Vitamin B, Safety Issues ADRIANNE BENDICH A N D MARVIN COHEN Hoflrnann-LaRoche Inc. Nutley, New Jersey 07110
INTRODUCTION The use of pyridoxine hydrochloride (vitamin B6) in very high doses has been associated with certain adverse clinical responses to the vitamin. While some indications for high-dose vitamin usage, such as pyridoxine-dependency homocystinuria, and oxal~sisl-~ have been clinically demonstrated, other proposed uses, such as treatment of carpal tunnel syndrome," premenstrual syndrome (PMS5), and autism6 are more controversial. Increasing clinical use of pyridoxine has resulted in concern about the safety of treatment regimens. Two specific issues that have appeared in the literature are peripheral neuropathy and the use of pharmacologic doses during pregnancy. Previous reviews of pyridoxine neuropathy have indicated that two factors-oral daily dose and duration of intake-are critical to the full assessment of the risk of adverse effects on sensory nerve function. Cohen and Bendich' in 1986 concluded that clinical doses of less than 500 mg/day were safe over periods as long as six years. Schaumberg and Berger' noted that subjects ingesting 500 mg/day did not report symptoms, while daily intake of 7-10 g resulted in neuropathy within two months. In his review, Bassler9 recommended that long-term intake of doses up to 200 mg/day could be considered safe. However, the need for clinical trials to determine the incidence of adverse effects more accurately was stressed by the author. Concern with the teratogenic potential of high-dose pyridoxine largely results from the controversy associated with Bendectin (doxylamine + pyridoxine) use by pregnant women. An earlier review of this subject' did not find any consistent evidence of teratogenicity for pyridoxine. This review updates the preclinical and clinical data on pyridoxine neurotoxicity to determine whether a more quantitative estimate of risk can be derived based on available data. Recent human and animal data showing lack of teratogenicity for pyridoxine are also summarized.
PYRIDOXINE AND NEUROPATHY-PRECLINICAL STUDIES Studies of pyridoxine and related compounds with vitamin B, activity have consistently shown low acute toxicity; representative data derived from the reports of Unna" and McCormick" are summarized in TABLE1. Repeated dose studies in rats and dogs have provided some of the evidence for the dose-time interaction seen in the development of neuropathy following pyridoxine administration. Krinke and Fitzgerald" studied the time of onset and severity of peripheral neuropathy in rats after different dosage regimens of pyridoxine. The data are summarized in TABLE2. A clear relationship between dose and time of onset of neuropathy is evident. The authors also noted that the severity of the neuropathy was related to the dose administered. 32 1
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TABLE 1. Acute Toxicity of Compounds with Vitamin
Pyridoxine Pyridoxine Pyridoxal-5’-phosphate Pyridoxal
6000 5500 2000 5000
Mouse Rat Mouse Mouse
OData derived from Unna” and McCormick.”
In another recent study, Bowe and Vealei3determined the sensitivity of peripheral nerves to the inhibitory effects of 4-aminopyridine in rats that had received 100 or 200 mg/kg per day pyridoxine i.p. for four weeks. A biphasic response was noted; the experimental animals were less sensitive than controls to 4-aminopyridine immediately after the pyridoxine-dosing regimen, but were more sensitive after a three-month recovery period. The time course for the development of pyridoxine-induced neuropathy has also been studied in dogs. TABLE3 summarizes some representative data. An apparent no-effect level was noted when 50 mg/kg per day pyridoxine was administered orally for 13 weeks.14 When doses of 150-300 mg/kg were g i v e r ~ , l neuropathy ~-~~ developed more rapidly as the dosage increased, similar to the response seen in rat studies. In a more recent study, Montpetit et al. l 9 administered pyridoxine to dogs at doses of 150 or 200 mg/kg per day p.0. for periods ranging from 4 to 100 days. The time to onset of clinical signs of peripheral neuropathy was not significantly different for the two groups (mean of 8.8 and 8.3 days, respectively). However, a detailed histologic comparison of neuronal damage in the two groups was not reported.
PYRIDOXINE AND NEUROPATHY -CLINICAL STUDIES The clinical spectrum of uses reported for high-dose pyridoxine therapy can be seen in TABLE 4. In most instances, the doses of pyridoxine used have not been associated with neuropathy. However, several reports of peripheral neuropathy in subjects 5 and 6 illustrate selected receiving pyridoxine have appeared in the literature. TABLES data from cases reported in the literature. In TABLE5, administration of 800 mg/day
Time-Course of Neuropathy Development in Rats Administered Pyridoxine
Time to Appearance of Neuropathy in Weeks 200
300 400; 5 days/wk 400; I days/wk 1200 a Data adapted from Krinke and Fitzgerald.”
>4 4 2 1.3
BENDICH & COHEN SAFETY ISSUES
Time Course of Neuropathy Development in Dogs after Pyridoxine Administration
Dose (mg/kg per day, P.o.) 50 150 3 00
Time to Appearance of Neuropathy in Weeks >13
Reference Phillips et ~ 1 . ' ~ Hoover & CarltonI6,'' Schaeppe & Krinke"
pyridoxine for 17 months (total dose 408 g) was not associated with neuropathy,20 while administration of the same dose for 24 months (total dose 576 g) was associated with n e ~ r o p a t h y .In~ contrast, Palareti et LIZ.*' did not report any adverse effects in subjects given 900 mg/day pyridoxine for 12 months (total dose 324 g), but Waterston and Gilligan22found neuropathy after administration of 1000 mg/day for 12 months 6 summarizes retrospective survey data from 172 women (total dose 365 g). TABLE that were reported by Dalton and Dalton.23 The authors found that subjects with neuropathy had taken pyridoxine for a significantly longer time than subjects without neuropathy symptoms (2.9 k 1.9 yr vs. 1.6 + 2.1 yr), even though the mean daily dose was almost equivalent (1 17 + 92 vs. 1 16 k 66 m g / d a ~ ) . ' In ~ this survey, the calculated mean total dose (based upon the mean daily dose) suggests that this parameter may be more predictive of neuropathy than daily intake level. However, none of the subjects surveyed had neurologic examinations. An attempt was made to quantitate the risk of neuropathy in terms of dose and duration of treatment using a graphic presentation of all data. Representative citations covering a wide range of "safe" dose regimens were used at one end of the dose-time spectrum2.21.23-27. , the available data on neuropathy associated with oral administration
Clinical Uses of High-Dose Pyridoxinea Autism Down's Syndrome Infantile Convulsions (Dependency) Migraine Headaches Schizophrenia Alcoholism Withdrawal Seizures Antagonism of Drugs (Isoniazid, Levo-DOPA) or Natural Products (Mushroom Poisoning) Carpal Tunnel Syndrome Diabetic Complications Preeclampsic Edema Premenstrual Syndrome Homocystinuria H yperoxaluria Xanthinuric Aciduria Asthma Radiation Sickness Sickle Cell Anemia
a Adapted from Bassler' and McCormick."
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TABLE 5. Selected Clinical Studies on Neuropathy Associated with Pyridoxine
Total Dose (grams)
24 12 12
No adverse effects reported Sensory neuropathy No adverse effects reported Sensory neuropathy
Reference Gill & Rose’ Berger & Schgumberg” Palareti et al. Waterston & Gilligan*’
of pyridoxine were used in all cases where a quantitative estimate of dose and duration of treatment could be made.20*22.23~’8-42 The results are shown in FIGURES 1 and 2. The data indicate areas of low and high-risk “zones” for pyridoxine administration; these are outlined by broken lines in each figure. For example, in FIGURE 1, doses of 500 mg/day pyridoxine for up to two years have not been associated with neuropathy, while doses above 1000 mg/day for variable periods of time have been almost consistently associated with neuropathy. Similarly, in FIGURE 2, total doses of 100 grams pyridoxine taken over a period of up to 20 months were not associated with neuropathy, while total doses of 1000 grams or more appeared to consistently produce neuropathy. The intermediate dose range contains studies in which similar doses may or may not have been associated with neuropathy. The clinical relevance of this somewhat mixed pattern can be clarified by using appropriate neurologic studies in regimens requiring high doses of pyridoxine. The appearance of neuropathy during oral pyridoxine therapy can markedly disrupt normal locomotor functions. The syndrome is usually reversible with the cessation of pyridoxine supplementation. Residual sensory impairment has been reported in some subjects who took daily doses exceeding -2 grams/day for extended period^,^'.^^ but discontinuance of treatment at the first appearance of neurologic symptoms results in a return of normal a ~ t i v i t y . ~ ~ , ~ ’
LACK OF TERATOGENICITY Leatham4’ reviewed the epidemiologic literature and concluded that, if Bendectin had teratogenic properties, they appeared to be slight. This is in agreement with
TABLE 6. Relationship of Duration
of Pyridoxine Therapy to Appearance of
Neuropathya Dose ( m d d a y1 116 117
Mean Total Dose (grams)
1.6 k 2.1 2.9 1.9
No neuropathy Neuropathy
’Adapted from Dalton and Dalt0n.2~ bMean
* standard deviation.
BENDICH & COHEN: SAFETY ISSUES
I'Jo E f t e c t (Group D a t a ) 140 E f f e c t (Individual Data) A PJeuiopathy (Group Data) A Neuropaihy (lndivldual D a t a ) 0 0
I I I
60-___-__________-___I I I A A 0
I I I
I A I I
6 0 0 8 , , l o @ , ,crp
previous reviews that found no consistent association between birth defects and Bendectin use.44i45 Engel and Lamm46analyzed published studies on Bendectin use and birth defects. A pooled relative risk for birth defects of 0.99 was calculated. Temporal trends in birth defects showed no changes with the withdrawal of the drug from the market, while hospitalization rates for nausea and vomiting showed approximately a twofold in-
0 No E f f e c t (Group Data) 0 No E f f e c t (Individual Data)
A Neuropathy (Group Data) A Neuropathy (Individual Data)
I I I I I
Total Dose (grams) FIGURE 2. Relationship between total dose of pyridoxine, duration of treatment, and occurrence of neuropathy.
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crease. The authors concluded that Bendectin was both safe (with respect to birth defects) and effective as an antiemetic. The available preclinical evidence continues to indicate that in rats, high doses of pyridoxine are not teratogenic. Administration of the vitamin a t dietary levels of 20-80 mg/kg diet had no effect on the offspring.4748 In a more recent study, Marathe and Thomas49administered pyridoxine in oral doses of 200,400, or 800 mg/kg to pregnant rats from gestation day 6 to 15. No effects on litter size or pup weight were noted. In addition, no gross visceral or skeletal malformations were found. administered 200, 500, or 800 mg/kg per day Bendectin equivalent to Tyl et 100,250, and 400 mg/kg per day pridoxine, respectively) to pregnant rats on gestation days 6-15. The incidence of litters with one or more malformed fetuses was increased only a t a dose of Bendectin (800 mg/kg per day) that produced maternal toxicity or mortality. studied the teratogenic potential of Bendectin in three primate Hendrickx et al. species. No fetal abnormalities were found in pregnant cynomolgous monkeys administered 2-20 times the human dose of Bendictin (1.3-13 mg/kg per day). In macaque
TABLE 7. Miscellaneous Side Effects Associated with Pyridoxine
Symptom and Incidence Acidity/indigestion 7/96 Nausea 6/96 Breast discomfort/tenderness 3/96 Photosensitivity 1/16 Vesicular dermatoses 2/400 Vesicular dermatosis; n = 1
Dose (mg/day) 100-200 x 1-5 yr 150 50 mg/kg x 9 yr 2000-4000x > 1 yr
Bernstein & Lobitz” Colemans4 Friedman et ~ 1 . ~ ’
monkeys and baboons that received up to 26.7 mg/kg per day, an increased incidence of ventricular septa1 defects in the heart was noted, but no dose-response relationship was evident.
OTHER SIDE EFFECTS TABLE7 summarizes some miscellaneous side effects that have been associated with pyridoxine therapy. noted a relatively low incidence (-3-776) of gastrointestinal disturbances (nausea, heartburn, indigestion) as well as breast discomfort and/or tenderness in 96 women taking 100-200 mg/day pyridoxine for PMS. However, the contribution of PMS itself to these side effects could not be determined from the data presented. Dermatologic lesions (vesicular dermatosis and/or increased sensitivity to sunlight) have been reported in three separate case report^,‘".^^,^^ but no relationship between this effect and the dose or duration of treatment is evident from the limited data available.
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Canham et ~ l . , in ’ ~an abstract, reported EEG changes in 9 out of 11 subjects following pyridoxine deficiency for 21 days. “Abnormal” EEG changes were also noted in 3 out of 8 subjects who received pyridoxine supplementation (200 mg/day x 33 days) and were examined eight days after the last dose. While preconvulsive or other EEG changes have been reported in studies on pyridoxine deficiency or dependency,’.’’ no additional information on EEG effects associated with pyridoxine supplementation has appeared in the literature since this 1964 preliminary report.
DISCUSSION The association of high-dose pyridoxine and sensory neuropathy indicates that there is a clear dose relationship in the development of this syndrome; in some instances, the length of administration is a contributing factor. Doses of less than 500 mg/day for up to two years have not been associated with neuropathy. Ingestion of total doses of less than 100 grams over a 20-month period has also not been associated with neurologic changes. Administration of pyridoxine within these dose and time limits appears to be safe. Daily doses exceeding 1000 mg or total doses of 1000 grams or more appear to represent high-risk treatment regimens. Use of pyridoxine in doses over 500 mg/day should be avoided unless there are sound reasons for such treatment; neurologic testing on a regular basis should be part of the treatment program. Clinical data on the dose region between the safe and toxic levels are currently incomplete and somewhat inconsistent. Many of the uncertainties associated with pharmacologic doses of pyridoxine in this range may be due to the clinical conditions being treated. In addition, double-blind, placebo-controlled studies have not been undertaken. The available clinical evidence indicates that there is a minimal risk of permanent adverse change in sensory nerve function, if pyridoxine supplementation is stopped when adverse changes in neurologic function are first noted. A review of literature relating to the teratogenic potential of pyridoxine did not disclose any evidence that it can affect fetal growth or structure. Preclinical as well as clinical data on this subject continue to reflect the safety of pyridoxine in pregnancy.
ACKNOWLEDGMENTS The assistance of Ms. Shanda Reed in preparing the manuscript and the critical review by Drs. V. N. Singh and L. J. Machlin are gratefully acknowleged.
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