Pediatr Drugs 2009; 11 (4): 251-257

ORIGINAL RESEARCH ARTICLE 1174-5878/09/0004-0251/$49.95/0

ª 2009 Adis Data Information BV. All rights reserved.

Potential Vitamin-Drug Interactions in Children

At a Pediatric Emergency Department
Ran D. Goldman,1-3 Sunita Vohra4 and Alex L. Rogovik1,5
1 Pediatric Research in Emergency Therapeutics (PRETx) Program, Division of Pediatric Emergency Medicine, BC Children’s Hospital,
Vancouver, British Columbia, Canada, and Division of Pediatric Emergency Medicine, The Hospital for Sick Children, Toronto, Ontario,
Canada
2 Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
3 Child & Family Research Institute (CFRI), Vancouver, British Columbia, Canada
4 Complementary and Alternative Research and Education (CARE) Program, Department of Pediatrics, Stollery Children’s Hospital,
Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
5 Clinical Nutrition & Risk Factor Modification Center, St. Michael’s Hospital, Toronto, Ontario, Canada

Abstract Background: A significant increase in vitamin use has been observed in recent years and interactions between
vitamins and medications have been reported.
Objective: To determine the frequency and types of potential interactions between vitamins and medications
in children arriving at a large tertiary, pediatric emergency department. We also compared family char-
acteristics of children with potential interactions with those of children with no potential interactions, in
order to determine children at a higher risk.
Methods: A cross-sectional study in which a survey was conducted of parents/caregivers and/or patients aged
0–18 years registered at a large pediatric emergency department in Canada. A total of 1804 families
underwent a face-to-face interview. The main outcome measure was the rate of potential vitamin inter-
actions in the preceding 3 months.
Results: A considerable number of patients (11% of our cohort) had potential vitamin-medication inter-
actions in the preceding 3 months, which could theoretically result in adverse events, and over one-third of
these children had more than one potential interaction. Patients with potential interactions and their parents
were significantly older (p < 0.001 for the child and mother, p = 0.02 for the father), the children were much
more likely to have a chronic illness (p < 0.001) and concurrently receive prescribed or over-the-counter
medication (p < 0.001), and more children with potential interactions were completely immunized (p = 0.02).
The child’s sex, parental education, employment status, family income, and primary language spoken at
home were not associated with potential interactions.
Conclusions: Taking into account the high rate of potential vitamin-drug interactions, especially among
older children and patients with chronic illness, parents and healthcare providers need to balance the
potential benefit of concurrent vitamin-medication use with its potential harms.

Background can interact with prescribed or over-the counter (OTC) medi-

Significant growth in vitamin use has been documented in
the literature in recent years both in children and adults.[1-3]
Vitamins, commonly consumed as multivitamin supplements,
are used by about one-third of Americans,[3] with similar pre-
valence in children and adults.[4] All vitamins have significant
pharmacologic activity and affect physiology. Therefore, they
cations and even other natural health products (NHPs) and
cause adverse events.
Interactions between vitamins and conventional pharma-
ceuticals in adults have been previously reported in the litera-
ture. For example, ascorbic acid (vitamin C) in high doses can
interfere with the anticoagulant effects of warfarin by reducing
prothrombin time.[5] It may also decrease the excretion of
252
acetaminophen (paracetamol) in the urine,[6,7] and increase its
blood concentrations and possibly toxicity. Furthermore, as-
corbic acid may increase the absorption of iron,[8] especially in
children. It also increases adverse effects associated with
aluminum-containing antacids[9] and decreases the absorption
of b-adrenoceptor antagonists.[10] Niacin and vitamin E may
increase the risk of bleeding if taken with warfarin, ibuprofen,
naproxen, aspirin (acetylsalicylic acid), or other drugs or NHPs
that affect blood clotting.[11-15]
Corticosteroids may reduce vitamin D absorption.[16,17]
Antioxidant vitamins, retinol (vitamin A), ascorbic acid, and
vitamin E, may lead to hydroxyl radical production if taken
with iron,[18] and may interfere with chemotherapy agents.[19]
Vitamin D may lead to hypermagnesemia if taken with magne-
sium, particularly in patients with decreased renal function.[11]
Establishing the population rate and types of potential inter-
actions between vitamins and conventional medications in
children can help determine the need for healthcare providers to
ask parents/caregivers about vitamin use to ensure the safety of
potentially interacting combinations. Therefore, the objective
of this study was to determine the frequency and types of
potential interactions between vitamins and conventional
medications in children arriving at a large tertiary, pediatric
emergency department (ED). Furthermore, we compared
family characteristics of children with potential interactions
with those of children with no potential interactions, in order to
determine children at a higher risk.
Methods
We conducted a large cross-sectional study of pediatric
patients aged 0–18 years. A trained research assistant approached
families of pediatric patients registered in a pediatric ED at The
Hospital for Sick Children (Toronto, ON, Canada) [between
12:00pm and 12:00am, March–November 2004] to ascertain their
willingness to participate in a face-to-face 15-minute interview.
This paper is part of a larger study pertaining to potential inter-
actions in children.[20] The study was approved by the Institu-
tional Review Board of The Hospital for Sick Children. Trained
translators interviewed families who preferred to speak in Span-
ish, Cantonese, or Mandarin. After English, these are the most
common languages spoken by families in our ED.
Exclusion criteria were lack of parental/legal guardian con-
sent or parents/caregivers unavailable to sign a consent; parent/
caregiver inability to communicate in any of the four study
languages; children who left the ED without being seen; pre-
vious participation in this study; and patients who required
resuscitation, based on a validated Canadian Triage and Acuity
ª 2009 Adis Data Information BV. All rights reserved.
Goldman et al.
Scale.[21] Patients aged 14–18 years were asked if they preferred
to complete the survey themselves or have their parents/
caregivers answer the survey on their behalf.
Interviews were conducted after triage and registration of
the child had been completed, while the family was waiting to be
seen by a pediatrician. The interviewers were senior medical
students specifically trained for the study. The interview cov-
ered the following domains: demographics (age, sex, parental
age and education, employment and income status, primary
language spoken at home), existing chronic illness (asthma,
diabetes, juvenile rheumatoid arthritis, cancer, cystic fibrosis,
neurologic disability, obesity, or other), and use of vitamins,
medications (open-ended questions were asked about the use
of prescribed or OTC medications), and NHPs in the preceding
3 months.
To determine likely interactions with the combinations being
used, a PubMed search was performed to determine reports
describing potential vitamin interactions. Reference lists of
identified studies were searched to identify additional sources
of information. In addition, potential interactions were deter-
mined using online drug databases: MEDLINEPlus,[11] Drug
Digest,[12] and the database of the University of Maryland
Medical Center.[13] Thus, pharmacokinetic and pharmaco-
dynamic (not clinical) interactions were detected.
Our main outcome measure was the rate of potential inter-
actions between vitamins and medications in the preceding
3 months. Secondary outcome measures included the types of
interactions and characteristics of the children and families
with potential interactions versus those without interactions.
Data were entered into a Microsoft Excel program (Micro-
soft Corp, Redmond, WA, USA) using double data entry for
quality assurance. Statistical analysis for comparison between
children with potential interactions and those without potential
interactions was performed using SPSS for Windows program
version 14.0 (SPSS Inc., Chicago, IL, USA). Results are ex-
pressed as absolute numbers (%) for categoric variables and
mean (standard deviation) for continuous variables. Pearson’s
chi-square (w2) test was used for comparison of categoric
variables and Student’s t-test for normally distributed con-
tinuous variables. Differences with a p-value of <0.05 were
considered significant.
Results
A total of 1804 parents/caregivers or children were inter-
viewed in this study. The average age of patients was 5.2 (range
0–18) years, 57% were male, and 28% had a chronic illness.
Sixty-seven percent of the interviews were with a mother and
Pediatr Drugs 2009; 11 (4)
Potential Vitamin-Drug Interactions in Children 253

26% with a father. The rest were with children over 14 years old
or a legal guardian.
A total of 582 (32%) parents/caregivers or children reported
vitamin use for children in the preceding 3 months. 193 (11%)
children with a potential vitamin-drug interaction were identi-
fied, i.e. one-third (193/582) of the children receiving vitamins.
Of these, 121 (63%) had one potential interaction, 21 (11%)
had two, 27 (14%) had three, and 24 (12%) had four or more
potential interactions. We identified interactions of vitamins
with 26 different medications, with 254 potential interaction
episodes documented (table I). The most common potential in-
teractions were ascorbic acid with acetaminophen (84 episodes,
33%), vitamins (D, pyridoxine [B6], folic acid [B9], cyano-
cobalamin [B12]) with corticosteroids (73, 29%), and vitamins
(niacinamide [B3], folic acid, E) with ibuprofen (37, 15%). The
most common type of vitamin-medication interaction was
pharmacokinetic (21, 60%); of these, modified absorption was the
most common (16, 46%). Of parents/caregivers administering
vitamins to their children, 362 (62%) reported the vitamin use to
their family physician and 117 (21%) thought that the vitamins
could cause harm.
When families of children with a potential vitamin-medication
interaction were compared with those with children with no
potential interaction (table II), we found that children with
potential interactions and their parents were significantly older
(p < 0.001 for the child and mother, p = 0.02 for father), the
children were much more likely to have a chronic illness
(p < 0.001) and concurrently receive prescribed or OTC medica-
tion (p < 0.001), and more children with potential interactions
were completely immunized (p = 0.02). The child’s sex, parental

Table I. A list of vitamin-medication combinations used by the children in our cohort that can interact with each other
Vitamin-medication pair Type of interaction n (%)
[6,7,11,13]
Ascorbic acid (vitamin C) – acetaminophen (paracetamol) PK-E 84 (33.1)
Vitamin D, pyridoxine (vitamin B6), folic acid (vitamin B9), cyanocobalamin PK-A[11,16,17] 73 (28.7)
(vitamin B12) – corticosteroids
Niacinamide (vitamin B3), folic acid, vitamin E – ibuprofen PD-B,[11] PD-O[11,22] 37 (14.6)
Riboflavin (vitamin B2) – sulfamethoxazole PD-O[13] 7 (2.8)
[8] [18]
Retinol (vitamin A), ascorbic acid, vitamin E – iron PK-A, PD-O 7 (2.8)
Folic acid – ranitidine PK-A[11,13,23] 6 (2.4)
[11,13]
Niacinamide – insulin PD-G 5 (2.0)
Vitamin D – magnesium PK-A[11] 4 (1.6)
[11,24]
Retinol, vitamin D, vitamin E – mineral oil PK-A 4 (1.6)
Folic acid, niacinamide – valproic acid PK-A[11,25,26] 3 (1.2)
[11,13,27-30] [11,14] [29,31]
Ascorbic acid, folic acid, niacinamide, vitamin E – aspirin (acetylsalicylic acid) PK-A, PD-B, PD-O 3 (1.2)
Niacinamide, folic acid, vitamin E – naproxen PD-B,[11] PD-O[11,22] 3 (1.2)
[11-13,32]
Cyanocobalamin, folic acid – omeprazole PK-A 2 (0.8)
Thiamine (vitamin B1), cyanocobalamin, vitamin E – chemotherapy PK-M,[13] PD-O[11,19,33] 2 (0.8)
Ascorbic acid – b-adrenoceptor antagonists PK-A [10,13]
2 (0.8)
Folic acid – pancreatic enzymes PK-A[11,34] 2 (0.8)
[11,13,35]
Retinol – isotretinoin PD-O 1 (0.4)
Folic acid, cyanocobalamin – mesalazine PK-A[11,36] 1 (0.4)
[11,13,37] [11,13] [11,38]
Folic acid, cyanocobalamin, thiamine, niacinamide – metformin PK-A, PD-G, PD-O 1 (0.4)
Ascorbic acid – aluminium PK-A[9,11] 1 (0.4)
[11]
Vitamin D – laxatives PK-A 1 (0.4)
[11]
Folic acid – clobazam PK-M 1 (0.4)
Folic acid – sulfasalazine PK-A, PK-M[11-13,22] 1 (0.4)
[11,12,39]
Ascorbic acid, cyanocobalamin – HIV medications (protease inhibitors) PK-M 1 (0.4)
Ascorbic acid, niacinamide, retinol, vitamin E – warfarin PD-B[5,11-13,15] 1 (0.4)
[13]
Vitamin D – amlodipine PK-A 1 (0.4)
A = absorption; B = risk of bleeding; E = elimination; G = blood glucose; M = metabolism; O = other; PD = pharmacodynamic; PK = pharmacokinetic.

ª 2009 Adis Data Information BV. All rights reserved. Pediatr Drugs 2009; 11 (4)
254 Goldman et al.

Table II. Characteristics of children and families with children with a potential vitamin-medication interaction compared with those with no potential interaction
Characteristic Patients with vitamin Group 1: potential Group 2: no potential p-Value
use (n = 582) interaction (n = 193) interaction (n = 389)
Child
Patient’s age, ya (range 0.04–18) 5.2 – 4.8 6.4 – 4.4 5.0 – 4.8 <0.001
Male sexb 345 (59.3) 112 (58.0) 233 (59.9) 0.67
Known chronic illness b
199 (34.2) 107 (55.4) 92 (23.7) <0.001
Complete immunizationb 565 (97.1) 192 (99.5) 373 (95.9) 0.02
Concurrent prescribed medications b
174 (29.9) 121 (62.7) 53 (13.6) <0.001
Concurrent OTC medicationsb 142 (24.4) 114 (59.1) 28 (7.2) <0.001
Family
Mother’s college or university educationb 433 (75.2) 147 (76.6) 286 (74.5) 0.59
b
Father’s college or university education 413 (72.0) 138 (72.6) 275 (71.6) 0.8
Maternal agea 36.9 – 6.9 37.3 – 7.2 35.2 – 7.3 <0.001
Paternal agea 39.5 – 7.4 39.8 – 7.2 38.4 – 7.9 0.02
Parental full-time employmentb 340 (58.9) 107 (56.0) 233 (60.4) 0.32
English as a primary language at homeb 378 (65.3) 131 (67.9) 247 (64.0) 0.35
a Mean ( – standard deviation), p-value calculated using t-test.
b Number (%), Pearson’s chi-square (w2) test.
OTC = over-the-counter.

education, employment status, and primary language spoken at
home were not associated with potential interactions (table II).
Furthermore, we identified theoretically possible interactions
of vitamins with 15 NHPs in 149 episodes. The most common
interactions were vitamins with aloe vera[40] (37; 25%), vitamins
with chamomile[11] (36; 24%), and niacinamide (vitamin B3) with
echinacea[11] (33; 22%). The most common type of potential
vitamin-NHP interaction was pharmacodynamic (16; 80%) with
a potential/theoretic increased risk of bleeding (10; 50%).
Discussion
This is the first study to determine the prevalence of potential
vitamin-drug interactions in a large population of children
visiting a tertiary ED. A considerable number of patients (11%
of our cohort) had potential vitamin-medication interactions in
the preceding 3 months, and over one-third of these children
had more than one potential interaction.
Since all vitamins are pharmacologically active substances
they can interact with medications as well as complementary
therapies. However, despite the widespread use of vitamins,
documented drug-vitamin interactions are sparse, especially in
children. The US FDA estimated that they are notified of
less than 1% of all adverse events associated with dietary
supplements, including vitamins, because many consumers
presume supplements to be safe and use these products without
the supervision of a healthcare professional.[41] While under-
reported, adverse events associated with concurrent drug
and vitamin use can be of similar magnitude as for ‘conven-
tional’ pharmaceuticals.[41] Furthermore, actual amounts of
vitamins in multivitamin compositions often exceed values
written on labels[42] because US legislation requires that the
amount of a vitamin is equal to or greater than the label
declaration. Overages of 30–100% of the declared value
for retinol; 50% for cyanocobalamin; 30–50% for vitamin D;
30% for thiamine (vitamin B1), riboflavin (vitamin B2), niacin-
amide, pyridoxine, folic acid, ascorbic acid, biotin (vitamin H),
vitamin K, and b-carotene; and 5% for vitamin E have been
reported by trade associations from the US and the UK.[42]
Furthermore, vitamin supplement users also tend to have higher
micronutrient intakes compared with nonusers,[3] which increases
the possibility of exceeding the upper tolerable level for the
vitamins. Intakes above the tolerable upper intake level in US
infants aged 4–24 months were noted for retinol (97% of tod-
dlers receiving supplement) and folic acid (18% of toddlers).[43]
In the FDA survey,[2] 87 of 2101 supplement users (4%) re-
ported experiencing adverse events, with 13% attributed to
multivitamins. Symptoms reported with multivitamin use in-
cluded abdominal pain, blood pressure problems, nausea, vo-
miting, allergy, dizziness, itching, rash, and other symptoms.

ª 2009 Adis Data Information BV. All rights reserved. Pediatr Drugs 2009; 11 (4)
Potential Vitamin-Drug Interactions in Children
While the authors[2] provided no information on medications
used, these adverse events could have resulted from a potential
drug-vitamin interaction. Although physicians infrequently
think of interaction-related causes of presenting symptoms, it is
possible that some of the symptoms in children presenting to
our ED were a result of a drug-vitamin interaction.
Interactions of vitamins with prescribed or OTC medi-
cations have not been systematically reviewed previously.
However, several clinical trials have been conducted and
cases have been described where interactions were docu-
mented as a potential threat or as an actual clinical
entity.[8,14,16,17,19,24-26,28,30,32,33,35-37] Some of them were serious
and potentially life threatening, for example, the addition of
anticoagulant effects of warfarin and vitamin E[44] or iron
overload related to ascorbic acid intake.[8] However, most of
the potential interactions we found in this study are theoretic
and may cause minor adverse events.
The most common drug-vitamin combinations with poten-
tial interactions in our population were ascorbic acid with
acetaminophen (33%), vitamins with corticosteroids (29%), and
vitamins with ibuprofen (15%). These potential interactions are
well documented. Ascorbic acid decreases the excretion of
acetaminophen in the urine[6,7] and thus increases the risk of
acetaminophen hepatic toxicity. Niacin and vitamin E may in-
crease the risk of bleeding if taken with ibuprofen.[11-13] Cortico-
steroids deplete pyridoxine, folic acid, cyanocobalamin, and
vitamin D,[16,17] and supplementation might be appropriate to
help prevent deficiency.
A considerable number of theoretically possible vitamin-
NHP interactions were documented in our patients. Our con-
cern is that half of them were associated with potential bleeding.
This especially relates to children who need surgery after ad-
mission to ED.[45] It is unlikely that bleeding occurred in our
patient population and we were unable to confirm this. Future
studies should investigate the occurrence of such episodes in
larger pediatric populations.
Most of the potential interactions documented in this study
were potentially negative. One exception of a potentially positive
vitamin-drug interaction reported in the literature is a possible
increase of anti-seizure action of valproic acid and other seizure
medications with niacin[11] that occurred in four (1%) patients.
Another example is the concurrent use of niacinamide and in-
sulin, which has been shown to lead to a reduction in insulin
dosage required in children with type 1 diabetes.[11] However, if
this effect is not taken into consideration, concurrent use could
potentially lead to hypoglycemia and therefore people taking
insulin should monitor their blood glucose levels closely when
taking niacin supplements.[13]
ª 2009 Adis Data Information BV. All rights reserved.
255
We found that older children with older parents, those with
chronic illness, and those receiving prescribed or OTC medi-
cations are more likely to be exposed to potential interactions.
This is expected considering that older children, especially with
a chronic illness, tend to take more medications,[46] increasing
the likelihood of interaction. More children with interactions
were completely immunized, which could also be related to the
older age of these patients.
Our study has several limitations. First, the rate of poten-
tial interactions in the ED population is probably higher than
in the general population, due to a higher proportion of
chronically ill children receiving medications. Recall bias could
also influence our results leading to underestimation of
the number of potential interactions. Furthermore, we did
not evaluate actual clinical interaction effects in this study.
In addition, some of the common potential interactions, for
example, acetaminophen with ascorbic acid, are clinically very
rare and may not be considered by many as significant ones.
Also, some potential interactions such as depletion of a number
of vitamins by corticosteroids, including reduced vitamin D
absorption, could be regarded as a side effect of taking
corticosteroids and not an interaction between the vitamins
and the corticosteroids. Additionally, precise daily timing
of the vitamin doses was not measured and this could bias
our results.
Conclusion
One-third of children receiving vitamins have potential inter-
actions with prescribed or OTC medications. Children who are
older or chronically ill are at a higher risk. Despite numerous
potential interactions and the perception by 21% of parents/
caregivers that these interactions can cause possible harm, not all
parents/caregivers (62%) disclosed vitamin use to their family
physicians and pediatricians. While we cannot confirm that these
were true interactions resulting in clinical symptoms, potential
interactions between drugs and concurrent vitamins should be
discussed with parents. If the known risks are low, then there may
be advantages to supplementation. If the risks outweigh the
benefits, then the supplement should be avoided. In each in-
stance, it depends on the individual health (and nutritional status)
of the specific person – it is not a ‘one size fits all’ approach to
vitamins (or any other therapy) that is ideal.
Taking into account the high prevalence of vitamin use, fu-
ture efforts should concentrate on encouraging research to
determine which potential interactions are clinically occurring,
but are under-recognized or under-reported, to avoid possible
adverse events.
Pediatr Drugs 2009; 11 (4)
256
Acknowledgments
The grant for the study was provided by the SickKids Foundation
(Toronto, ON, Canada). Dr Ran Goldman had full access to all the data in
the study and takes responsibility for the integrity of the data and the accuracy
of the data analysis. Dr Sunita Vohra receives salary support from the Alberta
Heritage Foundation for Medical Research and the Canadian Institutes of
Health Research. The authors have no conflicts of interest that are directly
relevant to the content of this study.
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Correspondence: Dr Ran D. Goldman, Division Head and Medical Director,
Division of Pediatric Emergency Medicine, BC Children’s Hospital,
Associate Prof., Department of Pediatrics, University of British Columbia,
Senior Associate Clinician Scientist, Child & Family Research Institute
(CFRI), Room K4-226, Ambulatory Care Building, 4480 Oak Street,
Vancouver, BC V6H 3V4, Canada.
E-mail: rgoldman@cw.bc.ca
Pediatr Drugs 2009; 11 (4)