PYRIDOXINE HCL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Administer with a meal preferably.

For acute isoniazid overdose
-If sufficient quantities of the injectable formulation are not available, consideration may be given to crushing oral pyridoxine tablets and administering with fluids via a nasogastric tube.

Extemporaneous Compounding-Oral
NOTE: Extemporaneous compounding of oral suspension from the injectable product is not FDA-approved.
-A 25 mg/mL oral suspension was compounded by diluting pyridoxine injection (100 mg/mL) with Oral Mix or Oral Mix SF suspension vehicles.
-Storage: The suspension was stable in amber glass bottles, plastic bottles, or oral plastic syringes at 25 degrees C or in amber glass bottles or plastic bottles at 4 degrees C for up to 91 days.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Intravenous (IV) Push
Vials for Injection
-Administration via slow IV push over 3 to 5 minutes has been suggested in cases of acute isoniazid overdose.

Intravenous (IV) Infusion
Vials for Injection
Dilution
-5 g diluted in 50 to 100 mL 5% Dextrose Injection has been suggested in cases of acute isoniazid overdose.

Intermittent IV Infusion
-Administration via IV infusion over 30 to 60 minutes or at a rate of 500 mg/minute has been suggested in cases of acute isoniazid overdose.

Pyridoxine is considered nontoxic in regular doses; however, nausea/vomiting, headache, paresthesias, and somnolence have been reported. Ataxia, incoordination, and seizures have been associated with very high doses (2000-6000 mg/day) of pyridoxine. In addition, excessive chronic administration (100-6000 mg/day) in adult patients has occasionally resulted in sensory peripheral neuropathy, characterized by bilateral paresthesias, hyperesthesia, limb pain, ataxia, and incoordination. Symptoms typically resolve within 6 months after pyridoxine withdrawal.

Sedation (drowsiness), hypotonia, and respiratory depression, including apnea and dyspnea requiring resuscitation have been reported after intravenous and oral administration of pyridoxine to infants with pyridoxine-dependent seizures. In addition, prolonged neurologic and respiratory depression, as well as depression of cerebral electrical activity have been reported. Bradycardia and hypotension have also been reported with intravenous pyridoxine use in this population. Neonates, infants, and children receiving pyridoxine for the diagnosis or treatment of seizures should be monitored carefully and resuscitative equipment should be readily available during administration of diagnostic doses.

Low serum folic acid levels have been reported with pyridoxine use. In addition, 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.

Pyridoxine is contraindicated in patients with a hypersensitivity to it or any component of the formulation.

Parenteral pyridoxine solutions contain aluminum. Patients with renal impairment and those receiving high doses or prolonged administration of pyridoxine are at risk for aluminum accumulation and toxicity. Premature neonates are at increased risk for aluminum toxicity because of their immature renal function and potential aluminum intake from other sources (e.g., parenteral calcium and phosphate solutions). Parenteral aluminum exposure > 4-5 mcg/kg/day is associated with central nervous system and bone toxicity; tissue loading may occur at lower daily doses.

Profound and prolonged CNS depression and respiratory depression, some requiring ventilatory assistance, have been reported after oral and parenteral administration of pyridoxine to neonates, infants, and children with pyridoxine-dependent seizures. In addition, bradycardia and hypotension have been reported in an infant receiving a 100 mg dose of intravenous pyridoxine. Neonates, infants, and children receiving pyridoxine for the diagnosis or treatment of pyridoxine-dependent seizures should be monitored carefully; resuscitative equipment should be readily available during administration of diagnostic doses.

Description: Pyridoxine, or vitamin B6, is a naturally occurring, water-soluble vitamin found in food such as cereal grains, legumes, vegetables, liver, meat, and eggs. Pyridoxine is used to treat and prevent vitamin B6 deficiency caused by inadequate nutrition, drugs or toxins, and/or inborn errors of metabolism. In neonates, infants, and young children, it is used to diagnose and treat pyridoxine-dependent seizures. In patients of all ages, pyridoxine is used to prevent or treat toxicity from isoniazid, cycloserine, penicillamine, or hydralazine; it is also used in the acute intoxication of Gyromitra esculenta mushrooms. Though considered nontoxic in regular doses, sensory peripheral neuropathies and seizures have been associated with very high doses. In addition, profound and prolonged central nervous system and respiratory depression, as well as hypotension and bradycardia, have been reported after administration of pyridoxine to infants with pyridoxine-dependent seizures. Pyridoxine is used in patients as young as neonates.

For nutritional supplementation:
Oral dosage:
Premature neonates: 150-210 mcg/kg/day PO. The daily requirement is directly related to protein intake.
Neonates and Infants <= 6 months: 0.1 mg/day PO is the adequate intake (AI). Alternatively, weight-based dosing is approximately 0.014 mg/kg/day.
Infants > 6 months: 0.3 mg/day PO is the adequate intake (AI). Alternatively, weight-based dosing is approximately 0.033 mg/kg/day.
Children 1-3 years: 0.5 mg/day PO is the recommended dietary allowance (RDA).
Children 4-8 years: 0.6 mg/day PO is the recommended dietary allowance (RDA).
Children >= 9 years and Adolescents 13 years: 1 mg/day PO is the recommended dietary allowance (RDA).
Adolescents >= 14 years: 1.2 mg/day PO is the recommended dietary allowance (RDA) for girls. In boys, the RDA is 1.3 mg/day PO.
Intravenous dosage*:
Neonates weighing < 2.5 kg: 0.4 mg/kg/day IV admixed with TPN. Max: 1 mg/day.
Neonates, Infants, Children, and Adolescents weighing 2.5-40 kg: 1 mg/day IV admixed with TPN.
Children and Adolescents weighing > 40 kg: Specific recommendations are not available; however, 10 ml/day of the IV adult parenteral multivitamin preparation, which contains 6 mg of pyridoxine, is recommended to be added to the TPN for nutritional supplementation in patients weighing > 40 kg.

For the treatment of vitamin B6 deficiency states, including neuritis, that are not drug-induced:
Oral dosage:
Children with neuritis: 10 to 50 mg/day for 3 weeks, then 1 to 2 mg/day PO supplemented in a multivitamin product. A pyridoxal phosphate concentration less than 20 nmol/L indicates a vitamin B6 deficiency.
Children without neuritis: 5 to 25 mg/day PO for 3 weeks, then 1.5 to 2.5 mg/day PO supplemented in a multivitamin product. A pyridoxal phosphate concentration less than 20 nmol/L indicates a vitamin B6 deficiency.

For the treatment of pyridoxine-dependent seizures* :
Intravenous dosage:
Neonates, Infants, and Children: 50 to 100 mg IV as a single dose for diagnostic purposes. If EEG and/or clinical improvement is not observed within 10 minutes, administer 100 mg IV sequentially every 5 to 10 minutes until improvement is seen. Recommended max: 500 mg total dose, however larger doses have been reported. Monitor neurologic, respiratory, and cardiovascular status carefully; resuscitative equipment should be readily available. If the patient responds to pyridoxine, it is recommended to begin a daily oral maintenance dose and discontinue other anticonvulsant medications.
Oral dosage (Diagnosis):
Neonates, Infants, and Children: 50 to 100 mg PO as a single dose; response should occur within 12 hours. Alternatively, 15 to 30 mg/kg/day PO has been used with a less dramatic clinical response occurring within 3 to 7 days of implementation. While some experts use a maximum dose similar to single dose therapy (50 mg), doses as high as 1000 mg/kg/day have been described. Monitor neurologic, respiratory, and cardiovascular status carefully during administration of large doses; resuscitative equipment should be readily available. Definitive diagnosis is made when therapy discontinuation results in a reemergence of seizure activity within several days to 6 weeks, which then again responds to pyridoxine monotherapy. Although dosing is provided for the oral formulation, most experts recommend IV pyridoxine for diagnosis. If the patient responds to a diagnostic dose of pyridoxine, it is recommended to begin a daily oral maintenance dose and discontinue other anticonvulsant medications.
Oral dosage (Maintenance):
Neonates, Infants, Children: If the patient responds to a diagnostic dose of pyridoxine, it is recommended to begin a daily oral maintenance dose and discontinue other anticonvulsant medications. An initial maintenance dose of 5 mg/kg/day PO once daily or divided twice daily, titrated as needed to suppress seizure activity has been recommended. Maintenance dosing is not firmly established; some experts recommend doses up to 20 mg/kg/day with a maximum dose of 500 mg. Typically, the final dose maintains efficacy throughout childhood, without weight-adjustment for growth. Dosing requirements may transiently increase with illness.

For the treatment of hydralazine toxicity* and penicillamine toxicity*:
Oral dosage:
Children: 10 to 50 mg/day PO.
Adolescents: 100 to 300 mg/day PO.

For hydralazine toxicity prophylaxis* and penicillamine toxicity prophylaxis*:
Oral dosage:
Children: 1 to 2 mg/kg/day PO.
Adolescents: 25 to 100 mg/day PO.

For the treatment of acute isoniazid overdose*, including drug-induced seizures*:
-for the treatment of acute isoniazid overdose in an asymptomatic person with a known amount of isoniazid ingested:
Intravenous dosage:
Infants, Children, and Adolescents: 1 g pyridoxine IV per 1 g isoniazid as a single dose. May repeat dose if necessary. Usual Max: 5 g or 80 mg/kg, whichever is lower.
Oral dosage:
Infants, Children, and Adolescents: 1 g pyridoxine PO per 1 g isoniazid if IV pyridoxine is unavailable. May repeat dose if necessary. Usual Max: 5 g or 80 mg/kg, whichever is lower.
-for the treatment of acute isoniazid overdose in an asymptomatic person with an unknown amount of isoniazid ingested:
Intravenous dosage:
Infants, Children, and Adolescents: 70 to 80 mg/kg/dose IV as a single dose. May repeat dose if necessary. Usual Max: 5 g or 80 mg/kg, whichever is lower.
Oral dosage:
Infants, Children, and Adolescents: 70 to 80 mg/kg/dose PO as a single dose if IV pyridoxine is unavailable. May repeat dose if necessary. Usual Max: 5 g or 80 mg/kg, whichever is lower.
-for the treatment of acute isoniazid overdose in a symptomatic person with a known amount of isoniazid ingested:
Intravenous dosage:
Infants, Children, and Adolescents: 1 g pyridoxine IV per 1 g isoniazid as a single dose. Alternatively, 0.5 mg/minute IV until seizures stop or maximum dose reached; once seizures stop, infuse the remainder of the dose over 4 to 6 hours to maintain pyridoxine availability during isoniazid elimination. May repeat dose if necessary. Usual Max: 5 g or 80 mg/kg, whichever is lower.
Oral dosage:
Infants, Children, and Adolescents: 1 g pyridoxine PO per 1 g isoniazid if IV pyridoxine is unavailable. May repeat dose if necessary. Usual Max: 5 g or 80 mg/kg, whichever is lower.
-for the treatment of acute isoniazid overdose in a symptomatic person with an unknown amount of isoniazid ingested:
Intravenous dosage:
Infants, Children, and Adolescents: 70 to 80 mg/kg/dose IV as a single dose. Alternatively, 0.5 mg/minute IV until seizures stop or maximum dose reached; once seizures stop, infuse the remainder of the dose over 4 to 6 hours to maintain pyridoxine availability during isoniazid elimination. May repeat dose if necessary. Usual Max: 5 g or 80 mg/kg, whichever is lower.
Oral dosage:
Infants, Children, and Adolescents: 70 to 80 mg/kg/dose PO as a single dose if IV pyridoxine is unavailable. May repeat dose if necessary. Usual Max: 5 g or 80 mg/kg, whichever is lower.

For the treatment of mushroom poisoning*, specifically Gyromitra esculenta:
Intravenous dosage:
Infants, Children, and Adolescents: 25 mg/kg IV administered over 15-30 minutes. Max initial dose: 5 grams. Repeat dose as necessary up to 300 mg/kg/day. Max: 15-20 grams/day.

For the treatment of isoniazid toxicity* (other than seizures) related to pyridoxine deficiency:
Oral dosage:
Infants, Children, and Adolescents: 2 to 5 mg/kg/dose (Max: 100 mg/dose) PO once daily.

For isoniazid toxicity prophylaxis:
-for isoniazid toxicity prophylaxis during treatment of tuberculosis infection:
Oral dosage:
Neonates*: 1 to 2 mg/kg/dose PO once daily for patients at risk of neuropathy (e.g., persons with HIV, nutritional deficiency, or breast-feeding children).
Infants, Children, and Adolescents: 0.5 to 2 mg/kg/dose (Max: 50 mg/dose) PO once daily for patients at risk of neuropathy (e.g., persons with HIV, diabetes, alcoholism, nutritional deficiency, chronic renal failure, or breast-feeding children).
-for isoniazid toxicity prophylaxis during daily treatment for latent tuberculosis infection (LTBI):
Oral dosage:
Infants, Children, and Adolescents: 0.5 to 2 mg/kg/dose (Max: 50 mg/dose) PO once daily for patients at risk of neuropathy (e.g., persons with HIV, diabetes, alcoholism, nutritional deficiency, chronic renal failure, or breast-feeding children).
-for isoniazid toxicity prophylaxis during weekly treatment of latent tuberculosis infection (LTBI):
Oral dosage:
Children and Adolescents 2 to 17 years: 50 mg PO once weekly for patients at risk of neuropathy (e.g., persons with HIV, diabetes, alcoholism, nutritional deficiency, chronic renal failure, or breast-feeding children).

For cycloserine toxicity prophylaxis*:
Oral dosage:
Infants, Children, and Adolescents: 0.5 to 2 mg/kg/dose (Max: 50 mg/dose) PO once daily.

For ethionamide toxicity prophylaxis:
Oral dosage:
Infants, Children, and Adolescents: 0.5 to 2 mg/kg/dose (Max: 50 mg/dose) PO once daily.

For the treatment of cycloserine toxicity* related to pyridoxine deficiency:
Oral dosage:
Infants, Children, and Adolescents: 2 to 5 mg/kg/dose (Max: 100 mg/dose) PO once daily.

Maximum Dosage Limits:
NOTE: The Tolerable Upper Intake Level (UL) is defined as the highest daily intake of a nutrient that is likely to pose no risk (e.g., sensory neuropathy) in otherwise healthy individuals. The ULs are not intended to apply to individuals with specific vitamin-deficiency conditions; maximum doses for these conditions are based on indication and patient response.
-Neonates
Tolerable upper intake level (UL) is not determinable. For pyridoxine-dependent seizures, a maximum diagnostic dose of 500 mg IV has been recommended; however, higher doses have been used. Dose is dependent on patient response.
-Infants
Tolerable upper intake level (UL) is not determinable. Maximum doses have not been established for treatment of isoniazid overdose; however, doses up to and exceeding 80 mg/kg/dose IV and PO have been recommended. Doses up to 20 g/day IV have been used for mushroom poisoning.
-Children
1 to 3 years: 30 mg/day PO is the tolerable upper intake level (UL). Maximum doses have not been established for treatment of isoniazid overdose; however, doses up to and exceeding 80 mg/kg/dose IV and PO have been recommended. Doses up to 20 g/day IV have been used for mushroom poisoning.
4 to 8 years: 40 mg/day PO is the tolerable upper intake level (UL). Maximum doses have not been established for treatment of isoniazid overdose; however, doses up to and exceeding 80 mg/kg/dose IV and PO have been recommended. Doses up to 20 g/day IV have been used for mushroom poisoning.
9 to 12 years: 60 mg/day PO is the tolerable upper intake level (UL). Maximum doses have not been established for treatment of isoniazid overdose; however, doses up to and exceeding 80 mg/kg/dose or 5 g IV and PO have been recommended. Doses up to 20 g/day IV have been used for mushroom poisoning.
-Adolescents
13 years: 60 mg/day PO is the tolerable upper intake level (UL). Maximum doses have not been established for treatment of isoniazid overdose; however, doses up to and exceeding 80 mg/kg/dose or 5 g IV and PO have been recommended. Doses up to 20 g/day IV have been used for mushroom poisoning.
14 years and older: 80 mg/day PO is the tolerable upper intake level (UL). Maximum doses have not been established for treatment of isoniazid overdose; however, doses up to and exceeding 80 mg/kg/dose or 5 g IV and PO have been recommended. Doses up to 20 g/day IV have been used for mushroom poisoning.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed with oral therapy. However, limit intravenous pyridoxine use as aluminum accumulation may result.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Pyridoxine is a precursor to pyridoxal phosphate (PLP) and pyridoxamine phosphate. Pyridoxine functions as a coenzyme in the metabolism of proteins, carbohydrates, and fats. Its 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 the synthesis of gamma aminobutyric acid (GABA) in the central nervous system and the synthesis of heme.

Treatment of Pyridoxine-Dependent Seizures
Abnormalities in pyridoxine homeostasis may result in alterations in neurotransmission of dopamine, serotonin, glutamic acid, and GABA. Iatrogenic pyridoxine deficiency is associated with reduced brain concentrations of pyridoxal phosphate (PLP), glutamic acid decarboxylase, and GABA. Increased glutamic acid (excitatory neurotransmitter) and decreased GABA (inhibitory neurotransmitter) formation reduces cerebral inhibition and may result in the development of intractable epileptic seizures.

Treatment of Hydrazide- and Hydrazine-induced Seizures
Hydrazides and hydrazines, including isoniazid, prevent the conversion of pyridoxine to pyridoxal phosphate (PLP) through inhibition of the enzyme pyridoxine phosphokinase. Additionally, hydrazides combine with and inactivate PLP, disrupting the formation of GABA. Decreased GABA (inhibitory neurotransmitter) formation and increased glutamic acid (excitatory neurotransmitter) reduces cerebral inhibition, contributing to the development of seizures seen with hydrazide and hydrazine toxicity.

Pharmacokinetics: Pyridoxine is administered orally and by intravenous or intramuscular injection. The vitamin B6 group is composed of pyridoxine, pyridoxamine, and pyridoxal. Pyridoxine is not protein bound and has a Vd of 0.6 L/kg in adult patients. Pyridoxine and pyridoxal are taken up by erythrocytes, where pyridoxine is partially converted to pyridoxal and bound by hemoglobin. A substantial portion of the group is stored in the liver. After phosphorylation by pyridoxal kinase, all 3 forms are oxidized to pyridoxal phosphate (PLP) and released into plasma, where it is extensively protein bound. PLP is then dephosphorylated by alkaline phosphatase and taken up into other tissues. Excess PLP is oxidized in the liver to 4-pyridoxic acid, which is excreted in the urine. The half-life is approximately 15-20 days.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Pyridoxine is rapidly absorbed in the jejunum within 20 minutes of administration. Pyridoxine doses of 10-800 mg result in pyridoxal phosphate (PLP) concentrations of 518-732 nmol/L 4 hours after ingestion in adult patients.

Intravenous Route
After intravenous infusion of pyridoxine 100 mg over 6 hours in adult patients, pyridoxal phosphate (PLP) plasma and erythrocyte concentrations increased rapidly from 37 nmol/L to 2183 nmol/L in the plasma and undetectable to 5593 nmol/L in erythrocytes. Peak concentrations were achieved at the end of the infusion.