allergy information

Certain substances can cause hypersensitivity reactions in patients. Hypersensitivity reactions can, for example, occur with medicinal products that contain the following substance(s):

• gluten
• benzyl alcohol
• propylene glycol 

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deleted from the list if a manufacturer decides to stop selling a medicinal product and the marketing authorisation is withdrawn.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 insert 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", see http://www.emea.europa.eu/pdfs/human/productinfo/3bc7a_200307en.pdf 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. ue 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 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
• dextromethorfan
• 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 Pharmacotherapeutic Group (PT) under which your product falls for specific file-related questions and questions of a more technical nature.