VA Class:VT109

ATC Class:A11HA02

AHFS Class:

• Vitamin B Complex 88:08

Generic Name(s):

• Pyridoxine Hydrochloride

Vitamin B₆ (as pyridoxine, pyridoxal, and pyridoxamine) is a water-soluble, B complex vitamin.

Pyridoxine Deficiency

Pyridoxine is used to prevent and to treat vitamin B₆ deficiency. Deficiency of the vitamin has rarely been identified in humans except in conjunction with deficiency of other B complex vitamins or when drug-induced. Whenever possible, poor dietary habits should be corrected, and many clinicians recommend administration of multivitamin preparations containing pyridoxine in patients with vitamin deficiencies since poor dietary habits often result in concurrent deficiencies. (See Multivitamins 88:28.)

Although an adequate amount of pyridoxine is usually obtained from dietary sources, pyridoxine deficiency may occur in patients with uremia, alcoholism, cirrhosis, hyperthyroidism, malabsorption syndromes, and congestive heart failure and in those receiving isoniazid, cycloserine, ethionamide, hydralazine, penicillamine, or pyrazinamide. Although increased pyridoxine requirements may occur in geriatric patients, clinical signs of deficiency are rare in these patients. Biochemical evidence suggestive of, but not conclusive for, pyridoxine deficiency may occur in women receiving oral contraceptives and can be corrected with pyridoxine administration. Angular stomatitis, glossitis, and abnormal glucose tolerance during pregnancy are sometimes associated with biochemical evidence of pyridoxine deficiency and may be improved by administration of pyridoxine.

Dietary Requirements

The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941.157 In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs).157 DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).157

The NAS has established an EAR and RDA for vitamin B₆ for adults based principally on a plasma pyridoxal phosphate concentration of 5 ng/mL.157 Because evidence currently available on the role of vitamin B₆ in reducing the risk of vascular disease (by reducing plasma homocysteine concentrations) is limited,157,  160,  161 the NAS did not use risk reduction as a basis for setting the EAR and RDA.157 Because vitamin B₆ is involved in amino acid metabolism, vitamin B₆ requirements are considered to parallel protein intake.157 However, not all studies support this relationship, and NAS concluded that expressing vitamin B₆ requirements in terms of protein intake does not add to the precision of the requirement.157 The EAR and RDA for children and adolescents 1-18 years of age was established based on data in adults, since only limited data in children and adolescents are available.157 An AI has been set for infants up to 6 months of age based on the observed mean vitamin B₆ intake of infants fed principally human milk.157 An AI for infants 6-12 months of age has been set based on the AI for younger infants and data from adults.157 (For a definition of Estimated Average Intake, Recommended Dietary Allowance, Adequate Intake, and other reference values for dietary nutrient intakes, see Uses: Dietary Requirements in Folic Acid 88:08.)

The principal goal of maintaining an adequate intake of vitamin B₆ in the US and Canada is to prevent vitamin B₆ deficiency.157 In the US, vitamin B₆ principally has been obtained from fortified ready-to-eat cereals; mixed dishes containing substantial portions of meat, fish, or poultry; white potatoes and other starchy vegetables; and noncitrus fruits.157

For specific information on currently recommended AIs and RDAs of vitamin B₆ for various life-stage and gender groups, see Dosage: Dietary and Replacement Requirements, under Dosage and Administration: Dosage.

Pyridoxine-dependent Seizures

Pyridoxine has been used in neonates and infants to treat seizures that are unresponsive to usual therapy. Pyridoxine-dependent seizures occur in infants with an inborn pyridoxine dependency rather than a deficiency of the vitamin.159

Metabolic Disorders

Xanthurenic aciduria, primary cystathioninuria, primary hyperoxaluria, and primary homocystinuria resulting from genetic abnormalities may respond to pyridoxine (generally in high doses). Homocystinuria is usually caused by diminished activity of cystathionine β-synthase; pyridoxal-5-phosphate is a cofactor for the enzyme and about 50% of these patients respond to pyridoxine therapy, which may completely reverse abnormal amino acid (i.e., homocysteine, methionine, cysteine-homocysteine, cysteine) concentrations.

Prevention or Treatment of Drug-induced Neurotoxicity

Pyridoxine has been used to prevent or treat neurotoxic adverse effects (e.g., peripheral neuropathy) associated with drugs such as isoniazid, ethionamide, or capecitabine. Since patients with HIV infection may be more likely to experience isoniazid-related peripheral neuropathy, the CDC recommends that pyridoxine hydrochloride (25-50 mg daily or 50-100 mg twice weekly) be administered to all HIV-infected patients receiving antituberculosis therapy with isoniazid to reduce the occurrence of isoniazid-induced adverse nervous system effects.

Pyridoxine is used as an adjunct to other measures for the treatment of acute toxicity resulting from isoniazid, cycloserine, or hydrazine overdosage. Pyridoxine is used to treat isoniazid-induced seizures and/or coma, usually in conjunction with other anticonvulsants. Isoniazid-induced seizures are thought to be associated with decreased γ-aminobutyric acid (GABA) concentrations within the CNS, possibly resulting from inhibition by isoniazid of brain pyridoxal-5-phosphate activity. Pyridoxine has also had a beneficial effect in correcting acidosis in some patients following isoniazid overdosage, possibly by controlling seizures and resulting lactic acidosis. Following acute hydrazine overdosage in one patient, IV pyridoxine therapy reversed CNS dysfunction (e.g., confusion, lethargy) and improved hepatic function within 24 hours.151 Although pyridoxine also has been used as an adjunct in the treatment of levodopa overdosage, its usefulness is not well established.

Mushroom Toxicity

Pyridoxine has been used as an adjunct to other measures for the treatment of acute toxicity caused by mushrooms of the genus Gyromitra .153,  154,  155 Pyridoxine has been used to treat marked neurologic effects (e.g., seizures, coma) induced by methylhydrazine, which results from hydrolysis of the toxins gyromitrins contained in these mushrooms.153,  154,  155

Other Uses

Pyridoxine has been used for the treatment of sideroblastic anemia associated with high serum iron concentration.

Although pyridoxine has not been shown by well-controlled trials to have any therapeutic value, the vitamin has been used for the management of acne, various dermatoses, appetite stimulation, hyperlipidemia, radiation sickness, hyperemesis gravidarum, vertigo, motion sickness, psychosis, depression associated with pregnancy and oral contraceptive use, hyperkinesis, acute chorea, chronic progressive hereditary chorea, tardive dyskinesia, asthma, absence (petit mal) seizures, amenorrhea-galactorrhea syndrome, gyrate atrophy of the choroid and retina, idiopathic nephrolithiasis, alcohol intoxication, and for the suppression of postpartum lactation, prevention of leukopenia secondary to mitomycin, and reversal of procarbazine neurotoxicity. There is conflicting evidence regarding the efficacy of pyridoxine in the management of premenstrual syndrome (PMS),125,  126,  127,  128,  129,  130,  131,  132,  133 and additional study is necessary to determine whether the vitamin is of any value in the management of this condition.126

Administration

Pyridoxine hydrochloride is usually administered orally; however, the drug may be given by IM, IV, or subcutaneous injection when oral administration is not feasible. In infants with seizures, pyridoxine hydrochloride should be administered by IM or IV injection.

Dosage

Although pyridoxine was previously considered nontoxic even at high dosages, current evidence indicates that chronic administration of large dosages (e.g., 2 g daily) for the management of various conditions can cause severe adverse neurologic effects,115,  120,  123 and the risk to benefit of such dosages must be carefully weighed.115,  120,  151,  152,  154 (See Chronic Toxicity.)

Dietary and Replacement Requirements

The Adequate Intake (AI) (see Uses: Dietary Requirements) of vitamin B₆ currently recommended by the National Academy of Sciences (NAS) for healthy infants up to 6 months of age is 0.1 mg (0.01 mg/kg) daily and for those 6-12 months of age is 0.3 mg (0.03 mg/kg) daily.157 The Recommended Dietary Allowance (RDA) of vitamin B₆ currently recommended by NAS for healthy children 1-3, 4-8, or 9-13 years of age is 0.5, 0.6, or 1 mg of vitamin B₆ daily, respectively.157 The RDA of vitamin B₆ for boys 14 up to 19 years of age is 1.3 mg of vitamin B₆ daily, and the RDA for girls 14 up to 19 years of age is 1.2 mg of vitamin B₆ daily.157 The RDA for healthy men and women 19-50 years of age is 1.3 mg of vitamin₆ daily.157 The RDA of vitamin B₆ for men 51 years of age or older is 1.7 mg daily, and the RDA for women 51 years of age or older is 1.5 mg daily.157

Pyridoxine Deficiency

For the treatment of pyridoxine deficiency in adults, the usual oral dosage of pyridoxine hydrochloride is 2.5-10 mg daily. After the clinical signs of deficiency are corrected, a multivitamin preparation containing 2-5 mg of pyridoxine hydrochloride should be given daily for several weeks. For the treatment of drug-induced deficiency anemia or neuritis, the usual oral dosage of pyridoxine hydrochloride is 100-200 mg daily for 3 weeks followed by the prophylactic oral administration of 25-100 mg daily. To correct biochemical evidence suggestive of pyridoxine deficiency in women taking oral contraceptives, the usual oral dosage of pyridoxine hydrochloride is 25-30 mg daily.

Pyridoxine-Dependent Seizures

For the treatment of pyridoxine-dependent seizures in neonates or infants, IM or IV pyridoxine hydrochloride doses of 10-100 mg have been recommended. Seizures generally stop within 2-3 minutes following administration of the drug. Some clinicians recommend administration of pyridoxine hydrochloride in any neonate with seizures for which no apparent cause can be found. Infants who have had pyridoxine-responsive seizures often require lifelong oral administration of pyridoxine hydrochloride dosages of 2-100 mg daily.

The RDA of vitamin B₆ recommended by the NAS for pregnant women is 1.9 mg of vitamin B₆ daily.157 To ensure a vitamin B₆ concentration in milk of 130 ng/mL, the NAS recommends a RDA of 2 mg of vitamin B₆ daily for lactating women.157

Sideroblastic Anemia

For the treatment of hereditary, sideroblastic anemia, the usual oral dosage of pyridoxine hydrochloride is 200-600 mg daily. If a therapeutic response does not occur after 1-2 months of pyridoxine therapy, other therapy should be considered. If an adequate response occurs, dosage of pyridoxine hydrochloride may be decreased to 30-50 mg daily; lifelong therapy with the vitamin may be required to prevent anemia in patients with this condition.

Metabolic Disorders

For the treatment of primary hyperoxaluria, primary homocystinuria, primary cystathioninuria, or xanthurenic aciduria, an oral pyridoxine hydrochloride dosage of 100-500 mg daily can generally overcome the metabolic defect. If an adequate response occurs, the same dosage should generally be continued indefinitely. Some patients with type I primary hyperoxaluria may be adequately treated with lower dosages (e.g., physiologic dosages or dosages less than 100 mg daily) than have usually been administered for this disorder.150 Consequently, some clinicians suggest that high dosages be used initially to attain a maximum reduction in urinary oxalate excretion in patients with type I primary hyperoxaluria and that dosage then be reduced in a stepwise fashion at not less than 3-month intervals to determine the minimum dosage required to maintain the initial effect of the drug.150 However, some patients with severe type I primary hyperoxaluria may require relatively high, potentially neurotoxic pyridoxine dosages to prevent irreversible renal damage associated with this condition, and careful monitoring for adverse effects of the drug is necessary if such dosages are used.152

Drug-Induced Pyridoxine Deficiency and Acute Intoxication

To prevent pyridoxine-deficiency anemia or neuritis in patients receiving isoniazid or penicillamine, an oral pyridoxine hydrochloride dosage of 10-50 mg daily has been recommended. To prevent seizures in patients receiving cycloserine, an oral pyridoxine hydrochloride dosage of 100-300 mg daily, given in divided doses, has been recommended.

For the treatment of seizures and/or coma resulting from acute isoniazid toxicity, a dose of pyridoxine hydrochloride equal to the amount of isoniazid ingested is usually given along with other anticonvulsants as needed. Generally, 1-4 g of pyridoxine hydrochloride is given IV followed by 1 g IM every 30 minutes until the entire dose has been given. For the treatment of cycloserine overdosage, a pyridoxine hydrochloride dose of 300 mg daily has been recommended. For the treatment of acute hydrazine toxicity, a pyridoxine hydrochloride dose of 25 mg/kg has been recommended; one-third of this dose is given IM and the rest is given by IV infusion over 3 hours. For the treatment of neurologic effects induced by ingestion of mushrooms of the genus Gyromitra (secondary to methylhydrazine), an IV pyridoxine hydrochloride dose of 25 mg/kg infused over 15-30 minutes and repeated as necessary to control such effects up to a maximum cumulative dose of 15-20 g daily has been suggested.153,  154,  155 Lower pyridoxine doses may be effective for the management of seizures associated with poisoning from these mushrooms when diazepam is used concomitantly.154,  155

Adverse Effects

Pyridoxine is usually nontoxic; however, chronic administration of large dosages has been associated with adverse neurologic effects. (See Chronic Toxicity.) Nausea, headache, paresthesia, somnolence, and increased serum AST (SGOT) and decreased serum folic acid concentrations have been reported. Burning or stinging at the injection site may occur following IM or subcutaneous injection of pyridoxine. Seizures have occurred following IV administration of very large doses. Allergic reactions have been reported occasionally in patients receiving the vitamin.

Precautions and Contraindications

Pyridoxine should not be used in patients with a history of sensitivity to the vitamin. According to one manufacturer, pyridoxine should not be administered IV to patients with heart disease.

Pyridoxine hydrochloride reverses the therapeutic effects of levodopa by accelerating peripheral metabolism of levodopa. Concomitant administration of carbidopa with levodopa prevents the reversal by pyridoxine of levodopa's effects. Pyridoxine hydrochloride should not be administered in dosages greater than 5 mg daily to patients receiving levodopa alone.

In one study, 200 mg of pyridoxine hydrochloride daily for 1 month resulted in a 50% decrease in serum concentrations of phenobarbital and phenytoin.

Although isoniazid interferes with pyridoxine metabolism, the American Academy of Pediatrics (AAP) states that children receiving isoniazid do not need pyridoxine supplements unless they have or are likely to have nutritional deficiencies.158 The AAP currently recommends that children and adolescents receiving meat- and milk-deficient diets, those with nutritional deficiencies (including symptomatic children with human immunodeficiency virus [HIV] infection), infants who are breast-feeding and their mothers, and pregnant women receive pyridoxine supplements.158

Laboratory Test Interferences

Pyridoxine has reportedly resulted in a false-positive determination for urobilinogen in the spot test using Ehrlich's reagent.

Chronic Toxicity

Pathogenesis

Although pyridoxine has generally been considered relatively nontoxic, long-term (i.e., 2 months or longer) administration of large (megadose) dosages (e.g., usually 2 g or more daily) of pyridoxine can cause sensory neuropathy or neuronopathy syndromes.115,  120,  123 The pathogenesis and biochemical basis of pyridoxine-induced neurotoxicity have not been determined.115 It has been suggested that the sensory syndrome produced by megadose pyridoxine may result from some anatomic vulnerability of the neurons of the dorsal-root ganglia.115,  120,  121,  123,  124 Adverse neurologic effects have also been reported rarely following chronic administration of lower dosages (e.g., 500 mg daily) of pyridoxine.122,  125 Although a causal relationship to pyridoxine was not established, sensory neuropathy with axonal degeneration and subsequent recovery has been reported in a patient who received a single IV pyridoxine dose of 10 g for the treatment of acute hydrazine toxicity.151

Manifestations

Development of profound impairment of th sense of position and vibration of the distal limbs and gradual, progressive sensory ataxia115,  122,  123,  125 have been reported in a limited number of patients receiving pyridoxine dosages of 2-6 g daily for 2-40 months.115,  123,  157 Sense of touch, temperature, and pain were less affected in these patients, and generalized weakness did not occur.115 Although deep tendon reflexes were diminished or absent, no signs of CNS dysfunction were present in these patients.115 Nerve conduction studies and somatosensory evoked responses indicated dysfunction of distal portions of peripheral sensory nerves.115,  123 In addition, nerve biopsies showed widespread, nonspecific axonal degeneration.115,  123

Following discontinuance of pyridoxine, neurologic dysfunction gradually improved,115,  122,  123,  125 and following a prolonged follow-up period, the patients reportedly recovered satisfactorily.115 Peripheral sensory neuropathy has been reported in individuals receiving pyridoxine dosages of 1-4 g daily.157,  159

Pharmacology

In humans, an exogenous source of vitamin B₆ is required for amino acid metabolism; the vitamin is also involved in carbohydrate and lipid metabolism. Pyridoxine, pyridoxal, and pyridoxamine are converted to the active forms of the vitamin, pyridoxal phosphate and pyridoxamine phosphate, which act as coenzymes in a wide variety of reactions in intermediary metabolism. The active forms of the vitamin are involved in transamination of amino acids and in the conversion of tryptophan to niacin. Pyridoxine appears to be essential in the synthesis of γ-aminobutyric acid (GABA) within the CNS and in the synthesis of heme.

Pyridoxine deficiency results in the accumulation and urinary excretion of xanthurenic acid (an intermediate metabolite of tryptophan) and in decreased glutamic oxaloacetic transaminase activity in erythrocytes; measurement of either of these may be used to diagnose pyridoxine deficiency. For determination of xanthurenic acid excretion, an oral loading dose of 2-10 g of tryptophan is usually given; urine is collected for 8 hours and then analyzed for xanthurenic acid. Urinary excretion of vitamin B₆ or 4-pyridoxic acid can also be analyzed to determine pyridoxine deficiency.

Pyridoxine deficiency in adults principally affects the peripheral nerves, skin, mucous membranes, and the hematopoietic system. In children, the CNS is affected. The usual clinical symptoms of vitamin B₆ deficiency are seborrheic dermatitis, microcytic anemia, seizures, and depression and confusion.157 Administration of pyridoxine completely reverses symptoms of deficiency. A hereditary syndrome of pyridoxine dependency in which unusually large amounts of pyridoxine are needed to prevent seizures has been identified in infants. Xanthurenic aciduria, cystathioninuria, hyperoxaluria, and primary homocystinuria resulting from genetic abnormalities have responded to pyridoxine administration. A pyridoxine-responsive, hereditary, sideroblastic anemia not related to pyridoxine deficiency has also been identified.

Pharmacokinetics

Absorption

Pyridoxine, pyridoxal, and pyridoxamine are readily absorbed from the GI tract following oral administration; however, GI absorption may be diminished in patients with malabsorption syndromes or following gastric resection. Normal serum concentrations of pyridoxine are 30-80 ng/mL.

Distribution

Vitamin B₆ is stored mainly in the liver with lesser amounts in muscle and brain. The total body store of vitamin B₆ is estimated to be about 167 mg.157 Pyridoxal and pyridoxal phosphate, the principal forms of the vitamin present in blood, are highly protein bound. Pyridoxal crosses the placenta, and plasma concentrations in the fetus are 5 times greater than maternal plasma concentrations. The concentration of vitamin B₆ in milk is about 150-240 ng/mL following maternal intake of 2.5-5 mg of vitamin B₆ daily.157 Following maternal intake of less than 2.5 mg of vitamin B₆ daily, vitamin B₆ concentration in milk averages 130 ng/mL.157

Elimination

In erythrocytes, pyridoxine is converted to pyridoxal phosphate and pyridoxamine is converted to pyridoxamine phosphate. In the liver, pyridoxine is phosphorylated to pyridoxine phosphate and transaminated to pyridoxal and pyridoxamine which are rapidly phosphorylated. Riboflavin is required for the conversion of pyridoxine phosphate to pyridoxal phosphate. The principal forms of the vitamin in the blood are pyridoxal and pyridoxal phosphate.

The biologic half-life of pyridoxine appears to be 15-20 days. In the liver, pyridoxal is oxidized to 4-pyridoxic acid which is excreted in urine. In cirrhosis, the rate of degradation may be increased. Pyridoxal is removed by hemodialysis.

Chemistry and Stability

Chemistry

Vitamin B₆ (as pyridoxine, pyridoxal, and pyridoxamine) is a water-soluble, B complex vitamin which is present in many foods including cereal grains, legumes, vegetables, liver, meat, and eggs. Commercially available pyridoxine hydrochloride is prepared synthetically. Pyridoxine hydrochloride occurs as white to practically white crystals or crystalline powder and is freely soluble in water and slightly soluble in alcohol. The drug has a slightly bitter, salty taste. Sodium hydroxide and/or hydrochloric acid are added to commercially available pyridoxine hydrochloride injections to adjust the pH to 2-3.8.

Stability

Pyridoxine hydrochloride is photosensitive and will degrade slowly when exposed to light. Pyridoxine hydrochloride preparations should be protected from light and stored in well-closed containers at a temperature less than 40°C, preferably between 15-30°C; freezing of the injection should be avoided.

Pyridoxine hydrochloride is incompatible with alkaline solutions, iron salts, and oxidizing agents.

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