Overview of Pyridoxine HCl (Vitamin B6) Injection
Dosage Strength of Pyridoxine HCl Injection
100 mg/mL 30 mL Vial (Preserved with Benzyl Alcohol. Chlorobutanol-Free)
Pyridoxine is a form of vitamin B6 – a water-soluble vitamin. Pyridoxine hydrochloride is the stable salt form of pyridoxine.1 Pyridoxine hydrochloride injection is prescribed when oral administration is not feasible, e.g., in case of gastric malabsorption syndromes, and pre-operative and post-operative conditions requiring parenteral nutrition.
Pyridoxine, or vitamin B6, is a naturally occurring vitamin found in food such as cereal grains, legumes, vegetables, liver, meat, and eggs. Pyridoxine is used to treat and prevent vitamin B6 deficiency; to prevent or treat toxicity from isoniazid, cycloserine, or hydralazine; and to treat sideroblastic anemia associated with elevated serum iron levels. It also has been used in pyridoxine-dependent neonates to treat seizures that are unresponsive to conventional therapy and in patients with metabolic disorders such as xanthurenic aciduria, primary hyperoxaluria, primary cystathioninuria, and primary homocystinuria. Pyridoxine hydrochloride has been commercially available since approval by the FDA in 1940.
Inside the body, pyridoxine is converted into its active form, the coenzyme pyridoxal 5’-phosphate. Pyridoxal 5’-phosphate is a versatile coenzyme participating in over 100 biochemical reactions mediating protein, carbohydrate, and lipid metabolism.2 It is crucial for the production of neurotransmitters, including dopamine, serotonin, norepinephrine, and GABA. It is also involved in regulating steroid hormone receptors and modulating the affinity of hemoglobin for oxygen.
Since humans lack the enzymes required for vitamin B6 (and pyridoxine) biosynthesis, it is an essential nutrient that needs to be procured through the diet. Dietary sources rich in vitamin B6 are fish, liver and other organ meats, potatoes and other starchy vegetables, and non-citrus fruits.3 Isolated vitamin B6 deficiency due to inadequate dietary intake is rare. Deficiency of vitamin B6 may occur in individuals with impaired renal function, genetic or autoimmune disorders, high alcohol intake, and with prolonged use of drugs including isoniazid, cycloserine, anti-epileptics, and oral contraceptives.345 In individuals with rheumatoid arthritis and inflammatory bowel disease, inflammatory cytokines cause low vitamin B6 levels, with greater deficiency associated with higher disease severity. People with celiac disease and other malabsorptive autoimmune disorders have vitamin B6 deficiency due to consuming a gluten-free diet low in essential vitamins.6 In people with alcohol dependence, the acetaldehyde produced from alcohol competes with the active form of pyridoxine for protein binding. Unbound pyridoxal 5’-phosphate – the active coenzyme form of pyridoxine – is rapidly hydrolyzed, resulting in vitamin B6 deficiency with high alcohol intake.7 Drugs like isoniazid and cycloserine interfere with enzymes that convert pyridoxine into pyridoxal-5-phosphate or enhance the catabolism and excretion of pyridoxine, resulting in vitamin B6 deficiency with prolonged use.23
Vitamin B6 deficiency may produce symptoms such as electroencephalogram abnormalities, seizures, peripheral neuropathy, depression, confusion, dermatitis with scaling lips and cracks at the corners of the mouth, glossitis, microcytic anemia, and a weakened immune system.3 Low levels of vitamin B6 are associated with an increased risk of cardiovascular disorders, cognitive impairment, and certain types of cancer.23 However, more evidence is needed to conclusively demonstrate whether vitamin B6 supplementation reduces the risk or severity of these conditions.
Mechanisms of Action
Vitamin B6 is composed of pyridoxine, pyridoxal, and pyridoxamine, and food usually contains all three forms. Pyridoxine is converted in erythrocytes to its active moiety, pyridoxal phosphate (requiring riboflavin for the conversion), while pyridoxamine is converted into pyridoxamine phosphate. These active forms act as coenzymes for no fewer than 60 metabolic processes including the metabolism of fat, protein, and carbohydrate. Their role in protein metabolism includes decarboxylation of amino acids, conversion of tryptophan to niacin or serotonin, deamination, and transamination of amino acids. In carbohydrate metabolism, it is necessary for the conversion of glycogen to glucose-1-phosphate. Pyridoxine is essential for synthesis of gamma aminobutyric acid (GABA) in the CNS and synthesis of heme.
Pyridoxine hydrochloride is used for the prophylaxis and treatment of vitamin B6 deficiency. Vitamin B6 is the collective term encompassing six closely-related compounds: pyridoxine, pyridoxal, and pyridoxamine, as well as their 5’-phosphate esters. Pyridoxal 5’-phosphate (PLP) and pyridoxamine 5’-phosphate (PMP) are the biologically active forms of vitamin B6.23
PLP is the primary coenzyme used by pyridoxine-dependent enzymes. It catalyzes various transamination, decarboxylation, and racemization reactions in the body by acting as an electron sink. PLP-catalyzed transamination of amino acids to keto acids occurs during gluconeogenesis. PLP-mediated decarboxylation of L-amino acids yields biogenic amines that are precursors of neurotransmitters and hormones. PLP also acts as a coenzyme for the synthesis of nucleic acids, sphingomyelin, and heme precursors.2
PLP plays a crucial role in the one-carbon unit generation and homocysteine metabolism. Therefore, pyridoxine is used in the management of B6-responsive homocystinuria. Homocystinuria is a genetic disorder caused by mutations in the gene encoding for the enzyme cystathionine β-synthase that converts methionine to cysteine.8 It is characterized by elevated plasma homocysteine and methionine levels.
Given its role in the synthesis of heme precursors, pyridoxine is used to treat congenital and acquired sideroblastic anemia. Sideroblastic anemia is characterized by iron overload and decreased production of mature red blood cells.9 Congenital sideroblastic anemia is caused by mutations in enzymes of the heme biosynthesis pathway. Acquired sideroblastic anemia is also linked to impaired heme biosynthesis due to excessive alcohol consumption, heavy metal toxicity, and prolonged use of certain medications.
Pyridoxine is administered orally and by intramuscular or intravenous injection. Vitamin B6 is stored in the liver, with small amounts in the brain and muscles. The total body storage for adults is between 16—27 mg. Pyridoxal crosses the placenta, with fetal concentrations five times that of maternal plasma concentrations. Pyridoxal and pyridoxal phosphate are the primary forms of vitamin B6 in the blood. Pyridoxal phosphate is 100% protein-bound. The half-life of pyridoxine is 15—20 days. Conversion of pyridoxine to pyridoxal phosphate, and pyridoxamine to pyridoxamine phosphate takes place in erythrocytes. Pyridoxine is also phosphorylated in the liver. Pyridoxal is oxidized in the liver to produce 4-pyridoxic acid, which is excreted in the urine.
All forms of orally administered vitamin B6 are absorbed in the small intestine, mainly in the upper jejunum.2 Orally administered pyridoxine has a bioavailability of 61% to 81%.12 Pyridoxine is rapidly taken up by mucosal cells lining the small intestine via active transport and diffusion. Once inside the cell, pyridoxine is phosphorylated by ATP-dependent pyridoxine kinase into pyridoxal 5-phosphate (PLP), preventing its transport out of the cell. PLP needs to be dephosphorylated in order to be transported across the basolateral membrane of mucosal cells and into the bloodstream. In circulation, PLP binds to albumin and is concentrated in red blood cells by binding to hemoglobin. PLP is mainly metabolized in the liver to 4-pyridoxic acid, which is then excreted through urine.13 In adults, the half-life of pyridoxine is 15 to 20 days.1
Bioavailability of parenterally administered pyridoxine was greater than oral administration.14 Intravenously infused pyridoxine is not protein-bound and easily penetrates cell membranes. When administered as an IV infusion of 100 mg pyridoxine hydrochloride over 6 hours, pyridoxine rapidly reached steady-state concentration in the plasma. High amounts of PLP were detected in plasma and concentrated in erythrocytes.14 Approximately 63% of the infused dose was excreted in urine as 4-pyridoxic acid, while less than 7% was excreted unchanged as pyridoxine.13
This medication is contraindicated in individuals with hypersensitivity to pyridoxine or any inactive ingredients in the parenteral formulation.
Parenteral pyridoxine solutions contain varying concentrations of aluminum. Patients with renal impairment, especially as seen in premature neonates, are at risk of aluminum accumulation which may result in toxicity. Limit intravenous pyridoxine therapy and consider the cumulative aluminum content among all therapies under administration in patients with renal impairment. It is noted that 4—5 mcg/kg/day of IV aluminum leads to accumulation at concentrations associated with CNS and bone toxicity; further, aluminum tissue loading is possible at lesser, but undefined, daily administration rates.15 Aluminum concentration in parenteral solutions can be obtained by direct manufacturer inquiry.
Pyridoxine may reduce the efficacy of levodopa by accelerating its metabolism. However, it may be used concurrently in patients receiving combination carbidopa and levodopa therapy.24 Pyridoxine may also inhibit the effectiveness or duration of action of altretamine, barbiturates, and anticonvulsant medications.25
Pyridoxine hydrochloride injection may be administered via intravenous (IV) or intramuscular (IM) routes. Administer as a direct IV injection or as an intermittent IV infusion in a standard IV solution. For IM administration, inject into a large muscle and rotate injection sites to avoid injury or discomfort upon repeated use.
Appropriate maternal pyridoxine intake is encouraged during pregnancy (FDA pregnancy risk category A), and the requirement for pyridoxine appears to be increased during pregnancy.15 Pyridoxine (up to 40 mg/day) in combination with doxylamine is FDA-approved for the treatment of pregnancy-induced nausea and vomiting. No increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride was noted in a meta-analysis. Further, no statistically significant relationships between fetal abnormalities and the first trimester use of the combination doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride were noted in a separate meta-analysis.16
The requirement for vitamin B6 increases during pregnancy and lactation. The use of vitamin B6 supplements to reduce nausea and vomiting in pregnant women has yielded mixed results. Two randomized controlled trials reported that 30 to 75 mg oral pyridoxine per day significantly reduced nausea in pregnant women.1718 However, a systematic review of 27 studies found limited evidence to support the benefits of pyridoxine for treating morning sickness.19 Greater benefits have been observed with an oral combination of vitamin B6 and doxylamine. Nonetheless, the American Congress of Obstetrics and Gynecology recommends starting with a daily dose of 10 to 25 mg of pyridoxine three to four times a day, and only adding doxylamine if monotherapy fails to confer any benefits.20
Pyridoxine is excreted in human milk. Appropriate maternal intake of pyridoxine (vitamin B6) is important during lactation, and no problems have been identified with maternal supplementation to achieve adequate intake goals during breastfeeding. The American Academy of Pediatrics (AAP) has considered the use of pyridoxine compatible with breastfeeding.21 Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Whether high doses of pyridoxine are effective in suppressing post-partum lactation has been tested. A systematic review of seven studies administered 450 to 600 mg pyridoxine orally for up to a week found the evidence inconclusive.22 Studies assessing pyridoxine safety found no untoward side effects. Pyridoxine levels in breast milk are associated with maternal pyridoxine intake. Pyridoxine supplementation during the first trimester of pregnancy was not associated with teratogenic effects in neonates.23
Adverse Reactions/Side Effects
High doses of pyridoxine hydrochloride injection may cause adverse effects due to aluminum in the parenteral formulation.1 In patients with impaired kidney function and premature neonates, aluminum in the formulation may reach toxic levels upon prolonged parenteral administration. Severe sensory neuropathy has been reported in patients treated with 1 to 6 g/day of pyridoxine hydrochloride.2 The lowest dose at which sensory neuropathy has been observed is 500 mg/day. Therefore, the Food and Nutrition Board has set a safe upper limit of 100 mg/day of pyridoxine for adults.26 These upper limits do not apply to individuals administered pyridoxine for medical treatment under the supervision of a physician. Common adverse events at low doses of pyridoxine include indigestion, nausea, breast tenderness, photosensitivity, and vesicular dermatoses.
Pyridoxine is considered nontoxic in regular doses; however, nausea/vomiting, headache, paresthesias, hyperesthesia, somnolence, and low serum folic acid levels have been reported. Excessive, chronic dosages of pyridoxine (2—6 grams/day) have been associated with a severe sensory peripheral neuropathy or neuronopathy syndrome. This may result from neuron susceptibility in the dorsal root ganglia. One patient who consumed 5 g/day developed pseudoathetosis of the outstretched arms, ataxia, and absent limb reflexes. Seven months after discontinuation of high-dose pyridoxine, she felt much improved, could walk steadily without a cane, could stand with her eyes closed, but still had shooting pains in her calves and shins. Other patients who took several g/day for several months developed unstable gait, perioral numbness, and a "stocking-glove" sensory loss. Seizures have occurred following large IV doses of pyridoxine. Seizures in neonates have occurred following the use of large doses of pyridoxine during pregnancy. Adverse neurologic reactions with lower dosages have been reported less frequently.15272829
A transient worsening of metabolic acidosis, which is frequently present in patients with seizures, may occur after rapid infusion of large pyridoxine doses. Pyridoxine injection is acidic (pH 2—3.8). In a randomized, controlled crossover trial of 5 adult patients, 5000 mg of pyridoxine administered over 5 minutes induced a significant but transient increase in the base deficit; mean maximal increase in base deficit was 2.74 mEq/L at 3 minutes after infusion. Resolution occurred 30 minutes after the infusion.15 
Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.
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