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PYRIDOXINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Pyridoxine is a water-soluble pyridine B-complex vitamin.

Specific Substances

    A) PYRIDOXINE
    1) 3-hydroxy-4,5-dimethylol-alpha-picoline
    2) 5-hydroxy-6-methyl-3,4-pyridine dimethanol
    3) PN
    4) Pridoxine
    5) Pyridoxal
    6) Pyridoxin
    7) Vitamin B6
    8) CAS 65-23-6
    PYRIDOXINE HYDROCHLORIDE
    1) Pyridoxal hydrochloride
    2) Pyridoxinium chloride
    3) Vitamin B6 hydrochloride
    4) CAS 58-56-0
    PYRIDOXINE TRIPALMITATE
    1) Pyridoxal tripalmitate
    2) Vitamin B6 tripalmitate
    3) CAS 4372-46-7
    PYRIDOXINE 5'-PHOSPHATE
    1) PNP
    PYRIDOXAL 5'-PHOSPHATE
    1) PLP
    PYRIDOXAL
    1) PL
    PYRIDOXAMINE 5'-PHOSPHATE
    1) PMP
    PYRIDOXAMINE
    1) PM

Available Forms Sources

    A) FORMS
    1) Pyridoxine hydrochloride is available in 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg tablets, 200 mg extended-release tablets, 150 mg capsules, and 25 mg mucous membrane lozenges/troches (Prod Info VITAMIN B-6 oral tablets, 2007; Prod Info VITAMIN B-6 oral liquid, 2007).
    2) Injectable pyridoxine hydrochloride contains 100 mg/mL (Prod Info pyridoxine HCl IM, IV injection, 2008).
    B) SOURCES
    1) Pyridoxine is found in various multi-vitamin preparations, as vitamin B6, as well as in vitamin preparations as the sole ingredient.
    C) USES
    1) Pyridoxine is indicated for the prophylaxis and treatment of pyridoxine deficiency, which can occur as a result of poor diet, specific disease states, and drug therapy (eg, isoniazid) (Prod Info VITAMIN B-6 oral tablets, 2007; Prod Info VITAMIN B-6 oral liquid, 2007; JEF Reynolds , 2000).
    2) Pyridoxine has also been used to treat seizures due to hereditary syndromes of pyridoxine deficiency or dependency in infants (JEF Reynolds , 2000).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Pyridoxine is indicated for the prophylaxis and treatment of pyridoxine deficiency, which can occur as a result of poor diet, specific disease states, and drug therapy (eg, isoniazid).
    B) PHARMACOLOGY: Vitamin B6 exists in nature as pyridoxine, pyridoxal, and pyridoxamine. They are converted in vivo to the active coenzyme form, pyridoxal-5-phosphate. Pyridoxal coenzymes are cofactors in over 60 physiological enzymatic reactions, including conversion of tryptophan to niacin, synthesis of neurotransmitters (norepinephrine, serotonin, histamine), and production of porphyrins and hemoglobin.
    C) TOXICOLOGY: The mechanism of pyridoxine-induced neurotoxicity has not been fully elucidated. There is some evidence of direct toxicity of pyridoxine base in dorsal root ganglia cell cultures.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) Clinical effects are likely related to chronic use. Paresthesia and somnolence can occur with use. There are sporadic anecdotal reports of patients who developed non-specific neurological symptoms (lethargy, somnolence, insomnia) after taking 5 to 100 mg/day. A reversible skin lesion similar to that of porphyria cutanea tarda may accompany the sensory neuropathy. Photosensitivity, dermatitis and insomnia have also been reported. Transient withdrawal symptoms (nervousness, tremors, abnormal EEG) have been described in some adults following the cessation of 200 mg/day for over a month.
    F) WITH POISONING/EXPOSURE
    1) The principal effect of pyridoxine overdose is sensory axonal neuropathy. Symptoms include numbness, burning, shooting, or tingling pain, clumsiness, and ataxia. Other neurologic symptoms may include depression, headache, tiredness, and irritability. 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. Neuropathy has been most commonly reported after chronic ingestion of high doses for months or years. It usually improves in all cases, following removal of pyridoxine. Nystagmus has also been observed in overdose. Several cases of subepidermal vesicular dermatosis, resembling porphyria cutanea tarda, have occurred over photosensitive areas in women taking megadose oral pyridoxine.
    0.2.20) REPRODUCTIVE
    A) U.S. Food and Drug Administration's Pregnancy Category A; if used in doses above the RDA it is classified as FDA Pregnancy Category C. The combination product doxylamine succinate/pyridoxine hydrochloride is approved for use in pregnant women. Epidemiological studies have reported no increased risk in malformations due to in utero exposure to doxylamine succinate/pyridoxine hydrochloride. A relationship between fetal abnormalities and exposure has not been established.

Laboratory Monitoring

    A) Monitor neurologic exam following a significant overdose. Nerve conduction studies may be useful to assess patients with clinical evidence of neuropathy.
    B) Determination of a pyridoxine plasma concentration may be useful in evaluating patients with chronic pyridoxine toxicity. Normal concentrations range from 3.6 to 18 ng/mL.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. There is no known antidote for prevention or treatment of the sensory neuropathy produced by high doses of pyridoxine. Recovery occurs slowly over several months or years. Careful neurologic assessment and follow-up is indicated in patients with neurologic signs or symptoms.
    C) DECONTAMINATION
    1) PREHOSPITAL: Although toxicity has not been reported after an acute ingestion, and prehospital decontamination is not generally necessary, it should be considered in patients with large/massive ingestions.
    2) HOSPITAL: Although toxicity has not been reported after an acute ingestion, consider activated charcoal only after very large ingestions 150 mg/kg (30 high-potency B-Complex tablets/capsules in a 10-kg child) or greater.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory distress.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Based on high water solubility, low protein-binding, and a very low volume of distribution, pyridoxine is probably effectively removed by dialysis.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable. Follow-up by an experienced neurologist should be extended for at least 7 days after an acute ingestion of potentially toxic amounts, since delayed neurologic effects have been reported.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted. Patients exhibiting neurological signs or symptoms should receive a thorough neurologic examination and should be admitted for neurological monitoring and possible admission to an intensive care unit. The few cases of acute human parenteral overdoses reported have also suggested a delayed onset of toxicity of days or weeks following completion of pyridoxine administration.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected pyridoxine overdose, the possibility of multidrug involvement should be considered. Early symptoms of overdose may be delayed or not evident.
    I) PHARMACOKINETICS
    1) Protein binding: Not bound to plasma proteins. Vd: 0.07 to 0.17 L/kg. Excretion: Pyridoxine is excreted primarily in the urine, mostly as 4-pyridoxic acid. Elimination half-life: After a 750 mg oral dose, it was 1.7 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause neuropathy.

Range Of Toxicity

    A) TOXICITY: The minimum acute oral toxic dose for humans is unknown. ACUTE TOXICITY: One patient who received approximately 140 mg/kg IV of pyridoxine developed reversible neuropathy; however, up to 357 mg/kg IV has been tolerated in patients treated for isoniazid overdose. Two adults who received greater than 2 g/kg IV over 3 days developed severe sensory neuropathy, weakness, and autonomic dysfunction. A single intravenous dose of 10 grams has caused neuropathy in an adult. CHRONIC TOXICITY: Chronic ingestion of 200 to 9,600 mg/day for months to years has resulted in neuropathy.
    B) THERAPEUTIC DOSE: ADULT: Vitamin B6 deficiency: Injection: 10 to 20 mg IM or IV daily for 3 weeks. Therapy for vitamin B6 dependency syndrome may require doses as high as 600 mg daily with a continuing daily dose of 30 mg for life. ORAL: Follow up to injection therapy: 2 to 5 mg orally with therapeutic multivitamin preparation daily for several weeks. Pyridoxine dependency syndrome: up to 600 mg/day IV/IM/orally. Deficiency related to isoniazid: 100 mg IV or IM daily for 3 weeks followed by a 30 mg daily maintenance dose. Toxicity due to isoniazid ingestion greater than 10 g: 4 g IV followed by 1 g IM every 30 minutes, to reach an amount equal to the number of grams of isoniazid ingested.
    C) THERAPEUTIC DOSE: PEDIATRIC: Pyridoxine deficiency: With peripheral neuropathy: Oral: 10 to 50 mg/day orally for 3 weeks, then 1 to 2 mg/day in a multivitamin product. Without neuritis: Oral: 5 to 25 mg/day orally for 3 weeks, followed by 1.5 to 2.5 mg/day in a multivitamin product. Pyridoxine-dependent seizures (PDS): IV: 50 to 100 mg IV as a single dose. If EEG improvement is not observed within 10 minutes, give additional 100-mg doses, up to 500 mg. ORAL: 15 to 30 mg/kg/day orally. MAINTENANCE: 3 to 5 mg/kg/day orally for life or daily dose sufficient to suppress seizure activity. Doses as high as 1000 mg/day have been reported for seizure control.

Clinical Effects

Summary Of Exposure

    A) USES: Pyridoxine is indicated for the prophylaxis and treatment of pyridoxine deficiency, which can occur as a result of poor diet, specific disease states, and drug therapy (eg, isoniazid).
    B) PHARMACOLOGY: Vitamin B6 exists in nature as pyridoxine, pyridoxal, and pyridoxamine. They are converted in vivo to the active coenzyme form, pyridoxal-5-phosphate. Pyridoxal coenzymes are cofactors in over 60 physiological enzymatic reactions, including conversion of tryptophan to niacin, synthesis of neurotransmitters (norepinephrine, serotonin, histamine), and production of porphyrins and hemoglobin.
    C) TOXICOLOGY: The mechanism of pyridoxine-induced neurotoxicity has not been fully elucidated. There is some evidence of direct toxicity of pyridoxine base in dorsal root ganglia cell cultures.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) Clinical effects are likely related to chronic use. Paresthesia and somnolence can occur with use. There are sporadic anecdotal reports of patients who developed non-specific neurological symptoms (lethargy, somnolence, insomnia) after taking 5 to 100 mg/day. A reversible skin lesion similar to that of porphyria cutanea tarda may accompany the sensory neuropathy. Photosensitivity, dermatitis and insomnia have also been reported. Transient withdrawal symptoms (nervousness, tremors, abnormal EEG) have been described in some adults following the cessation of 200 mg/day for over a month.
    F) WITH POISONING/EXPOSURE
    1) The principal effect of pyridoxine overdose is sensory axonal neuropathy. Symptoms include numbness, burning, shooting, or tingling pain, clumsiness, and ataxia. Other neurologic symptoms may include depression, headache, tiredness, and irritability. 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. Neuropathy has been most commonly reported after chronic ingestion of high doses for months or years. It usually improves in all cases, following removal of pyridoxine. Nystagmus has also been observed in overdose. Several cases of subepidermal vesicular dermatosis, resembling porphyria cutanea tarda, have occurred over photosensitive areas in women taking megadose oral pyridoxine.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) NYSTAGMUS
    a) CASE SERIES: Nystagmus was described in two adults who received 132 and 183 grams of pyridoxine, respectively, intravenously over 3 days. The high dose of the chlorobutanol preservative also received may account for this finding (Albin et al, 1987).
    b) CASE SERIES: Puffy eyes occurred in 26/58 patients with reported blood concentrations above the therapeutic range (Dalton, 1985).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CHEST PAIN
    1) WITH POISONING/EXPOSURE
    a) Chest pain probably secondary to chronic pyridoxine therapy has been described (Dalton & Dalton, 1987).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Respiratory arrest was reported in a 27-year-old woman who received 132 grams of IV pyridoxine. The chlorobutanol preservative was implicated (Albin et al, 1987).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Uncontrolled studies claim that pyridoxine neuropathy may occur after daily intake (for months to years) of as little as 75 mg/day (Dalton, 1985), although more common doses in symptomatic patients would be from 500 mg/day (Berger & Schaumberg, 1984) to 2000 mg/day (Waterston & Gilligan, 1987; McLachlan & Brown, 1995).
    b) Sensory neuropathy, including paresthesias and reduced proprioception, occurred in 5 of 8 patients, who ingested pyridoxine 600 to 1200 mg/day for years (Ludolph et al, 1993).
    c) CASE REPORT/CHRONIC USE: A woman diagnosed with a 20-year history of systemic lupus, who appeared to be in remission, developed a peripheral sensory neuropathy that affected her hands and feet. Upon review of her medications, it was noted that the patient had been taking vitamin B supplements for 10 years, and they contained 50 times the recommended daily amount of pyridoxine. The patient was advised to stop the supplements, and after several months her neuropathy gradually resolved (Silva & D'cruz, 2006).
    2) WITH POISONING/EXPOSURE
    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) CASE REPORT/CHRONIC: Pure sensory neuropathy with profound muscle weakness and a positive Romberg's test was observed in a 75-year-old, wheelchair bound, man who self-administered 9.6 grams pyridoxine daily for 3 years for a presumed citric acid cycle imbalance. Therapy was stopped immediately. One year later, the patient was ambulating without assistance (Gdynia et al, 2008).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Exacerbation of seizures in one patient and deterioration of the EEG pattern in another have been reported after administration of pyridoxine hydrochloride to 2 patients with encephalitis (FDA, 1979).
    C) DRUG WITHDRAWAL
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Transient withdrawal symptoms (nervousness, tremors, abnormal EEG) were described in 3 of 8 adult men following cessation of doses of 200 mg/day for 33 days (Ekelund et al, 1969).
    1) However these findings have not been reproduced by other investigators (Shipman & Parker, 1986).
    D) DROWSY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Lethargy was reported in an adult receiving 50 mg/day chronically (Baumblatt & Winston, 1970). Somnolence was reported in some pyridoxine-sensitive individuals taking as little as 5 mg daily (Stein, 1969).
    E) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Excessive energy and insomnia were reported in a woman taking 100 mg/day, which resolved at a dose of 50 mg/day (Baumblatt & Winston, 1970).
    F) FACIAL PALSY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A Bell's palsy was reported in a patient taking 50 mg/day of pyridoxine hydrochloride for one month, but may have been coincidental and unrelated (FDA, 1986).
    G) NEURITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Neuritis was reported in a 99-year-old woman after receiving 800 mg intravenously (FDA, 1986).
    H) AMNESIA
    1) WITH THERAPEUTIC USE
    a) High-dose pyridoxine, 100 or 250 mg/day for 10 days, appeared to adversely affect memorization abilities in a placebo-controlled volunteer study (Molimard et al, 1980).
    I) DISORDER OF AUTONOMIC NERVOUS SYSTEM
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: Signs of autonomic dysfunction (ileus, acute urinary retention) were described in 2 patients who received more than 2 g/kg of intravenous pyridoxine (Albin et al, 1987).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) RATS: Seizures, ataxia, and peripheral neuropathy were reported in rats receiving 4 to 6 g/kg IV (Perry et al, 2004; Unna, 1940).
    2) NEUROTOXICITY
    a) PREDISPOSING CONDITIONS: One study reported that dietary protein deficiency increased the risk of neurotoxicity of pyridoxine in rats. After 3 or 7 days of pretreatment with protein-free semisynthetic diets, clinical neurological signs and histological lesions (in trigeminal ganglia) from pyridoxine injections were accelerated and intensified. The loss of body weight, decreased protein binding in serum, decreased consumption of water, and decreased volume of urine, which reduce the urinary losses of the toxicant, were found to cause these results. These clinical signs or lesions in ganglia were not observed following the administration of the related substances pyridoxal and pyridoxamine, or the coenzyme pyridoxal 5-phosphate, even after the use of maximum tolerated doses(Levine & Saltzman, 2004)

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 50-year-old woman who had been taking vitamin B6 3 times daily (total dose: 300 mg daily) for 6 months, presented with intermittent diarrhea, vomiting, and an increase in brown-colored skin, 10 months after undergoing a bariatric surgery procedure. Following the discontinuation of vitamin B6, her symptoms resolved, her pyridoxalphosphate levels decreased from 2083 nmol/L to 4.68 nmol/L (normal range: 6 to 34 nmol/L) and pyridoxal levels decreased from 129 nmol/L to 7.17 nmol/L (normal range: 16 to 78 nmol/L) (Cupa et al, 2015).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 50-year-old woman who had been taking vitamin B6 3 times daily (total dose: 300 mg daily) for 6 months, presented with intermittent diarrhea, vomiting, and an increase in brown-colored skin, 10 months after undergoing a bariatric surgery procedure. Following the discontinuation of vitamin B6, her symptoms resolved, her pyridoxalphosphate levels decreased from 2083 nmol/L to 4.68 nmol/L (normal range: 6 to 34 nmol/L) and pyridoxal levels decreased from 129 nmol/L to 7.17 nmol/L (normal range: 16 to 78 nmol/L) (Cupa et al, 2015).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: The development of end-stage renal failure was associated with the chronic ingestion of piridoxilate (600 mg/day), a vasodilator that is comprised of 27 mg glyoxalate and 73 mg pyridoxine, in a 71-year-old woman. The patient's lab analysis showed elevated serum creatinine and BUN concentrations and a renal biopsy showed renal tubules with varying degrees of atrophy and dilation and filled with calcium oxalate crystals (Mousson et al, 1993).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC PURPURA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Thrombocytopenic purpura was reported in a 67-year-old woman taking 250 mg daily orally (FDA, 1986).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Several cases of subepidermal vesicular dermatosis, resembling porphyria cutanea tarda, have occurred over photosensitive areas in women taking megadose oral pyridoxine.
    1) This lesion accompanies the neuropathy and gradually resolves following withdrawal of pyridoxine (Friedman et al, 1986).
    b) CASE REPORT: A 17-year-old laboratory assistant developed eczema on her hands and face following occupational exposure to pyritinol, a pyridoxine derivative (Wigger-Alberti & Elsner, 1997).
    B) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 35-year-old woman began taking 2 tablets of a multivitamin preparation, each tablet containing 100 mg pyridoxine, and, 1 month later, developed pruritic erythema on the sun-exposed areas of her neck. An oral photochallenge test with pyridoxine and UVA irradiation was positive (Morimoto et al, 1996).
    C) DISORDER OF SKIN COLOR
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 75-year-old caucasian man self-administered 9.6 grams pyridoxine daily for 3 years, and at presentation had significant yellowish-brown skin color. One year after stopping therapy, his skin had lost its yellowish color (Gdynia et al, 2008).
    b) CASE REPORT: A 50-year-old woman who had been taking vitamin B6 3 times daily (total dose: 300 mg daily) for 6 months, presented with intermittent diarrhea, vomiting, and an increase in brown-colored skin, 10 months after undergoing a bariatric surgery procedure. Following the discontinuation of vitamin B6, her symptoms resolved, her pyridoxalphosphate levels decreased from 2083 nmol/L to 4.68 nmol/L (normal range: 6 to 34 nmol/L) and pyridoxal levels decreased from 129 nmol/L to 7.17 nmol/L (normal range: 16 to 78 nmol/L) (Cupa et al, 2015).

Reproductive

    3.20.1) SUMMARY
    A) U.S. Food and Drug Administration's Pregnancy Category A; if used in doses above the RDA it is classified as FDA Pregnancy Category C. The combination product doxylamine succinate/pyridoxine hydrochloride is approved for use in pregnant women. Epidemiological studies have reported no increased risk in malformations due to in utero exposure to doxylamine succinate/pyridoxine hydrochloride. A relationship between fetal abnormalities and exposure has not been established.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) DOXYLAMINE/PYRIDOXINE
    a) The combination product doxylamine succinate/pyridoxine hydrochloride is approved for use in pregnant women. Epidemiological studies have reported no increased risk in malformations due to in utero exposure to doxylamine succinate/pyridoxine hydrochloride. A relationship between fetal abnormalities and exposure has not been established (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).
    b) An observational cohort study showed that prenatal exposure to the doxylamine succinate and pyridoxine hydrochloride combination product does not appear to adversely affect fetal brain development. The cohorts studied included 3 groups of mother-child pairs: 1) mothers with nausea and vomiting during pregnancy (NVP) treated with the doxylamine succinate and pyridoxine hydrochloride combination (n=45), 2) maternal NVP not treated with the combination (n=47), and 3) no NVP (n=29). When the children were between the ages of 3 and 7 years, they were assessed with a comprehensive battery of intelligence and neurocognitive tests. All children from the 3 groups scored within the normal range for IQ, with children from group 1 scoring significantly higher on Performance IQ than children from group 2 (P=0.01) or group 3 (P=0.002). Children from group 3 (no NVP) had significantly lower scores on the neuropsychology (NEPSY) test for verbal fluency compared with group 1 (P=0.013) or group 2 (P=0.047). Children from group 3 also had significantly lower scores on the McCarthy Numerical Memory Forward test compared with group 1 (P=0.004) or group 2 (P=0.018). While children from group 3 scored significantly lower on the NEPSY Phonological Processing test than children in group 1 (P=0.033), there was no difference in scores compared with group 2. A linear regression analysis determined that severity of NVP and maternal IQ were predictors of higher scores in children. Limitations of this study include its potential for recall bias due to its retrospective nature, cohort selectivity limited to 1 database, the use of different versions of assessment tests, and the broad range in ages of the children (Nulman et al, 2009).
    c) Ecological analyses of population results showed no evidence of teratogenic effects from the use of the doxylamine succinate and pyridoxine hydrochloride combination with or without dicyclomine hydrochloride (Bendectin, the product was reformulated in 1976 to remove the dicyclomine component). Specific birth defect data for the period from 1970 to 1992 obtained from the CDC's nationwide Birth Defect Monitoring Program were compared graphically to the annual sales in the United States (US) of the combination product for the treatment of nausea and vomiting during pregnancy (NVP) and annual US rates for hospitalization for NVP. None of the specific birth defects, including CNS, cardiac, facial cleft, gastrointestinal, genital, limb, genetic, and third trimester malformation, examined for the time from 1970 to 1992 show changes in temporal trends in prevalence rates that reflect the decline in Bendectin use from 1980 to 1984 (the manufacturer ceased production in June 1983). The rate of hospitalizations for NVP doubled from 7 per 1000 live births in the period from 1974 to 1980 to 15 or 16 per 1000 live births from 1980 to 1987. The lack of any evidence for decreased incidence of birth defects contemporaneously with decreased Bendectin use suggest an association between the product and teratogenic effects does not exist (Kutcher et al, 2003).
    d) Meta-analyses of 16 cohort and 11 case-control studies during pregnancy showed no significant difference in the relative risk of birth defects in infants whose mothers received the dicyclomine hydrochloride, doxylamine succinate, and pyridoxine hydrochloride combination product during the first trimester of pregnancy as compared with those infants whose mothers had not received the combination. The pooled estimate of the odds ratio (OR) for any malformation associated with exposure to the combination product during the first trimester was 0.95 (95% CI, 0.88 to 1.04). No evidence of heterogeneity was found among the studies included in the meta-analyses, which is consistent with the assumption that all the studies were measuring the same relative risk. A separate meta-analysis was conducted on each specific category of defect. The pooled OR for cardiac defects was 0.9 (95% CI, 0.77 to 1.05); for CNS malformations, it was 1.0 (95% CI, 0.83 to 1.2); for neural tube defects, 0.99 (95% CI, 0.76 to 1.29); for limb reduction defects, 1.12 (95% CI, 0.83 to 1.48); for genital tract defects, 0.98 (95% CI, 0.79 to 1.22); for oral cleft defects, 0.81 (95% CI, 0.64 to 1.03); and for pyloric stenosis, 1.04 (95% CI, 0.85 to 1.29). The test for heterogeneity showed no significant heterogeneity for each category of malformation, except for oral clefts and for pyloric stenosis, which showed significant heterogeneity (P=0.009 and P=0.004, respectively). The authors concluded that the therapeutic use of the combination product was unlikely the cause of human birth defects, because as a group, the studies showed no difference in the risk of birth defects for those infants who were exposed to the combination prenatally and those infants who were not exposed (McKeigue et al, 1994).
    3.20.3) EFFECTS IN PREGNANCY
    A) FETOTOXICITY
    1) The fetus has the ability to concentrate pyridoxal phosphate 6.6 times above maternal plasma concentrations (Brophy & Siiteri, 1975).
    2) Administration of large amounts during pregnancy resulted in an infant with a requirement for supplemental vitamin B6 (Hunt, 1954; Shane & Contractor, 1975).
    B) PHOCOMELIA
    1) The administration of 50 mg/day of pyridoxine during the first 7 months of pregnancy was associated with phocomelia in the newborn (Gardner et al, 1985).
    C) PREGNANCY CATEGORY
    1) The manufacturer has classified doxylamine succinate/pyridoxine hydrochloride as FDA pregnancy category A (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).
    2) Pyridoxine is classified as FDA pregnancy category A.
    3) The combination product doxylamine succinate/pyridoxine hydrochloride is approved for use in pregnant women. Epidemiological studies have reported no increased risk in malformations due to in utero exposure to doxylamine succinate/pyridoxine hydrochloride. A relationship between fetal abnormalities and exposure has not been established. Use the lowest effective dose when treating nausea and vomiting (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACTATION PUERPERAL DECREASED
    1) Doses greater than 100 to 200 mg daily of pyridoxine have been shown to inhibit lactation when given to nursing mothers, presumably due to inhibition of prolactin secretion (Lande, 1979).
    B) DOXYLAMINE/PYRIDOXINE
    1) Pyridoxine hydrochloride is excreted into breast milk. It is unknown if doxylamine succinate is excreted into breast milk, however, the molecular weight is low enough that excretion can be expected. Nursing infants have developed excitement, irritability, and sedation following exposure to doxylamine succinate through breast milk. Infants with apnea or other respiratory syndromes may be at greater risk for sedative effects of doxylamine succinate/pyridoxine hydrochloride resulting in worsening of their apnea or respiratory conditions. Due to the lack of information regarding the combination product and the potential for adverse effects in nursing infants, the manufacturer does not recommend the use of doxylamine succinate/pyridoxine hydrochloride in women who intend to breastfeed (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor neurologic exam following a significant overdose. Nerve conduction studies may be useful to assess patients with clinical evidence of neuropathy.
    B) Determination of a pyridoxine plasma concentration may be useful in evaluating patients with chronic pyridoxine toxicity. Normal concentrations range from 3.6 to 18 ng/mL.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Determination of a pyridoxine plasma concentration may be useful in evaluating patients with chronic pyridoxine toxicity. Normal concentrations range from 3.6 to 18 ng/mL.
    4.1.4) OTHER
    A) OTHER
    1) ELECTROPHYSIOLOGICAL TESTING
    a) Thorough neurological testing is indicated in patients with evidence of pyridoxine toxicity. Nerve conduction studies may demonstrate slowing of sensory fibers and prolonged distal motor latencies (Waterston & Gilligan, 1987).

Methods

    A) CHROMATOGRAPHY
    1) A high performance liquid chromatographic (HPLC) technique has been developed to determine pyridoxine and 4-pyridoxic acid concentrations in plasma and urine. However, the lowest concentration that could be accurately measured was 300 ng/mL, which makes this technique not sensitive enough in the therapeutic range (3.6 to 18 ng/mL) (O'Reilly et al, 1980).

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) Patients with severe symptoms despite treatment should be admitted.
    B) Patients exhibiting neurological signs or symptoms should receive a thorough neurologic examination and should be admitted for neurological monitoring and possible admission to an intensive care unit.
    1) Based primarily on acute animal toxicity data (Unna, 1940), onset of neurologic symptoms can be delayed for several days following acute ingestion of a toxic dose.
    C) The few cases of acute human parenteral overdose also suggest a delayed onset of toxicity of days or weeks following completion of pyridoxine administration (Albin et al, 1987; Harati & Niakan, 1986).
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    B) Follow-up by an experienced neurologist should be extended for at least 7 days after an acute ingestion of potentially toxic amounts, since delayed neurologic effects have been reported (Unna, 1940; Albin et al, 1987; Harati & Niakan, 1986).

Monitoring

    A) Monitor neurologic exam following a significant overdose. Nerve conduction studies may be useful to assess patients with clinical evidence of neuropathy.
    B) Determination of a pyridoxine plasma concentration may be useful in evaluating patients with chronic pyridoxine toxicity. Normal concentrations range from 3.6 to 18 ng/mL.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Although toxicity has not been reported after an acute ingestion, and prehospital decontamination is not generally necessary, it should be considered in patients with large/massive ingestions.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) Although toxicity has not been reported after an acute ingestion, consider activated charcoal only after very large ingestions 150 mg/kg (30 high-potency B-Complex tablets/capsules in a 10-kg child) or greater).
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. There is no known antidote for prevention or treatment of the sensory neuropathy produced by high doses of pyridoxine. Recovery occurs slowly over several months or years. Careful neurologic assessment and follow-up is indicated in patients with neurologic signs or symptoms.
    B) MONITORING OF PATIENT
    1) Monitor neurologic exam following a significant overdose. Nerve conduction studies may be useful to assess patients with clinical evidence of neuropathy.
    2) Determination of a pyridoxine plasma concentration may be useful in evaluating patients with chronic pyridoxine toxicity. Normal concentrations range from 3.6 to 18 ng/mL.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Based on high water solubility, low protein-binding, and a very low volume of distribution, pyridoxine is probably effectively removed by dialysis.

Abstracts

Case Reports

    A) ADULT
    1) Intravenous administration of 132 grams of pyridoxine over 3 days resulted in severe sensory neuropathy in a 27-year-old woman being treated for Gyromitra mushroom poisoning. Sequelae 12 months after hospitalization included inability to walk. Administration of 183 grams over 3 days to the 33-year-old husband of this woman resulted in similar symptoms. Both patients also developed autonomic and motor nerve dysfunction, which is inconsistent with animal models of pyridoxine toxicity. Some of these signs may be attributable to the large amount of chlorobutanol administered as a preservative in the pyridoxine preparation (Albin et al, 1987).
    2) ADVERSE EFFECTS
    a) A 24-year-old man who unintentionally ingested a mouthful of hydrazine received 10 grams of pyridoxine intravenously over a few hours (143 mg/kg assuming a body weight of 70 kg). One week after this therapy he developed paresthesias and mild distal limb weakness. Three weeks later ataxia and diminished sensory response to pinprick, vibration, touch, and position was noted. Bilateral optic neuropathy was also present. Spontaneous recovery occurred over 6 months. Although hydrazine itself is neurotoxic, the clinical presentation was consistent with pyridoxine-induced sensory neuropathy (Harati & Niakan, 1986).
    B) PEDIATRIC
    1) Zegher et al (1985) report a 3-week-old infant with severe primary oxalosis who was treated with pyridoxine 400 mg/day for 6 weeks. At 9 weeks of age the dose was increased to 1000 mg/day. Within a few days the infant became hypotonic, and within a week she became areflexic with an abnormal EEG. Tachycardia and poor peripheral circulation were also noted. The areflexia persisted for 4 months after decreasing the dose to 400 mg/day, although sensory and motor nerve conduction velocities were normal within 5 weeks.

Range Of Toxicity

Summary

    A) TOXICITY: The minimum acute oral toxic dose for humans is unknown. ACUTE TOXICITY: One patient who received approximately 140 mg/kg IV of pyridoxine developed reversible neuropathy; however, up to 357 mg/kg IV has been tolerated in patients treated for isoniazid overdose. Two adults who received greater than 2 g/kg IV over 3 days developed severe sensory neuropathy, weakness, and autonomic dysfunction. A single intravenous dose of 10 grams has caused neuropathy in an adult. CHRONIC TOXICITY: Chronic ingestion of 200 to 9,600 mg/day for months to years has resulted in neuropathy.
    B) THERAPEUTIC DOSE: ADULT: Vitamin B6 deficiency: Injection: 10 to 20 mg IM or IV daily for 3 weeks. Therapy for vitamin B6 dependency syndrome may require doses as high as 600 mg daily with a continuing daily dose of 30 mg for life. ORAL: Follow up to injection therapy: 2 to 5 mg orally with therapeutic multivitamin preparation daily for several weeks. Pyridoxine dependency syndrome: up to 600 mg/day IV/IM/orally. Deficiency related to isoniazid: 100 mg IV or IM daily for 3 weeks followed by a 30 mg daily maintenance dose. Toxicity due to isoniazid ingestion greater than 10 g: 4 g IV followed by 1 g IM every 30 minutes, to reach an amount equal to the number of grams of isoniazid ingested.
    C) THERAPEUTIC DOSE: PEDIATRIC: Pyridoxine deficiency: With peripheral neuropathy: Oral: 10 to 50 mg/day orally for 3 weeks, then 1 to 2 mg/day in a multivitamin product. Without neuritis: Oral: 5 to 25 mg/day orally for 3 weeks, followed by 1.5 to 2.5 mg/day in a multivitamin product. Pyridoxine-dependent seizures (PDS): IV: 50 to 100 mg IV as a single dose. If EEG improvement is not observed within 10 minutes, give additional 100-mg doses, up to 500 mg. ORAL: 15 to 30 mg/kg/day orally. MAINTENANCE: 3 to 5 mg/kg/day orally for life or daily dose sufficient to suppress seizure activity. Doses as high as 1000 mg/day have been reported for seizure control.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) DOXYLAMINE SUCCINATE/PYRIDOXINE HYDROCHLORIDE
    a) The recommended dose of doxylamine/pyridoxine is 2 tablets orally before bed (each tablet contains doxylamine succinate 10 mg/pyridoxine hydrochloride 10 mg). Dose may be increase to a MAXIMUM recommended dose of 4 tablets daily (one tablet in the morning, one mid-afternoon, and 2 before bed) (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).
    2) PYRIDOXINE
    a) RECOMMENDED DAILY ALLOWANCE
    1) VITAMIN B6 DEFICIENCY: TREATMENT AND PROPHYLAXIS (recommended daily allowance):
    1) ADULTS UP TO 50 YEARS OF AGE: 1.3 mg/day
    2) MEN OVER 50 YEARS OF AGE: 1.7 mg/day
    3) WOMEN OVER 50 YEARS OF AGE: 1.5 mg/day
    4) PREGNANT WOMEN: 1.9 mg/day
    5) LACTATING WOMEN: 2 mg/day
    2) VITAMIN B6 DEFICIENCY THERAPY
    a) INJECTION: The recommended dose is 10 to 20 mg IM or IV daily for 3 weeks. Therapy for VITAMIN B6 DEPENDENCY SYNDROME may require doses as high as 600 mg daily with a continuing daily dose of 30 mg for life (Prod Info pyridoxine HCl IM, IV injection, 2008).
    b) ORAL: FOLLOW UP TO INJECTION THERAPY: The recommended dose is 2 to 5 mg orally with therapeutic multivitamin preparation daily for several weeks (Prod Info pyridoxine HCl IM, IV injection, 2008).
    3) POLYNEUROPATHY, PERIPHERAL
    a) PROPHYLAXIS: 25 to 50 mg orally daily.
    b) TREATMENT: 50 to 300 mg orally daily.
    4) DEFICIENCY RELATED TO ISONIAZID (INH)
    a) The usual dose is 100 mg IV or IM daily for 3 weeks followed by a 30 mg daily maintenance dose (Prod Info pyridoxine HCl IM, IV injection, 2008).
    b) TOXICITY DUE TO ISONIAZID INGESTION GREATER THAN 10 G: The recommended dose is 4 g IV followed by 1 g IM every 30 minutes, to reach an amount equal to the number of grams of isoniazid ingested (Prod Info pyridoxine HCl IM, IV injection, 2008).
    5) In patients who must receive large doses of pyridoxine for medical purposes, it has been suggested that periodic drug abstinence may protect the patient from neurotoxicity (Krinke & Fitzgerald, 1988). However, It has not been clearly established that periodic drug abstinence will in fact protect the patient from neurotoxicities.
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) DOXYLAMINE SUCCINATE/PYRIDOXINE HYDROCHLORIDE
    a) Safety and efficacy have not been established for pediatric patients (Prod Info DICLEGIS(R) oral delayed-release tablets, 2013).
    2) PYRIDOXINE
    a) PYRIDOXINE DEFICIENCY
    1) WITH PERIPHERAL NEUROPATHY: ORAL: 10 to 50 mg/day orally for 3 weeks, then 1 to 2 mg/day in a multivitamin product (Kleinman, 2009).
    2) WITHOUT NEURITIS: ORAL: 5 to 25 mg/day orally for 3 weeks, followed by 1.5 to 2.5 mg/day in a multivitamin product (Kleinman, 2009).
    b) PYRIDOXINE-DEPENDENT SEIZURES (PDS)
    1) INTRAVENOUS: 50 to 100 mg IV as a single dose. If EEG improvement is not observed within 10 minutes, give additional 100-mg doses, up to 500 mg. If seizures are controlled within 30 minutes and then recur (within days to weeks), and cease again with the same starting dose of pyridoxine, the diagnosis of PDS is confirmed (Gospe, 2002; Baxter, 1999; Gospe, 1998). Some patients may require higher doses for seizure control (Gospe, 2002).
    2) ORAL: 15 to 30 mg/kg/day orally. If seizures are controlled within 7 days and then recur (within days to weeks), and cease again with the same starting dose of pyridoxine, the diagnosis of PDS is confirmed (Gospe, 2002; Baxter, 1999). Some patients may require higher doses for seizure control (Baxter, 1999).
    3) MAINTENANCE: 3 to 5 mg/kg/day orally for life (Kleinman, 2009; Gospe, 1998) or daily dose sufficient to suppress seizure activity (Koul, 2009). Doses as high as 1000 mg/day have been reported for seizure control (Basura et al, 2009).

Maximum Tolerated Exposure

    A) The amount of pyridoxine that is orally acutely toxic is not known for man. When used in the treatment of isoniazid overdose, intravenous doses of 70 to 357 mg/kg were well tolerated in 5 patients (Wason et al, 1981).
    1) The minimum intravenous amount acutely associated with neuropathy in humans is 10 g in an adult (143 mg/kg, assuming a body weight of 70 kg) (Harati & Niakan, 1986).
    B) CASE REPORTS
    1) CHRONIC
    a) CASE REPORT: A 50-year-old woman who had been taking vitamin B6 3 times daily (total dose: 300 mg daily) for 6 months, presented with intermittent diarrhea, vomiting, and an increase in brown-colored skin, 10 months after undergoing a bariatric surgery procedure. Following the discontinuation of vitamin B6, her symptoms resolved, her pyridoxalphosphate levels decreased from 2083 nmol/L to 4.68 nmol/L (normal range: 6 to 34 nmol/L) and pyridoxal levels decreased from 129 nmol/L to 7.17 nmol/L (normal range: 16 to 78 nmol/L) (Cupa et al, 2015).
    b) CASE REPORT: Pure sensory neuropathy with profound muscle weakness was observed in a 75-year-old, wheelchair bound, man who self-administered 9.6 g of pyridoxine daily for 3 years. Therapy was stopped immediately. One year later, the patient was ambulating without assistance (Gdynia et al, 2008).
    c) There are 6 cases of neuropathy in patients taking 75 to 500 mg/day for 8 months to 8 years (Parry & Bredesen, 1985; Berger & Schaumberg, 1984; Podell, 1985; Dalton & Dalton, 1987).
    d) There is also a report of 22 patients who were treated with 250 to 500 mg/day for 1 to 6 years who developed no signs or symptoms of neurotoxicity, and had normal nerve conduction studies (Mitwalli et al, 1984).
    e) In another anecdotal report, 6 elderly patients received 225 mg/day for one year and developed no side effects (Baker & Frank, 1984).
    2) ACUTE
    a) Two adults who received greater than 2 g/kg IV over 3 days developed severe sensory neuropathy, weakness, and autonomic dysfunction. Some of the neurological changes were permanent (Albin et al, 1987).
    3) ISONIAZID OVERDOSE
    a) In the following cases the doses did not cause toxicity:
    1) Acute IV doses of as high as 52 g in 1 patient (almost 1 g/kg) (Sievers & Herrier, 1975) or 70 to 357 mg/kg in 5 patients (Wason et al, 1981) have been tolerated without adverse effects in the treatment of isoniazid toxicity.
    2) A 7-year-old child was given 250 mg/kg initially followed by 125 mg/kg during dialysis without reported adverse effects (Orlowski et al, 1988).
    3) DOSES CAUSING TOXICITY: Administration of 10 g of pyridoxine IV to a patient with hydrazine toxicity resulted in paresthesias one week later and sensory neuropathy within 3 weeks (Harati & Niakan, 1986).
    4) Doses reported to produce neuropathy in adults are summarized below:
    a) Maximum daily dose: 75 mg; duration: 2 years (Dalton & Dalton, 1987)
    b) Maximum daily dose: 200 mg; duration: 36 months (Parry & Bredesen, 1985)
    c) Maximum daily dose: 500 mg; duration: 8 months (Parry & Bredesen, 1985)
    d) Maximum daily dose: 500 mg; duration: 24 months (Parry & Bredesen, 1985)
    e) Maximum daily dose: 500 mg; duration: 2 years (Berger & Schaumberg, 1984)
    f) Maximum daily dose: 500 mg; duration: 8 years (Podell, 1985)
    g) Maximum daily dose: 2 grams; duration: 24 months (Parry & Bredesen, 1985)
    h) Maximum daily dose: 2 grams; duration: 36 months (Parry & Bredesen, 1985)
    i) Maximum daily dose: 2 grams; duration: greater than 12 months (Parry & Bredesen, 1985)
    j) Maximum daily dose: 2 grams; duration: 3 months (Parry & Bredesen, 1985)
    k) Maximum daily dose: 2 grams; duration: 4 months (Schaumburg et al, 1983)
    l) Maximum daily dose: 2 grams; duration: 40 months (Schaumburg et al, 1983)
    m) Maximum daily dose: 2 grams; duration: 34 months (Schaumburg et al, 1983)
    n) Maximum daily dose: 75 mg; duration: 2 years (Friedman et al, 1986)
    o) Maximum daily dose: 2.5 grams; duration: 12 months (Parry & Bredesen, 1985)
    p) Maximum daily dose: 2.5 mg; duration: 9 months (Parry & Bredesen, 1985)
    q) Maximum daily dose: 2.5 grams; duration: 6 years (Davidson, 1984)
    r) Maximum daily dose: 3 grams; duration: 4 months (Schaumburg et al, 1983)
    s) Maximum daily dose: 3 grams; duration: 6 months (Vasile, 1984)
    t) Maximum daily dose: 3.5 grams; duration: 10 months (Parry & Bredesen, 1985)
    u) Maximum daily dose: 3.5 grams; duration: 1 month (Parry & Bredesen, 1985)
    v) Maximum daily dose: 4 grams; duration: 72 months (Parry & Bredesen, 1985)
    w) Maximum daily dose: 4 grams; duration: 10 months (Schaumburg et al, 1983)
    x) Maximum daily dose: 4.5 grams; duration: 12 months (Parry & Bredesen, 1985)
    y) Maximum daily dose: 5 grams; duration: 2 months (Schaumburg et al, 1983)
    z) Maximum daily dose: 5 grams; duration: 2 months (Parry & Bredesen, 1985)
    aa) Maximum daily dose: 5 grams; duration: 4 months (Parry & Bredesen, 1985)
    ab) Maximum daily dose: 6 grams; duration: 3 months (Schaumburg et al, 1983)
    ac) Maximum daily dose: 10 grams; duration: acute (Harati & Niakan, 1986)
    ad) Maximum daily dose: 132 grams; duration: over 3 days (Albin et al, 1987)
    ae) Maximum daily dose: 183 grams; duration: over 3 days (Albin et al, 1987)

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Normal plasma pyridoxine concentrations are 3.6 to 18 nanograms/mL (Schaumburg et al, 1983).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL: 40% to 60% of patients with a serum B6 concentration above 18 nanograms/mL had symptoms of a peripheral neuropathy (Dalton & Dalton, 1987; Dalton, 1985).
    2) CASE REPORT: A 50-year-old woman who had been taking vitamin B6 3 times daily (total dose: 300 mg daily) for 6 months, presented with intermittent diarrhea, vomiting, and an increase in brown-colored skin, 10 months after undergoing a bariatric surgery procedure. Following the discontinuation of vitamin B6, her symptoms resolved, her pyridoxalphosphate levels decreased from 2083 nmol/L to 4.68 nmol/L (normal range: 6 to 34 nmol/L) and pyridoxal levels decreased from 129 nmol/L to 7.17 nmol/L (normal range: 16 to 78 nmol/L) (Cupa et al, 2015).
    3) CASE REPORT/CHRONIC EXPOSURE: An elderly man developed pure sensory neuropathy while self-administering 9.6 grams pyridoxine daily and had a pyridoxine blood concentration of 1850 mcg/L (normal: 40 to 120 mcg/L). The patient clinically improved with drug cessation (Gdynia et al, 2008).
    4) CASE REPORT: A patient with pyridoxine-induced neuropathy who had been taking 4 grams/day had a plasma pyridoxine concentration of 30 nanograms/mL three hours after her last dose. One month after discontinuation, the concentration was 17 nanograms/mL (Schaumburg et al, 1983).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) PYRIDOXINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 966 mg/kg (Unna, 1940)
    2) LD50- (ORAL)RAT:
    a) 4000 mg/kg ((RTECS, 2000))
    3) LD50- (SUBCUTANEOUS)RAT:
    a) 3100 mg/kg (Unna, 1940)
    B) PYRIDOXINE HYDROCHLORIDE
    1) LD50- (ORAL)MOUSE:
    a) 5500 mg/kg (Unna, 1940)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 2450 mg/kg ((RTECS, 2000))
    3) LD50- (ORAL)RAT:
    a) 4000 mg/kg ((RTECS, 2000))
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 3700 mg/kg (Unna, 1940)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Vitamin B6 exists in nature as pyridoxine, pyridoxal, and pyridoxamine. They are converted in vivo to the active coenzyme form, pyridoxal-5-phosphate (FDA, 1979).
    B) Pyridoxal coenzymes are cofactors in over 60 physiological enzymatic reactions, including conversion of tryptophan to niacin, synthesis of neurotransmitters (norepinephrine, serotonin, histamine), and production of porphyrins and hemoglobin (FDA, 1979).

Toxicologic Mechanism

    A) The mechanism of pyridoxine-induced neurotoxicity has not been fully elucidated. There is some evidence of direct toxicity of pyridoxine base in dorsal root ganglia cell cultures (Windebank et al, 1984).
    B) DATA FROM DOG EXPERIMENTS: Dogs receiving 200 to 1000 mg/kg/day developed an unsteady gait and had histologic evidence of sensory neuronopathy (Krinke et al, 1980; Schaeppi & Krinke, 1982).
    C) DATA FROM RAT EXPERIMENT
    1) Rats receiving 1200 mg/kg/day IP for 7 days developed limb ataxia after 3 days and slowed sensory and motor nerve conduction velocities by day 7. These findings normalized 3 weeks after discontinuation (Sladky et al, 1987).
    2) Axonal degeneration may result from alterations in neuronal metabolism. In lower doses (100 to 200 mg/kg/day IP) rats recovery of neuronal function occurred within 12 weeks after removal of pyridoxine exposure (Windebank et al, 1985).
    3) Rats given 1200 mg/kg/day IP for up to 10 days developed dorsal root ganglion nuclear membrane irregularity and neurofilamentous accumulation in proximal axonal segments within 24 hours. Degenerative changes began in sensory neurons and progressed to the distal axon. Motor neurons were not affected (Yue et al, 1987; Krinke & Fitzgerald, 1988; Yue et al, 1989; Montpetit et al, 1988).
    4) One study identified the L4 DR ganglion and the P nerve as the areas most susceptible to pyridoxine toxicity in rats (Krinke & Fitzgerald, 1988).
    a) Results of investigations, using dogs, by Montpetit et al (1988) suggest that the primary site of pyridoxine neurotoxicity is in the soma of neurons of the DR ganglion (Montpetit et al, 1988).
    5) It appears that pyridoxine toxicity in the rat is dependent on the dose and rate of pyridoxine administration. In the high dose treatment groups, expression of neuropathy with ataxia and neuronal necrosis developed after the total pyridoxine dose reached 4000 mg/kg. After chronic low-dose administration of pyridoxine there is a more insidious onset of axonal atrophy and degeneration (Yue et al, 1989; Montpetit et al, 1988).

Physicochemical

Ph

    A) 2.5 (for a 10% solution of pyridoxine hydrochloride) (Unna, 1940)
    B) 2.44 (for a 1% solution of pyridoxine hydrochloride) (Weigand et al, 1940)

Molecular Weight

    A) PYRIDOXINE HYDROCHLORIDE: 205.6

References

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