specific product categories
For product-specific information, click one of the links
below:
Medicinal products containing benzyl alcohol (see
below)
Medicinal products containing gluten (see
below)
Medicinal products containing propylene
glycol (see below)
Medicinal products
containing gluten
Gluten can cause hypersensitivity
reactions in patients with coeliac disease. Wheat starch and
pregelatinised starch prepared from wheat starch are pharmaceutical
raw materials that contain gluten. The use of pregelatinised starch
prepared from wheat starch has not been permitted since 1 January
1998. However, wheat starch may (still) be incorporated into
medicinal products. In the past, the botanical origin of starch was
not recorded in the marketing authorisation file of the medicinal
product, which is why the list also reports the products containing
starch of unknown botanical origin.
A product can sometimes be removed from this list because the
marketing authorisation holder has replaced the wheat starch with
another type of starch by means of an amendment approved by the
MEB. In such a case, batches containing the old composition in
which gluten might be present could still be on the market. The
medicinal product is also deleted from the list if a manufacturer
decides to stop selling a medicinal product and the marketing
authorisation is withdrawn. The medicinal product may be sold off
for another year afterwards.
As a result, patients who are in doubt should always check the
package leaflet for the exact composition of the medicinal
product in the package.
The MEB regularly updates the list of medicinal products that
contain gluten. The date of the last revision is reported on the
list.
Please pass on any comments or remarks you may have by sending an
e-mail to info@cbg-meb.nl.
List of medicinal products containing gluten
Medicinal products
containing benzyl alcohol
Benzyl alcohol is used as a
preservative. The problem with this compound is that young children
cannot metabolise benzyl alcohol into hippuric acid using benzoic
acid, which can result in an accumulation of chiefly benzoic acid.
The side effects that have been described as a result of this
substance accumulating in the central nervous system include
metabolic acidosis, vasodilation, paralysis, epileptic seizures,
respiratory depression and death.
The European Directive "Excipients in the Label and Package leaflet of
Medicinal Products for Human Use" states the following with
respect to the parenteral use of benzyl alcohol:
Exposure to less than 90 mg/kg/day:
"Must not be given to premature babies or neonates. May cause
toxic reactions and allergic reactions in infants and children up
to 3 years old."
Exposure to more than 90 mg/kg/day:
"Must not be given to premature babies or neonates. Due to the
risk of fatal toxic reactions arising from exposure to benzyl
alcohol in excess of 90 mg/kg/day, this product should not be used
in infants and children up to 3 years old."
The administration of parenteral products to neonates and
children up to 3 years of age is, therefore, contraindicated!
The systemic or topical use of products containing benzyl alcohol
by pregnant women is not harmful for the foetus.
The list of products containing benzyl alcohol
provides an overview of all products containing
benzyl alcohol (including the concentration) that are authorised
in the Netherlands. The list is divided into preparations for
injection, radiopharmaceuticals, other systemics (e.g.
suppositories and suspensions) and other topicals (e.g. creams).
Products are classified according to the name of the active
ingredient. The MEB regularly updates the list. Furthermore, the
product information will be checked over the next few months for
the presence of a contraindication for administration to
neonates and children less than 3 years old.
The date of the last revision is reported on the list.
Medicinal products containing propylene
glycol
Propylene glycol is frequently used, sometimes in large quantities,
in medicinal products. Young children and patients with a poor
renal function run the greatest risk of intoxication as a result of
this. To make physicians aware of this problem, the MEB publishes
an explanatory note and a list of parenterally administered medicinal
products that contain propylene (including the
concentration).
Propylene glycol (PG) is a clear, colourless and odourless fluid
with a sweet taste [1]. PG is, for example, used as an excipient
and/or preservative in intravenous administrations, dermatics and
cosmetics, and is considered to be an excipient with a low toxicity
[1].
Many medicinal products contain PG, sometimes even in large
quantities. As a result of this, the PG limit is exceeded even when
these pharmaceuticals are administered at normal dosages.
The European Directive "Excipients in the Label and Package Leaflet of
Medicinal Products for Human Use" states a maximum daily
load for both oral and parenteral administration of 400 mg/kg
for adults and 200 mg/kg for children.
Under normal conditions, PG is partially (12-45%) excreted by the
kidneys in an unaltered form. The remaining quantity of PG is
metabolised into lactate by the liver enzyme alcohol dehydrogenase.
The lactate is then further metabolised into pyruvate and
eventually into carbon dioxide and water [1-4].
Known side effects of PG include hyperosmolarity, haemolysis,
cardiac arrhythmia, convulsions, coma and agitation [4]. The
clinical picture corresponds to sepsis and systemic inflammatory
response syndrome with the symptoms of lactate acidosis,
hypotension and organ failure [4]. PG intoxication is a potentially
life-threatening situation [4]. Metabolic acidosis and
hyperosmolarity frequently develop and are mostly expressed as an
increase in the osmolar and anion gap, with or without lactate
acidosis. The metabolic acidosis is possibly a direct consequence
of an increased PG metabolism [4]. Clinical abnormalities are
observed at higher PG concentrations (1,040-1,440 mg/l). Metabolic
abnormalities are observed at a somewhat lower PG concentration
(580-1,270mg/l) [5].
Risk groups
Young children
The half-life of PG is at least three times shorter in young
children. As PG is possibly more quickly metabolised in young
children, metabolic acidosis is observed more quickly in this group
of patients.
Patients with a poor renal function
Due to the partial renal clearance of PG, the excipient will
accumulate sooner in patients with reduced renal function
[5-7].
PG intoxication must therefore be part of a differential diagnosis
when an inexplicable anion gap, metabolic acidosis, hyperosmolarity
and/or clinical abnormalities are observed.
The list (Dutch) of medicinal products
containing propylene glycol provides an overview of parenterally
administered products that contain PG and that are authorised in
the Netherlands. The products are classified according to the
active ingredient and the concentration is stated in the last
column. The MEB updates the list and the date of the last
revision is reported on the list.
References
1. Wilson, K.C., C. Reardon, and H.W. Farber, Propylene glycol
toxicity in a patient receiving intravenous diazepam. N Engl J Med,
2000. 343(11): p. 815.
2. Speth, P.A., et al., Propylene glycol pharmacokinetics and
effects after intravenous infusion in humans. Ther Drug Monit,
1987. 9(3): p. 255-8.
3. Demey, H.E., et al., Propylene glycol-induced side effects
during intravenous nitroglycerin therapy. Intensive Care Med, 1988.
14(3): p. 221-6.
4. Wilson, K.C., et al., Propylene glycol toxicity: a severe
iatrogenic illness in ICU patients receiving IV benzodiazepines: a
case series and prospective, observational pilot study. Chest,
2005. 128(3): p. 1674-81.
5. Cawley, M.J., Short-term lorazepam infusion and concern for
propylene glycol toxicity: case report and review. Pharmacotherapy,
2001. 21(9): p. 1140-4.
6. Al-Khafaji, A.H., W.E. Dewhirst, and H.L. Manning, Propylene
glycol toxicity associated with lorazepam infusion in a patient
receiving continuous veno-venous hemofiltration with dialysis.
Anesth Analg, 2002. 94(6): p. 1583-5
Exemptions to the bioequivalence
investigation list
For a number of substances, it is
generally accepted that these do not cause bioavailability problems
when incorporated in conventional pharmaceutical forms for oral
use.
Therefore, the MEB does not believe it is necessary to carry out
bioequivalence investigations for the purpose of registering
medicinal products in a conventional oral pharmaceutical form if
these contain one of the concerned substances as the active
ingredient.
The concerned substances are reported in the list below. This list
is only applicable for strictly national applications.
- amoxicillin
- dextromethorphan
- diazepam
- doxycycline
- phenoxymethylpenicillin potassium
- flunarizine
- indomethacin
- isosorbide-5-mononitrate
- lorazepam
- lormetazepam
- metoprolol
- naproxen
- nitrazepam
- oxprenolol
- paracetamol
- pindolol
- piroxicam
- salbutamol
- temazepam
Please contact the secretariat of the Pharmaco-therapeutic Group
(PT) under which your product falls for specific file-related
questions and questions of a more technical nature.
