Vitamin B12

Class: Vitamin B Complex
VA Class: VT100
Chemical Name: 5,6-dimethyl-benzimidazolyl cyanocobamide,
CAS Number: 68-19-9
Brands: Nascobal

Introduction

A cobalt-containing, B complex vitamin.a Cyanocobalamin and hydroxocobalamin are synthetic forms of vitamin B12.a

Hydroxocobalamin: Antidote for cyanide poisoning.104

Uses for Vitamin B12

Vitamin B12 Deficiency

Treatment of pernicious anemia and other vitamin B12 deficiency states.a 102 105

Parenteral cyanocobalamin or hydroxocobalamin: Treatment of vitamin B12 deficiency due to inadequate intrinsic factor (IF) secretion; impaired intestinal absorption; or dietary deficiency associated with a vegetarian diet.a 102 105

Cyanocobalamin is considered the parenteral vitamin B12 preparation of choice; hydroxocobalamin may be preferred for initial treatment.a

Cyanocobalamin nasal spray: Used to maintain hematologic status in adults with pernicious anemia with no nervous system involvement who have responded to parenteral vitamin B 12 therapy.103 Also used as a supplement for vitamin B12 deficiency due to dietary deficiency, impaired absorption, inadequate secretion of IF, or certain other conditions.103

Dietary Requirements

Adequate intake needed to prevent vitamin B12 deficiency and neurologic complications associated with vitamin B12 deficiency.101

Adequate intake of vitamin B12 usually can be accomplished through consumption of foodstuffs; however, about 10–30% of geriatric individuals are unable to absorb naturally occurring vitamin B12 and should consume vitamin B12-fortified food or supplements.101 Inadequate intake can occur in vegetarians and their breast-fed infants.a Mixed foods whose main ingredient is meat, fish, or poultry; milk; and fortified ready-to-eat cereals are the main sources of vitamin B12 in the diet of US adults and children.101

Recommended Dietary Allowance (RDA) in adults based on amount needed to maintain hematologic status and normal serum vitamin B12 concentrations.101

Adequate intake (AI) established for infants ≤6 months of age based on observed mean vitamin B12 intake of infants fed principally human milk; AI for infants 7–12 months of age based on AI for younger infants and data in adults.101

RDA for children 1–18 years of age based on data in adults.101

Metabolic Disorders

Parenteral cyanocobalamin: Management of hereditary deficiency of transcobalamin II.a

Schilling Test

Parenteral cyanocobalamin and hydroxocobalamin: Used in conjunction with cyanocobalamin Co 57 in Schilling test to study vitamin B12 absorption. a

Cyanide Poisoning

Hydroxocobalamin (Cyanokit): Treatment of known or suspected cyanide poisoning.104 107 108 109 Used in conjunction with airway and cardiovascular support and management of seizure activity.104

Vitamin B12 Dosage and Administration

Administration

Cyanocobalamin is administered orally, intranasally, or by IM or deep sub-Q injection.a 102 103

Hydroxocobalamin is administered by IM injection or IV infusion.104 105

Oral Administration

Oral therapy is inferior to parenteral therapy. a May be used for treatment of dietary vitamin B12 deficiency in patients with normal GI absorption.a

Parenteral Administration

Cyanocobalamin: Administer by IM or deep sub-Q injection.102 If administered sub-Q, avoid injection into the dermis or upper subcutaneous tissue.a Avoid administering IV; vitamin is rapidly excreted in urine when administered IV.102

Hydroxocobalamin: Administer by IM injection (vitamin deficiency)105 or by IV infusion (cyanide poisoning).104 Avoid administering IV for vitamin deficiency.105

For drug compatibility information, see Compatibility under Stability.

IV Administration for Cyanide Poisoning

Hydroxocobalamin: (Cyanokit); Administer by IV infusion.104

May require a dedicated IV line.104 Administration through the same IV line as blood products not recommended.104

Reconstitution

Reconstitute vial containing 2.5 g of hydroxocobalamin with 100 mL of 0.9% sodium chloride injection; invert or rock vial for at least 30 seconds.104 Do not shake vial.104 Lactated Ringer's injection or 5% dextrose injection can be used if 0.9% sodium chloride injection is not available.104 Reconstituted solution contains 25 mg/mL.104

Rate of Administration

Initial 5-g dose: 15 minutes.104

Second 5-g dose: 15 minutes (for patients in extremis) to 2 hours; rate depends on patient condition.104

Intranasal Administration

Administer intranasally using a metered-dose pump.103 Administer 1 hour before or 1 hour after ingestion of hot foods or liquids.103

Prior to intranasal administration, clear nasal passages.110 Insert the nasal adapter 1 cm into one nostril, point the tip of the adapter toward the back of the nose, hold the other nostril closed, and tilt head slightly forward, pump the drug into nostril, sniff gently during and immediately after dosing, return head to upright position, remove pump unit from nose.110 a

Efficacy has not been established in patients with nasal congestion, allergic rhinitis, or upper respiratory tract infection; defer use until these symptoms have subsided.103

Prime the pump before each use.103

Dosage

Vitamin B 12 deficiency: Duration of therapy depends on cause; long-term therapy not needed when other therapeutic measures correct the underlying cause of the deficiency.a

Cyanocobalamin metered-dose pump delivers 500 mcg of the drug (0.1 mL) per actuation.103

Pediatric Patients

Vitamin B 12 Deficiency
IM

Hydroxocobalamin: Initially, single doses of 100 mcg to total dose of 1–5 mg given over ≥2 weeks.105

Hydroxocobalamin: Maintenance, 30–50 mcg every 4 weeks.105

Dietary and Replacement Requirements
Oral

Infants born to vegan mothers: Supplement with AI from birth because these infants' vitamin B12 stores are low and their mother’s milk may supply very small amounts of the vitamin.101

Infants ≤6 months of age: Recommended AI is 0.4 mcg (0.06 mcg/kg) daily.101

Infants 7–12 months of age: Recommended AI is 0.5 mcg (0.06 mcg/kg) daily.101

Children 1–3 years of age: RDA is 0.9 mcg daily.101

Children 4–8 years of age: RDA is 1.2 mcg daily.101

Children 9–13 years of age: RDA is 1.8 mcg daily.101

Children 14-18 years of age: RDA is 2.4 mcg daily.101

The RDAs will not meet the needs of individuals with malabsorption syndrome.101

Cyanide Poisoning
IV

Hydroxocobalamin: 70 mg/kg has been used.104 107

Adults

Vitamin B 12 Deficiency
IM or Sub-Q

Cyanocobalamin: Initially, 100 mcg daily for 6–7 days.102 If clinical manifestations improve and reticulocyte response observed, administer 100 mcg every other day for 7 doses and then 100 mcg every 3–4 days for 2–3 weeks.102

Cyanocobalamin: Maintenance, 100 mcg every month.102

IM

Hydroxocobalamin: Initially, 30 mcg daily for 5–10 days.105

Hydroxocobalamin: Maintenance, 100–200 mcg every month.105

Intranasal

Maintenance, 500 mcg (one actuation) once weekly.103 Increase dose in patients who experience a decline in serum vitamin B12 concentrations after 1 month of therapy.103

Dietary and Replacement Requirements
Oral

Men and women ≥19 years of age: RDA is 2.4 mcg daily.101

Adults ≥51 years of age should obtain most of their vitamin B12 from fortified food or a vitamin B12 supplement.101

The RDAs will not meet the needs of individuals with malabsorption syndrome.101

Cyanide Poisoning
IV

Hydroxocobalamin: Initially, 5 g (two 2.5-g vials).104 A second 5-g dose may be administered, based on the severity of the poisoning and clinical response.104

Schilling Test
IM or Sub-Q

Cyanocobalamin: Flushing dose is 1000 mcg.102

IM

Hydroxocobalamin: Flushing dose is 1000 mcg. 105

Special Populations

Pregnant Women

RDA for pregnant women is 2.6 mcg daily.101

Lactating Women

RDA for lactating women is 2.8 mcg daily.101

Requirements increased in lactating women to ensure adequate concentration of the vitamin in milk.101

Cautions for Vitamin B12

Contraindications

  • Known hypersensitivity to vitamin B12, cobalt, or any ingredient in the formulation.102 103 105

  • No contraindications when used for treatment of cyanide poisoning.104

Warnings/Precautions

Warnings

Hypokalemia

Fatal hypokalemia reported in intensively treated patients with megaloblastic anemia.a 102 103 105 Monitor serum potassium concentrations during early vitamin B12 therapy and administer potassium if necessary.105 a

Polycythemia Vera

Vitamin B12 deficiency may suppress signs of polycythemia vera; treatment may unmask this condition.a

Ocular Effects

Avoid use in patients with early Leber’s disease (hereditary optic nerve atrophy); rapid and severe optic nerve atrophy reported.102 103

Sensitivity Reactions

Sensitivity Reactions

Anaphylaxis reported with parenteral preparations.102 103

Hydroxocobalamin (Cyanokit): Rash, mainly acneiform, reported in 20 or 44% of individuals receiving a 5- or 10-g dose, respectively.104

Skin Test

Administer an intradermal test dose prior to administration of vitamin B12 for vitamin deficiency in patients who may be sensitive to cobalamins.a

General Precautions

Laboratory Monitoring

Obtain hematocrit, reticulocyte count, vitamin B12, folate, and iron levels prior to treatment for vitamin B12 deficiency.102 103 Monitor hematologic parameters as necessary during therapy.102 103

Aluminum

Some cyanocobalamin injection preparations contain aluminum, which may be toxic.102 Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired.102 Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.102

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum >4–5 mcg/kg daily accumulate aluminum at levels associated with CNS and bone toxicity.102 Tissue loading may occur at even lower rates of administration.102

Benzyl Alcohol in Neonates

Cyanocobalamin injection may contain benzyl alcohol as a preservative; benzyl alcohol has been associated with toxicity in neonates.102 111 112 113 114 115 116 (See Pediatric Precautions.)

Blood Pressure

Transient elevations in BP reported in individuals receiving IV hydroxocobalamin.104

Undiagnosed Anemia

Use extreme caution if folic acid is administered to patients with undiagnosed anemia; may obscure the diagnosis of pernicious anemia by alleviating hematologic manifestations of the disease while allowing neurologic complications to progress.a

Renal Effects

Oxalate crystals observed in the urine of healthy individuals and cyanide poisoning victims following administration of hydroxocobalamin.104

Specific Populations

Pregnancy

Category C.102 103 104 105

Lactation

Distributed into human milk.102 103

Hydroxocobalamin (Cyanokit): Caution advised; no data available to determine when breast-feeding may be restarted following administration of IV hydroxocobalamin.104

Pediatric Use

Hydroxocobalamin (Cyanokit): Safety and efficacy not established.104

Cyanocobalamin: Benzyl alcohol has been associated with toxicity (“gasping syndrome”) in neonates; each mL of cyanocobalamin injection (e.g., preparation manufacturered by Abraxis) contains 15 mg of benzyl alcohol.102 111 112 113 114 115 116

Geriatric Use

Hydroxocobalamin (Cyanokit): No substantial differences in safety and efficacy relative to younger adults.104 Dosage adjustment not needed.104

Hepatic Impairment

Hydroxocobalamin (Cyanokit): Safety and efficacy not studied in patients with hepatic impairment.104

Renal Impairment

Hydroxocobalamin (Cyanokit): Safety and efficacy not studied in patients with renal impairment.104 Hydroxocobalamin and cyanocobalamin excreted unchanged in urine.104

Common Adverse Effects

Usually nontoxic even in large doses; mild transient diarrhea, peripheral vascular thrombosis, itching, transitory exanthema, urticaria, body swelling reported in patients receiving parenteral preparations.a

Interactions for Vitamin B12

Colchicine, aminosalicylic acid and its salts, and excessive alcohol intake lasting >2 weeks may reduce absorption of vitamin B12 from the GI tract.102 103

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Ascorbic acid

May destroy substantial amounts of dietary vitamin B12a

Consider this if large doses of ascorbic acid are ingested within 1 hour of administration of oral vitamin B12 a

Chloramphenicol

May antagonize the hematopoietic response to vitamin B12 in vitamin-deficient patientsa

Monitor; consider alternate anti-infectives a

Cyanide antidotes

Safety of concomitant use of hydroxocobalamin with other cyanide antidotes not established104

Caution104 (See Parenteral under Stability and IV Administration under Dosage and Administration)

Laboratory parameters determined by colorimetric methods

Hydroxocobalamin (Cyanokit): Deep red color in blood and/or urine may interfere with certain laboratory tests (e.g., clinical chemistry, hematology, coagulation, urine parameters)104

Consult the product labeling for specific information

Methotrexate

Invalidates diagnostic microbiologic blood assays for vitamin B12102 103

Prednisone

Increased absorption of vitamin B12 and secretion of IF reported in a few patients with pernicious anemiaa

Does not occur in patients with partial or total gastrectomy; clinical importance unknowna

Pyrimethamine

Invalidates diagnostic microbiologic blood assays for vitamin B12102 103

Test for intrinsic factor (IF) antibodies

Prior administration of cyanocobalamin may result in false-positive test resultsa

Vitamin B12 Pharmacokinetics

Absorption

Bioavailability

Irregularly absorbed from the distal small intestine following oral administration. a Requires gastric IF for active absorption from the GI tract.a

Following parenteral (IM or sub-Q) administration, hydroxocobalamin is absorbed more slowly than cyanocobalamin.a

Following administration of cyanocobalamin nasal spray, bioavailability is about 6.1% compared with IM administration.103

Distribution

Extent

Distributed into liver, bone marrow, and other tissues.103 a

Crosses the placenta and is distributed into milk.a

Elimination

Elimination Route

50–98% may be excreted in urine.102

Stability

Storage

Oral

Tablets

Cool dry place. 106

Parenteral

Solution for Injection

20–25°C; protect from light.102

Powder for Injection

25°C (may be exposed to 15–30°C).104 May be stored for short periods at temperatures that occur with usual transport (15 days 5–40°C), transport in the desert (4 days 5–60°C), and freeze/defrost cycles (15 days in a range from -20 to 40°C).104

Store reconstituted solution at ≤40°C; discard 6 hours after reconstitution.104

Nasal Spray

Upright at 15–30°C; protect from light. 103 Keep covered in carton until needed.103 Protect from freezing.103

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Hydroxocobalamin (Cyanokit): Incompatible with ascorbic acid, diazepam, dobutamine, dopamine, fentanyl, nitroglycerin, pentobarbital, propofol, sodium nitrite, sodium thiosulfate, thiopental.104

Cyanocobalamin injection: Reported to be incompatible with chlorpromazine hydrochloride, phytonadione, prochlorperazine edisylate, warfarin sodium, ascorbic acid, dextrose, heavy metals, oxidizing or reducing agents, and alkaline or strongly acidic solutions.a

Cyanocobalamin: Solution CompatibilityHID

Compatible

Dextran 6% in dextrose 5%

Dextran 6% in sodium chloride 0.9%

Dextrose-Ringer's injection combinations

Dextrose-Ringer’s injection, lactated, combinations

Dextrose-saline combinations

Dextrose 2½, 5, or 10% in water

Fructose 10% in sodium chloride 0.9%

Fructose 10% in water

Invert sugar 5 and 10% in sodium chloride 0.9%

Invert sugar 5 and 10% in water

Ionosol products

Ringer's injection

Ringer's injection, lactated

Sodium chloride 0.45 or 0.9%

Sodium lactate (1/6) M

Cyanocobalamin: Drug Compatibility
Admixture CompatibilityHID

Compatible

Ascorbic acid injection

Chloramphenicol sodium phosphate

Metaraminol bitartrate

Vitamin B complex with C

Y-Site CompatibilityHID

Compatible

Heparin sodium

Hydrocortisone sodium succinate

Potassium chloride

Vitamin B complex with C

Actions

  • An exogenous source of vitamin B12 is required for nucleoprotein and myelin synthesis, cell reproduction, normal growth, and the maintenance of normal erythropoiesis.a

  • In cyanide poisoning, hydroxocobalamin binds to the cyanide ion to form cyanocobalamin which is excreted in the urine.104

Advice to Patients

  • Advise patients with pernicious anemia that they must receive maintenance dosages of cyanocobalamin or hydroxocobalamin for the remainder of their lives to prevent irreversible neurologic damage.a

  • Advise patient of necessity of follow-up tests to confirm adequacy of therapy.103

  • Advise individuals who follow a vegetarian diet that contains no animal products to take oral vitamin B12 regularly.102 103

  • Importance of informing patients using intranasal cyanocobalamin to administer the dose at least 1 hour before or after ingestion of hot foods or liquids.103

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.102 103

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.102 103 Importance of vitamin B12 supplements in pregnant and lactating women who follow a vegetarian diet.102 103 Advise women given hydroxocobalamin for cyanide poisoning to discuss timing of resumption of breast-feeding with their clinician.104

  • Advise patients given hydroxocobalamin for cyanide poisoning that skin redness may last up to 2 weeks and urine coloration may last up to 5 weeks.104 Importance of avoiding direct sun exposure while skin is discolored.104

  • Importance of informing patients of other important precautionary information.a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Cyanocobalamin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mcg*

50 mcg*

100 mcg*

250 mcg*

500 mcg*

1000 mcg*

Parenteral

Injection

100 mcg/mL*

1000 mcg/mL*

Nasal

Spray

500 mcg/metered spray

Nascobal (with benzalkonium chloride)

QOL Medical

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Hydroxocobalamin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

1000 mcg/mL*

For Injection

2.5 g

Cyanokit

Dey

Vitamin B12 is also commercially available in combination with other vitamins and minerals.a

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cyanocobalamin 1000MCG/ML Solution (AMERICAN REGENT): 1/$12.99 or 5/$17.97

Cyanocobalamin 1000MCG/ML Solution (AMERICAN REGENT): 30/$35.99 or 90/$82.97

Nascobal 500MCG/0.1ML Solution (PAR): 1/$313.99 or 4/$908.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. National Research Council Food and Nutrition Board Subcommittee on the Tenth Edition of the RDAs. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press; 1989:158-65.

101. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998. (Prepublication copy uncorrected proofs.)

102. Abraxis Pharmaceuticals. Cyanocobalamin injection prescribing information. Schaumburg, IL; 2005 Jun.

103. QOL Medical Company. Nascobal (cyanocobalamin nasal spray) prescribing information. Kirkland, WA; 2006 Aug.

104. Dey. Cyanokit (hydroxocobalamin for injection) prescribing information. Napa, CA; 2006 Dec. (

105. Watson Laboratories. Hydroxocobalamin injection prescribing information. Corona, CA; 2006 Feb.

106. Nature's bounty vitamin B12 1000 mcg tablets package information. From (). Accessed 31 May 2007.

107. Geller RJ, Barthold C, Saiers JA, Hall AH. Pediatric cyanide poisoning: causes, manifestations, management, and unmet needs. Pediatrics. 2006; 118:2146-58. [PubMed 17079589]

108. Borron SW, Baud FJ, Mégarbane B, Bismuth C. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. Am J Emerg Med. 2007; 25:551-8. [PubMed 17543660]

109. Borron SW, Baud FJ, Barriot P et al. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med. 2007; 49:794-801. [PubMed 17481777]

110. QOL Medical Company. Nascobal (cyanocobalamin nasal spray) patient information. Kirkland, WA; 2006.

111. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041]

112. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12:10-11. [PubMed 7188569]

113. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-91. [IDIS 150868] [PubMed 6810084]

114. Gershanik J. Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

115. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

116. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

a. AHFS drug information 2007. McEvoy GK, ed. Vitamin B12. Bethesda, MD: American Society of Health-System Pharmacists, 2007; 3628-31.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:444-7.

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