Sulfites in Pharmaceutical Products

Sulfites are a group of sulfur-based compounds with preservative and antioxidant properties. Their antimicrobial activity is related to their ability to release sulfur dioxide gas. Sulfites are added to some medications, foods and drinks. They are also naturally present in some foods, and small amounts are produced endogenously as a by-product of amino acid metabolism.

Sulfites used as preservatives include:

• Sulfur dioxide;
• Potassium bisulfite;
• Potassium metabisulfite;
• Sodium bisulfite;
• Sodium metabisulfite; and
• Sodium sulfite.

Sulfites used in pharmaceuticals

Sulfites are used in a range of pharmaceuticals and cosmetics. For example, they are used as an antioxidant to extend the shelf life of products containing adrenaline and adrenaline derivatives. This includes noradrenaline, phenylephrine, and dopamine. Table 1 includes some additional examples of medications that contain sulfites.

Table 1. Examples of products that may contain sulfites

*The presence of sulfite preservatives may differ between brands and presentations of drugs. The presence or absence of sulfites can be confirmed by reviewing the product label or product information.

Sulfite sensitivity

Sulfites are substances that are generally regarded as safe but can cause adverse reactions in sensitive individuals. These reactions can include dermatitis, urticaria, flushing, hypotension, abdominal pain, and diarrhoea. At the more severe end of the spectrum, sulfites may cause asthmatic episodes or anaphylactic symptoms.

The true prevalence of sulfite sensitivity is unknown but is thought to affect around 1% of the general population. However, the prevalence is significantly higher in people with asthma, with studies reporting a prevalence of 3% to 10%. Risk factors for more severe reactions in this population may include steroid-dependent asthma, marked airway hyperresponsiveness, and children with chronic asthma.

The Therapeutic Goods Administration (TGA) requires the presence of sulfites to be declared on the product label of therapeutic goods. This is mandatory regardless of the medicine’s intended route of administration. Australian law also requires the presence of sulfites to appear on food labelling. This is indicated by using the word ‘sulfite’, or the code numbers 220 through 228. Sulfites are also widely used in a range of industries. Occupational asthma linked to sulfite exposure has been reported in workers of seafood processing plants and pulp mills, among others.

Sulfur Allergy vs Sulfite Sensitivity

The term ‘sulfur allergy’ is commonly used by patients and even documented in clinical records. However, this is an imprecise term that can cause confusion. When the term ‘sulfur allergy’ is used, it is unclear whether this refers to sulfonamide antibiotics, sulfite compounds, or some other sulfur-containing product.

Sulfites and sulfonamides are chemically unrelated and do not cross-react. Therefore, an allergy to a sulfonamide antibiotic does not imply an allergy to sulfites. Whenever allergies and sensitivities are recorded, it is important to be accurate and comprehensive. The term ‘sulfur allergy’ should not be used.

Management of Sulfite Sensitivity

Some individuals may experience significant bronchospasm when sulfites are inhaled but do not react when sulfites are ingested orally. This is important to note as some medications may be used by inhalation on an ‘off-label’ basis. An example of this is gentamicin.

Gentamicin is an aminoglycoside antibiotic that is registered in Australia for intravenous or intramuscular use. However, some evidence supports the use of nebulised gentamicin in the management of cystic fibrosis and bronchiectasis. This would require the off-label use of gentamicin solution for injection administered via inhalation. There are many brands of gentamicin for injection registered for use in Australia. However, only one brand of gentamicin ampoules is free of sulfites.

Differences in excipients should be considered when using a different brand of a medicine. This is particularly important when products are used off-label, as the product information may not alert the user to potential safety issues specific to the clinical scenario in question.

People with sulfite sensitivity should avoid sulfite exposure wherever possible. For some medicines, there may be an alternative presentation available that does not contain a sulfite preservative. This would include preservative-free formulations and those using a non-sulfite preservative, such as a hydroxybenzoate or phenol. The presence of a sulfite sensitivity would not be considered a contraindication to the use of sulfite-containing adrenaline products in emergency situations.

For individuals who also have asthma, optimising asthma control is a vital part of managing sulfite sensitivity. Patients should be encouraged to continue using their asthma medications as prescribed by their doctor. Referral to a clinical immunologist or allergy specialist is recommended for patients who have a severe reaction to sulfites.