Benzyl Alcohol in Pharmaceutical Products

Benzyl alcohol is an excipient used in a variety of pharmaceuticals. It is most commonly found in parenteral medicines but is also included in some products for oral or topical use. Benzyl alcohol is primarily utilised as a solubilising agent or antimicrobial preservative. However, it may also be included in a formulation for its local anaesthetic effects. This is of particular benefit for medications that are administered intramuscularly.

The antimicrobial efficacy of benzyl alcohol against different pathogens varies, as shown in Table 1. However, when used as a preservative, the concentration is usually in the range of 0.9% to 2%. For example, bacteriostatic water contains benzyl alcohol 9mg/mL (0.9%).

Table 1. Minimal inhibitory concentration (MIC) for benzyl alcohol

When used as a local anaesthetic agent, the European Medicines Agency (EMA) reports a median concentration of 150mg per injection or 30mg/mL. As a local anaesthetic, the EMA found that benzyl alcohol was primarily used in intramuscular injections of antibiotics, anti-inflammatories, and neuroleptics.

Metabolism

Benzyl alcohol is completely absorbed when administered orally and exhibits significant absorption (up to 60%) when administered topically. It can then be metabolised by alcohol dehydrogenase, an enzyme primarily found in the liver but also in the intestine and kidney. This reaction forms benzaldehyde, which is then oxidised to benzoic acid before being conjugated with glycine and excreted in the urine as hippuric acid.

This metabolic pathway is saturable. It is also underdeveloped in neonates, particularly premature neonates. In these cases, accumulation of benzyl alcohol or its metabolites can occur.

Toxicity

When applied topically, benzyl alcohol can cause mild local irritation. However, serious events have occurred following parenteral exposure in young children.

The intravenous administration of benzyl alcohol has been associated with serious adverse effects and deaths in neonates. In 1982, the US Centers for Disease Control and Prevention (CDC) reported on sixteen neonatal deaths thought to be caused by benzyl alcohol. These deaths occurred in pre-term neonates who had central intravascular catheters that were flushed with bacteriostatic normal saline. It was estimated that affected infants received at least 99mg/kg/day of benzyl alcohol.

In neonates, benzyl alcohol toxicity typically involves metabolic acidosis that progresses to respiratory distress and gasping syndrome. Central nervous system dysfunction may also develop, with convulsions and intracranial haemorrhage, as well as hypotension and cardiovascular collapse. There is currently no agreed safe dosing level for benzyl alcohol in this patient group.

The World Health Organization (WHO) has established an acceptable daily oral intake (ADI) for benzyl alcohol of 0-5mg/kg/day in adults. While there is no established limit for children, there is a risk that children could be exposed to levels exceeding the adult ADI. This is particularly true for paediatric patients admitted to intensive care units who require multiple medications.

One retrospective study looked at excipient exposure in very low birth weight infants admitted to a facility over a 12-month period. The authors found that excipient exposure was common, with 98% of subjects exposed to at least one excipient of interest and 85% exposed to two or more. Products containing benzyl alcohol were administered to 34% of the cohort. Of these patients, 11% had a benzyl alcohol exposure greater than 5mg/kg/day. However, the highest exposure in this study was still substantially lower than the fatal doses reported by the CDC. Of the patients with the highest exposure, 67% died prior to discharge. However, it should be noted that infants exposed to benzyl alcohol in this study were generally classified as critically ill.

While benzyl alcohol can be toxic in neonates and infants, it is generally regarded as safe in adults at concentrations up to 5%. The main concern centres on its potential to accumulate when used in patients with immature metabolic processes, renal or hepatic impairment, or when large amounts are given. Ethnic polymorphisms of the alcohol dehydrogenase enzyme may also cause some variations in benzyl alcohol elimination.

Benzyl alcohol should be avoided in all neonates (pre-term and full-term). Excipients should be closely reviewed for all medications, flushing solutions and diluents used in this age group. Caution is also required in young children, with the EMA recommending benzyl alcohol not be used in children up to three years of age.

While allergic reactions have been reported, benzyl alcohol is typically well tolerated in adults at typical exposure levels seen with the therapeutic use of benzyl alcohol-containing medicines. However, large amounts of benzyl alcohol should only be used where clinically necessary due to the risk of accumulation and toxicity. Particular caution should be exercised before administering large amounts to patients with impaired hepatic or renal function or during pregnancy and lactation.

Challenges

One of the challenges of avoiding particular excipients is that their presence varies according to the formulation of the medication and potentially also the brand. The medication label is one way of checking the presence or absence of benzyl alcohol. In Australia, antimicrobial preservatives must be declared on the medicine label for products applied to skin or mucous membranes. For injectable medicines, all excipients must be declared on the label. Alternatively, the excipient section of the product information can be reviewed.

Examples of medications containing benzyl alcohol are shown in Table 2, along with some formulations that do not contain benzyl alcohol.

Table 2. Medications containing benzyl alcohol

While Table 2 contains some benzyl alcohol-free products, these medicines may not be appropriate alternatives to the benzyl alcohol-containing product in all cases. For example, benzyl alcohol is included in the tetracosactide suspension for injection (depot formulation) but not the solution for injection. These two products have different approved indications and dosing instructions, which must be taken into account. Additional considerations may also be required if bacteriostatic water for injection or bacteriostatic sodium chloride are replaced with preservative-free alternatives to prepare parenteral medicines.

Summary

Benzyl alcohol is present in many pharmaceutical products and is generally considered safe for adults. However, it is associated with serious adverse events in neonates and should not be used in this patient group. The medication label or product information should be reviewed to determine the presence or absence of benzyl alcohol. Care should also be taken when switching brands of the same medication, as excipients may differ.