reactions were noted at 48 hours (Goldman & Rapaport, 1986).
    C) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Topical use of a vitamin E cream produced erythema multiforme eruptions in 2 cases (Saperstein et al, 1984).
    D) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Consumption of very high doses of beta-carotene has been associated with skin discoloration due hypercarotenemia (Hathcock, 1997).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) CALCINOSIS
    1) WITH POISONING/EXPOSURE
    a) Bone Oxalate Deposition: Oxalate crystals surrounded by fibrosis were reported in a bone biopsy of a hemodialyzed patient taking 2.6 g/day of vitamin C (Ott et al, 1986).
    B) DRUG-INDUCED MYOPATHY
    1) WITH THERAPEUTIC USE
    a) A chronic alcoholic developed myopathy several months after he underwent treatment with nicotinic acid (niacin) for cholesterol reduction. The myopathy resolved after discontinuation of nicotinic acid (Goldstein, 1989).
    b) Litin & Anderson (1989) reported 3 additional patients that developed myopathy (severe leg cramps) associated with nicotinic acid therapy for hypercholesterolemia. In each case the myopathy improved after discontinuation of nicotinic acid (Litin & Anderson, 1989).

Immunologic

    3.19.1) SUMMARY
    A) Anaphylactoid reactions occur rarely after intravenous thiamine.
    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) An anaphylactoid reaction was reported following the IV administration of 100 mg of thiamine in a 32-year-old man (Stephen et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) There is a well-established association between some vitamin A congeners and a teratogenic outcome in infants whose mothers were exposed during pregnancy.
    3.20.2) TERATOGENICITY
    A) TERATOGENICITY
    1) VITAMIN A: There is a well-established association between some vitamin A congeners and a teratogenic outcome in infants whose mothers were exposed during pregnancy (Kizer et al, 1990).
    a) Until further studies are completed, the US Food and Drug Administration's maximum recommended daily allowance of vitamin A (diet and supplements) is 8000 international units for pregnant females (MMWR, 1987).
    b) Some authors have suggested caution in vitamin A intake in pregnancy, others have suggested stronger action such as clarification of warning statements on multivitamin preparations or removal of vitamin A from multivitamin preparations (Presbury, 1997; Smithells, 1996).
    c) In a prospective study of 22,755 women, high intake of vitamin A (retinol greater than 15,000 international units/day from combined sources of food and supplements or greater than 10,000 international units/day from supplements) was associated with an increased incidence of birth defects (Rothman et al, 1995).
    1) The increase was most striking for malformations of tissues derived from neural crest cells (craniofacial, CNS, thymus, and heart) and less pronounced for musculoskeletal and urogenital defects. There was no increase in neural tube defects.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    FOLIC ACIDA*
    LEUCOVORIN CALCIUMC
    NIACINA*
    NIACINAMIDEA*
    PANTOTHENIC ACIDA*
    RIBOFLAVINA*
    THIAMINEA*
    VITAMIN B-12A*
    VITAMIN CA*
    VITAMIN EA*
    MULTIPLE VITAMINSA**
    *Risk Factor C if used in doses above recommended daily allowance
    **Risk Factor varies for amounts exceeding recommended daily allowance. See individual vitamins.
    Reference: Briggs et al, 1998.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Routine laboratory studies are usually not indicated.
    B) Obtain iron levels as indicated following a significant exposure with a vitamin product that contains iron (see IRON Management).
    C) Serum calcium and phosphate levels should be monitored closely if vitamin D toxicity is suspected.
    D) Plasma vitamin A levels may be helpful in diagnosis, but are not clinically useful in treatment. Obtain serum aminotransferase levels, bilirubin, INR, and calcium levels in patients with chronic overdose of multivitamins which contain vitamin A.
    E) Plasma levels of the individual vitamins are not clinically useful.
    4.1.2) SERUM/BLOOD
    A) LABORATORY INTERFERENCE
    1) High doses of vitamin C may cause false negatives with Clinisticks, or false positives with Clinitest tablets or Benedict's solution (Ivey, 1979).
    2) Excessive folate may mask laboratory evidence of megaloblastic anemia secondary to cyanocobalamin deficiency (Alhadeff et al, 1984).
    B) BLOOD/SERUM CHEMISTRY
    1) Plasma levels of the individual vitamins are not clinically useful. However, if iron toxicity is suspected, a serum iron should be determined (see IRON Management).
    2) Serum calcium and phosphate levels should be monitored closely if vitamin D toxicity is suspected.
    3) Plasma vitamin A levels may be helpful in diagnosis, but are not clinically useful in treatment. Obtain serum aminotransferase levels, bilirubin, INR, and calcium levels in patients with chronic overdose of multivitamins which contain vitamin A.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Children who are symptomatic (eg, vitamin A or D toxicity, iron toxicity) should be admitted for observation and possible further treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An inadvertent ingestion by an asymptomatic child of a multivitamin without iron can be safely managed at home with dilution. Children displaying mild symptoms (ie, nausea, mild abdominal pain) only following a multivitamin ingestion without iron can be monitored at home with a responsible adult. Any progression of GI symptoms or alterations in mental status should be observed in a healthcare facility. Asymptomatic adults who ingest several extra doses or with chronic overuse can be managed at home.
    1) FOLIC ACID: In a retrospective review conducted by the Texas Poison Center Network consisting of calls to 6 poison centers, the effects of folic acid exposure as a single ingredient resulted in no significant clinical effects. Of the 252 cases involving only folic acid exposure, 232 (92.1%) were safely managed at home, 16 (6.3%) patients were already at a healthcare setting at the time of poison center contact, and 4 (1.6%) patients were referred to a healthcare center for further evaluation (Forrester, 2005).
    2) In a series of 275 cases, 94% were treated at home. Cases with a history of greater than 25,000 International units/kilogram of vitamin A were referred to a health care facility for observation. No significant toxic effects occurred (Dean & Krenzelok, 1988).
    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 may be discharged to home once symptoms have resolved and laboratory studies are within normal limits.

Monitoring

    A) Routine laboratory studies are usually not indicated.
    B) Obtain iron levels as indicated following a significant exposure with a vitamin product that contains iron (see IRON Management).
    C) Serum calcium and phosphate levels should be monitored closely if vitamin D toxicity is suspected.
    D) Plasma vitamin A levels may be helpful in diagnosis, but are not clinically useful in treatment. Obtain serum aminotransferase levels, bilirubin, INR, and calcium levels in patients with chronic overdose of multivitamins which contain vitamin A.
    E) Plasma levels of the individual vitamins are not clinically useful.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Gastrointestinal decontamination is not necessary in most cases..
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity is unlikely following acute ingestion of multiple vitamin preparations without iron and GI decontamination is generally not necessary. Iron toxicity may occur following ingestion of those preparations which contain iron salts (see Multivitamins - Iron management).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Toxic symptoms should be monitored closely and treated symptomatically. Toxicity is very unlikely.
    B) MONITORING OF PATIENT
    1) Routine laboratory studies are usually not indicated.
    2) Serum calcium and phosphate levels should be monitored closely if vitamin D toxicity is suspected.
    3) Plasma vitamin A levels may be helpful in diagnosis, but are not clinically useful in treatment. Obtain serum aminotransferase levels, bilirubin, INR, and calcium levels in patients with chronic overdose of multivitamins which contain vitamin A.
    4) Obtain iron levels as indicated following a significant exposure with a vitamin product that contains iron.
    C) ASCORBIC ACID
    1) Ingestion of vitamin C with minimal fluid intake has resulted in esophageal injury. Since fluid intake may be minimal in accidental ingestion, dilution with fluids may be indicated to facilitate tablet dissolution.
    D) IRON
    1) See Iron Management
    E) VITAMIN A
    1) See Vitamin A Management
    F) VITAMIN D
    1) See Vitamin D Management
    G) VITAMIN E
    1) Daily intake of 200 to 600 mg vitamin E is innocuous. Blood levels greater than 3.5 mg% may lead to a higher incidence of necrotizing enterocolitis in premature infants (Bieri et al, 1983).
    H) NIACIN
    1) FLUSHING: The results of a preliminary study suggest that pretreatment with 325 mg of aspirin, 30 minutes prior to a dose of niacin, decreases the warmth and flushing but not the itching and tingling associated with niacin.
    a) A dose of 80 mg of aspirin was no more effective than placebo (Whelan et al, 1992).
    b) Aspirin may reduce elevations in serum prostaglandin E2, which is associated with nicotinic acid-induced flushing (Nozaki et al, 1987).

Range Of Toxicity

Summary

    A) TOXICITY: Toxicity following acute overdoses of multiple vitamin preparations is unlikely unless the preparation contains significant amounts of iron, vitamin A, or vitamin D. IRON: A potentially toxic oral dose of elemental iron is between 20 and 40 mg/kg. VITAMIN A: Oral ingestions of greater than 300,000 International Units by children have resulted in significant CNS toxicity; acute toxicity in adults is rare. VITAMIN D: Chronic ingestions of vitamin D in excess of 1600 units/day may cause toxicity. Daily ingestions in excess of 2000 units in children or 75,000 units in adults may produce toxic symptoms associated with hypervitaminosis D.

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) VITAMIN C
    a) Acute renal failure and death have been described after a single IV dose of 45 g (Lawton et al, 1985).
    2) NICOTINIC ACID
    a) Nicotinic acid is several hundred times less toxic than the parent nicotine and has no action on the autonomic ganglia. Doses of 2 g daily have been lethal in dogs (Chen et al, 1984).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) FOLIC ACID
    a) Fifteen mg/day for 1 month produced cognitive changes, sleep disturbance, and gastrointestinal effects (Hunter et al, 1970).
    b) The suggested recommended dietary allowance is 200 mcg for adults with the Safe Upper Limit being 1000 mcg supplemental, 1500 mcg total to avoid masking of vitamins B-12 deficiency (Mulholland & Benford, 2007).
    c) In a retrospective review by the Texas Poison Center Network of folic acid as a single-ingredient exposure, no significant adverse events were reported. Of the 194 cases reported during 2000 through 2003 to 6 poison centers in the region, 8 (4.1%) patients developed minor clinical effects, which included vomiting (n=4) and one case each of hives, diarrhea, confusion, and dizziness (Forrester, 2005).
    d) Sixty mg/day for 3 years produced no obvious toxic effects in one adult (Sheehy, 1973).
    e) ANIMALS: Large doses of folic acid produced renal hypertrophy and epithelial cell hyperplasia in rats (Taylor et al, 1968). Similar effects have NOT been seen in humans (Butterworth & Tamura, 1989).
    2) IODINE
    a) The suggested recommended dietary allowance is 150 mcg for adults with the Safe Upper Limit being 500 mcg supplemental, 930 mcg total to avoid disruption of thyroid metabolism (Mulholland & Benford, 2007).
    3) NIACIN
    a) Hepatotoxicity appears to be dose-related, but has been seen in patients receiving as low as 3 g/day for 1 month (Clementz & Holmes, 1987), and 4.5 g/day for 6 months (Patterson et al, 1983). In all but one reported case (Sugerman & Clark, 1974) the daily dose has been equal to or greater than 3 g.
    4) THIAMINE
    a) CASE REPORT: A 47-year-old woman developed headache, increased irritability, insomnia, rapid pulse, weakness, and trembling while taking thiamine hydrochloride 10 g daily for 2.5 weeks. Her symptoms resolved upon discontinuation of the daily thiamine intake (Mills, 1941).
    5) VITAMIN A
    a) Acute ingestion of 300,000 International Units (children) or 1 million or more International Units (adults) may result in toxicity with an onset of symptoms of 12 to 24 hours (Windhorst & Nigra, 1982).
    b) No significant toxic effects were noted in children ingesting multivitamins containing 1500 to 225,000 Units of vitamin A (Dean & Krenzelok, 1988).
    c) LACK OF EFFECT/PEDIATRIC: Three children between the ages of 30 months to 5 years consumed between 100 to 150 chewable jelly vitamins each containing 2000 International Units (200,000 to 300,000 International Units of vitamin A) of vitamin A as retinyl palmitate and 200 International Units of vitamin D over several days and were asymptomatic with no physical findings on exam. Serum retinol concentrations were increased above the reference range (0.7 to 1.5 micromol/L) in one child but slowly declined over time. Serum retinyl palmitate concentrations were elevated at the time of admission in 2 of the patients with levels of 371 and 437 nmol/L, respectively (reference median concentration: less than 244 nmol/L). Serial blood samples were followed at regular intervals for 6 months with concentrations remaining elevated in one patient for over 3 weeks after exposure. At 6 months, concentration for the 3 patients were 280, 260 and 220 nmol/L, respectively. No clinical complications occurred in any child. Other laboratory studies including serum hydroxyvitamin D remained normal throughout the study period (Lam et al, 2006).
    6) VITAMIN B6
    a) The suggested recommended dietary allowance is 2 mg for adults with the Safe Upper Limit being 10 mg to avoid nerve damage (Mulholland & Benford, 2007).
    b) CASE REPORT: A woman with a delusional disorder developed severe sensory and mild motor neuropathy after chronic high daily doses (approximately 10 g daily for 5 years) of pyridoxine. Symptoms included paresthesias, stocking-glove distributed sensory loss, the absence of deep tendon reflexes in all extremities and marked ataxia. The patient continued excessive pyridoxine therapy and refused further care (Morra et al, 1993).
    7) VITAMIN C
    a) To avoid producing gastrointestinal effects (ie, osmotic diarrhea), the maximum safe intake is approximately 1 g (Mulholland & Benford, 2007).
    b) Acute hemolysis has been reported in patients with G6PD deficiency associated with high-dose ascorbic acid therapy. Hemolysis has occurred in adults at 80 to 160 g of IV ascorbic acid and 3 to 4 g in children. A 9-month old infant with G6PD deficiency developed acute hemolytic anemia following ascorbic acid (2000 mg (or 2 g) every 4 hours IV) therapy. He recovered with supportive therapy (Huang et al, 2014).
    c) CASE REPORT/CHILD: A 9-year-old child was admitted with left colic pain, hematuria, mild nausea and vomiting for 1 month. Plain x-rays of the kidneys, ureters and bladder found a left ureteral stone. It was reported by the parents that the child had been taking 3 g/day of Vitamin C effervescent tablets for approximately 6 years to avoid colds. Blood chemistry studies were all within normal limits. A urinalysis was positive for RBCs, WBCs and 2+ Vitamin C (normal range, negative). A 24-hour urine collection was extremely high for oxalate (278 mg/24 hr). Lithotripsy was successful in breaking up the ureteral stone. Vitamin C was discontinued and the child had no further symptoms (Chen et al, 2014).
    8) VITAMIN D
    a) The following information is for vitamin D in general (Brin M, 1976):
    1) Chronic ingestion of vitamin D in excess of 1600 units may cause toxicity.
    2) Daily ingestion in excess of 75,000 units/day in adults will produce the toxic symptoms associated with hypervitaminosis D.
    3) Decreased renal function may prevent excretion thereby resulting in elevated serum levels and enhance the possibility of toxicity.
    b) 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).
    c) 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).
    9) ZINC
    a) The suggested recommended dietary allowance is 15 mg for adults with the Safe Upper Limit being 25 mg supplemental, 42 mg total to avoid inhibition of copper absorption (Mulholland & Benford, 2007).
    10) MULTIVITAMINS
    a) One source has listed the following MAXIMUM SAFE DAILY DOSE for vitamins (not necessarily a toxic dose) (Anon, 1986):
    VITAMINMAXIMUM DAILY DOSE
      
    Thiamine50 to 100 times the RDA
    Riboflavinat least 100 times the RDA
    Pyridoxine50 to 100 times the RDA
    Niacin50 to 100 times the RDA
    Pantothenic acidat least 100 times the RDA
    Folic acidat least 100 times the RDA
    Biotinat least 100 times the RDA
    Vitamin B12at least 100 times the RDA
    Vitamin Cat least 100 times the RDA
    Vitamin A10 to 50 times the RDA
    Vitamin Dup to 10 times the RDA
    Vitamin Eat least 100 times the RDA
    Vitamin K10 to 50 times the RDA

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) CYANOCOBALAMIN -
    1) Intravenous administration of vitamin B12 at 2500 micrograms 3 times a week resulted in elevated serum vitamin B12 levels in 93.4% of hemodialysis patients.
    2) The mean level was 627 picograms (pcg)/milliliter (mL) in untreated and 1446 pcg/mL in treated patients. Serum levels normalized 3 years after discontinuation of vitamin supplementation.
    3) No signs or symptoms of toxicity could be attributed to these high levels (Mangiarotti et al, 1986).
    b) VITAMIN C -
    1) Normal serum vitamin C levels are around 10 micrograms (mcg)/milliliter (mL). Hemodialysis patients taking 500 to 1000 milligrams/day orally had elevated vitamin C (up to 34 mcg/mL) and oxalate levels (up to 18.9 mcg/mL) (Pru et al, 1985).
    UNITED STATES RECOMMENDED DAILY ALLOWANCES OF VITAMINS AND MINERALS
     UnitsAdults and children greater than 4 yearsPregnant or lactating women
    Vitamin AInternational Units50008000
    Vitamin DInternational Units400400
    Vitamin EInternational Units3030
    Vitamin Cmg6060
    Folic Acidmg0.40.8
    Thiamine B1mg1.51.7
    Riboflavin B2mg1.72
    Niacinmg2020
    Vitamin B6mg22.5
    Vitamin B12mcg68
    Biotinmg0.30.3
    Pantothenic Acidmg1010
    Calciumg11.3
    Phosphorusg11.3
    Iodinemcg150150
    Ironmg1818
    Magnesiummg400450
    Coppermg22
    Zincmg1515
    UNITED STATES
    RECOMMENDED DAILY ALLOWANCES OF VITAMINS AND MINERALS
     UnitsInfants (0 to 12 mo)Children less than 4 yearsAdults and Children greater than 4 years
    Vitamin AInternational Units150025005000
    Vitamin DInternational Units400400400
    Vitamin EInternational Units51030
    Vitamin Cmg354060
    Folic Acidmg0.10.20.4
    Thiamine B1mg0.50.71.5
    Riboflavin B2mg0.60.81.7
    Niacinmg8920
    Vitamin B6mg0.40.72
    Vitamin B12mcg236
    Biotinmg0.050.150.3
    Pantothenic Acidmg3510
    Calciumg0.60.81
    Phosphorusg0.50.81
    Iodinemcg4570150
    Ironmg151018
    Magnesiummg70200400
    Coppermg0.612
    Zincmg5815
    UNITED STATES
    RECOMMENDED DAILY ALLOWANCES OF VITAMINS AND MINERALS
     UnitsInfants (0 to 12 mo)Children less than 4 yearsAdults and Children greater than 4 years
    Vitamin AInternational Units150025005000
    Vitamin DInternational Units400400400
    Vitamin EInternational Units51030
    Vitamin Cmg354060
    Folic Acidmg0.10.20.4
    Thiamine B1mg0.50.71.5
    Riboflavin B2mg0.60.81.7
    Niacinmg8920
    Vitamin B6mg0.40.72
    Vitamin B12mcg236
    Biotinmg0.050.150.3
    Pantothenic Acidmg3510
    Calciumg0.60.81
    Phosphorusg0.50.81
    Iodinemcg4570150
    Ironmg151018
    Magnesiummg70200400
    Coppermg0.612
    Zincmg5815

Pharmacology Toxicology

Toxicologic Mechanism

    A) VITAMIN C: Vitamin C is hydrolyzed to 2-3 diketo-L-gluconic acid and then metabolized to L-threomic acid and oxalic acid. Systemic oxalosis may result in deposition of oxalate crystals in kidney tissue (Atkins et al, 1964).

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