Transcript investigating the adverse effects of excipients to help provide

Adverse effects of
excipients: implications for
their use in children
Sheridan Roth, Teresa Brooks and
Penny North Lewis
Leeds Teaching Hospitals NHS Trust
The authors
Getting the right start: National Service
Framework for Children …
Standard for Hospital Services
“policies and procedures … ensuring that
formulations of medicines are appropriate
to the age and ability of the child”
Huge task!
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Extemps project
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Rationalise preparations
Formulary/Catalogue
Standard worksheets
Excipients
Excipients Project
Aim
 To investigate the safety profile of
commonly used excipients in particular
adverse effects in children
 To identify any specific concerns with
excipients
 To identify the acceptable level or
threshold dose for each excipient
Method
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The following excipients were investigated
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Hydroxybenzoates (parabens)
Benzoates (benzyl alcolhol, sodium benzoate, benzoic acid)
Benzalkonium chloride
Chloroform
Ethanol
Propylene glycol
Aspartame
Saccharin
Sorbitol
Lactose
Method
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Searches
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Medline (Ovid) and Embase – using adverse
effects, drug toxicity, poisoning and
contraindication as search terms
Meyler’s Side Effects of Drugs
Micromedex
Pharmline
Google
Method
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Data was collected and summarised to
include:
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Special concerns with that excipient for a
particular patient or age group
The acceptable intake or threshold level
where available
Adverse effects reported
Results
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Several thousand hits for some excipients
which made finding answers long winded
Lots of work done in the 70’s and 80’s,
more recent research tends to relate to
carcinogenicity
Changing opinion as to safe limits e.g.
saccharin 5mg/kg to 2.5mg/kg to 5mg/kg
Results
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Lots of chat sites referring to excipients on
the internet
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Often not referenced
Gossipy!
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Rarely a definitive answer
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Acceptable daily limits include other
sources
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Sweeteners - dietary
Chloroform - showers
Excipient
Age/other
concerns
Concentrations/threshold
Adverse effects reported
Benzoates:
-benzyl alcohol
(Benzyl alcohol
is oxidised in
vivo to benzoic
acid.)
Neonates can
receive high mg
dose per kg of
benzoates and have
an immature
benzoic acid
detoxification
pathway leading to
the accumulation. If
possible, benzoates
should be avoided
completely in
premature, VLBW
infants.
In neonates,
benzoates can
displace bilirubin
from albumin
binding sites.
Non-fatal toxicity has been
reported following a daily intake
of 32-105mg/kg/day.
100mg/kg/day is the lowest dose
reported to have caused death in
infants.
Gasping syndrome in very low birth
weight infants that received benzyl
alcohol from IV preparations. This
includes:
-metabolic acidosis
-seizures
-neurological deterioration
-renal dysfunction
-hepatic dysfunction
-cardiovascular collapse
-death
Also seen in neonates: intraventricular
haemorrhage, cerebral palsy and
developmental delay.
If given intrathecally can cause
paraparesis.
Hypersensitivity, skin rashes, contact
dermatitis, nausea, fever and
angiodema.
Acceptable daily intakes were
established by the World Health
Organization at 5 mg/kg for total
Benzyl Alcohol, Benzoic Acid,
and Sodium Benzoate.
Topically could be used safely at
concentrations up to 5% and 10%
for hair dyes.
Excipient
Age/other
concerns
Concentrations/threshold
Adverse effects reported
Ethanol
Little is known
about the
pharmacokinetics
of ethanol in the
very young who
may be extremely
sensitive to its toxic
effects.
Adverse reactions
after alcohol
ingestion were
mainly reported by
those subjects who
showed the lack of
aldehyde
dehydrogenase
isozyme I. This
deficiency is mostly
seen in
Asian/oriental
people.
In general, a small amount (eg. 15%v/v) is unlikely to be harmful
unless relatively large volumes
are administered. The effects of
chronic dosing and accumulation
also require consideration.
Many reported mostly associated with
larger doses and include:
Sedation/CNS depression
Induction of hepatic enzymes
(chronic use)
Narcosis, coma
Respiratory failure, death (at large
doses)
Hypothermia, hypertension
Acidosis, electrolyte disturbance
Hepatotoxicity
Hypoglycaemia (especially in
children)
Radiating pain (IV)
Haematological abnormalities
Headache, cerebral ischaemia
Seizures, neuropathy
Ataxia, slurred speech
Allergy, vasomotor rhinitis
The American Academy of
Paeditrics has arbitrarily
established a blood ethanol
concentration (BEC) of 25mg
per 100mL as a value that
should not be exceeded
following a single dose of
ethanol containing medication.
Ethanol
volume  %ethanol(v / v)  0.79
BEC (mg / 100mL) 
0.6 L / kg  weight (kg)
Where:
volume
% ethanol
0.79
0.6L/kg
weight
=
=
=
=
=
of dose of medicine
of the formulation
specific gravity of ethanol
volume of distribution of ethanol
weight of the child in kg
Ethanol
Standard phenobarbital elixir BP (15mg/5ml)
contains 38% alcohol
A dose of 5mg/kg in a 3kg baby gives a BEC
of 83mg/100ml
Legal limit for drink driving is 80mg/100ml!
Problem excipients
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Hydroxybenzoates in neonates – esp if
hyperbilirubinaemic
Benzoates in neonates
Propylene glycol in children under 4 yrs
Ethanol – esp in infants
Sorbitol, aspartame, lactose – children
with metabolic disorders
Conclusion
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Children more at risk of ADRs to excipients
– especially neonates
Can of worms!
Future steps
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Extend list of excipients, including dyes
Develop guidelines with maximum
concentrations of excipient which can be
used when making purchase decisions, if
necessary buying off contract for paeds
Review formulations currently stocked to
assess potential for harm
Future steps
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Extemp project
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Divide formulations into 2 groups with a
reduced excipient load formulation available
for at risk groups e.g. neonates
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Shorter shelf life
Thanks to Sheridan and Teresa and the QC
department at LTHT