Safe Use of High-Risk Medications

 

Medication-related harm is thought to contribute to around 250,000 hospital admissions each year in Australia. The estimated annual cost of this is $1.4 billion.

Improving medication safety was the focus of a major global drive headed by the World Health Organization. This challenge aims to reduce medication errors by 50% over the five years to 2025. The Australian Government made a commitment to participate in the challenge, with the national response developed by the Australian Commission on Safety and Quality in Health Care (ACSQHC).

Reducing harm from high-risk medications was one of the main goals of this challenge.

What are high-risk medications?

A high-risk medication is one that has a higher risk of causing significant patient harm or death if used in error. They include medications with a narrow therapeutic index and those that present a high risk when administered via the wrong route. A narrow therapeutic index means that the difference between the dose required to achieve the desired effect and the dose likely to achieve toxic effects is small. Therefore, any errors that cause even minor changes in the plasma level are likely to be significant.

While the incidence of errors with high-risk medications is not necessarily higher than other medicines, the consequences of errors can be much more severe. For example, errors involving the administration of vincristine intrathecally instead of intravenously have an 85% fatality rate. Of the patients who survive this particular medication error, devastating neurological effects occur, including quadriplegia and persistent vegetative state.

There is no standardised list of high-risk medications in Australia, and the assigning of risk may vary between hospitals. However, the APINCH acronym can assist healthcare professionals to identify medication groups known to be associated with a higher risk of medication-related harm. An ‘S’ was later added to the original acronym. This represents ‘systems’ which includes other evidence-based practices known to improve safety, such as independent-double checks.

According to the Institute for Safe Medication Practices (ISMP), independent double checks can detect up to 95% of medication errors before they reach the patient. The independent nature of the double-check appears to be a critical element in the process. Studies demonstrate that mandated checks are often not independent, as healthcare professionals typically share information with the person performing the check which can lead to confirmation bias. These “primed” checks have not been shown to reduce medication errors.

  Example medications
A Antimicrobials Aminoglycosides
Vancomycin
Amphotericin (liposomal)
P Potassium and other electrolytes Injections of concentrated  electrolytes e.g.  potassium, magnesium, calcium, hypertonic sodium chloride
I Insulin All insulins
N Narcotics and other sedatives Hydromorphone, oxycodone, morphine, fentanyl, alfentanil, remifentanil, and analgesic patches
Benzodiazepines
Thiopentone, propofol and other short-term anaesthetics
C Chemotherapeutic agents Vincristine, methotrexate, etoposide, azathioprine
Oral chemotherapy
H Heparin and other anticoagulants Warfarin, enoxaparin, heparin
Direct oral anticoagulants (DOACs): dabigatran, rivaroxaban, apixaban
S Systems Medication safety systems such as independent double checks, safe administration of liquid medications using oral syringes, standardised order sets and medication charts etc.

The APINCHS acronym includes many routinely used medications, highlighting the need for constant vigilance. While this acronym does not cover every medication that could be considered high-risk, it is a useful tool and may be used by facilities to develop their own list of high-risk medications. This may further assist in the identification of potential risks and facilitate the implementation of risk-reduction strategies.

How can risks be minimised?

According to Standard 4 of the National Safety and Quality Health Service (NSQHS) Standards, health services must identify high-risk medications used and take appropriate action to ensure they are used appropriately. Actions to minimise risk should address every stage of medication use, from storage through to prescribing, dispensing and finally, administration to the patient.

A single strategy is rarely sufficient to achieve significant improvements in medication safety. Therefore, a layered approach is required. Strategies that could be used to improve the safety of high-risk medicines in the hospital environment include:

  • Monitor and analyse incident reports and logs;
  • Monitor occurrence and reporting of adverse drug reactions;
  • Monitor published literature from medication safety and patient safety organisations;
  • Assess local situations regarding alerts, advisories and reports;
  • Conduct risk assessments and audits;
  • Staff education;
  • Automation;
  • Implementation of forcing functions (i.e. prevent something from happening until certain conditions are met);
  • Implementation of fail-safes (i.e. prevent malfunction or unintentional operation by reverting back to a predetermined safe state if a failure occurs); and
  • Limiting access or use (e.g. restrict access to certain medications, require special conditions for administration of a particular medication).

The ISMP ranks risk-mitigation strategies in their Hierarchy of Effectiveness. According to this hierarchy, the least effective strategies are education and rules/policies; the most effective strategies are automation, forcing functions and constraints.

The removal of potent high-risk medications from certain clinical areas is an example of a highly effective strategy. For example, the use and storage of concentrated potassium ampoules in patient care areas is a well-documented root cause of fatal errors. A simple strategy for reducing the risk associated with this product has been to remove it from general patient care areas and replace it with pre-mixed solutions. For critical areas where high concentrations of potassium are required, a risk assessment should be completed before it is decided to keep the ampoules as ward stock. If the ampoules are kept, they must be stored separately and be readily identifiable from preparations with similar packaging.

Clear therapeutic guidelines should also be developed for the safe use of high-risk medications such as potassium within a facility. Points that could be considered include:

  • Use oral potassium instead of IV where clinically appropriate;
  • IV potassium chloride orders should always be written in millimoles;
  • Encourage the use of standardised pre-mixed solutions;
  • Define the maximum allowable concentration of an IV solution;
  • Define the maximum hourly rate and daily limits; and
  • Specify the recommended infusion rate, infusion pump requirements, and patient

Contributing factors

There are many additional factors that may increase the risk of medication-related harm in an individual, including:

  • Advanced age;
  • Renal impairment;
  • Presence of chronic disease and comorbidities;
  • Higher complexity of the patient’s medication regimen; and
  • The use of multiple

Polypharmacy is a noteworthy contributor to risk, with each additional medication exponentially increasing the risk of medication-related harm. Studies show that the risk of harm is 13% for the administration of two medications, yet jumps to 82% when seven or more medications are administered.

Summary

High-risk medications present a significant risk to patient safety. Not only are errors associated with these medications more likely to result in serious patient harm, but the medicines are also commonly used in the clinical setting. Reducing errors with this diverse range of medications requires a collaborative approach among healthcare professionals, as the most effective risk management tools target multiple points in the medication use process.

The ACSQHC has recently published a status report to evaluate the impact of programs implemented in relation to the WHO challenge. A summary of Australia’s progress towards reaching the WHO Global Patient Safety Challenge goals can be found on the ACSQHC website.

 

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

Microorganism MIC (mcg/mL)
Aspergillus niger 5000
Candida albicans 2500
Escherichia coli 2000
Pseudomonas aeruginosa 2000
Staphylococcus aureus 25

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

Drug Products with benzyl alcohol Products without benzyl alcohol

Topical

Methylprednisolone aceponate Advantan® cream

Advantan® lotion

Advantan® ointment

Advantan® Fatty ointment

Imiquimod Aldara®

Aldiq®

Triamcinolone acetonide Aristocort® cream Aristocort® ointment
Mupirocin Bactroban® cream Bactroban® ointment
Hydrocortisone DermAid® cream DermAid® Soft cream

DermAid® solution

Parenteral

Amiodarone Amiodarone GH injection

Amiodarone Juno

Cordarone® X

Clindamycin Dalacin® C Clindamycin Viatris
Lincomycin Lincocin®

Lincomycin SXP

Clonazepam Rivotril® ampoules
Lorazepam Lorazepam SXP
Thiamine Biological Therapies Thiamine Hydrochloride
Tetracosactide (tetracosactrin) Synacthen® Depot Synacthen®
B group vitamins Biological Therapies B-Dose Forte Biological Therapies B-Dose

 

Water for injection Bacteriostatic Water for injection Water for injection
Sodium chloride 0.9% Bacteriostatic Sodium Chloride 0.9% Sodium Chloride 0.9%

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.

 

Semaglutide for Weight Management

Semaglutide is a glucagon-like peptide 1 (GLP-1) agonist originally approved for managing type 2 diabetes. Glucagon-like peptide 1 is an incretin hormone that stimulates insulin secretion and reduces glucagon secretion in a glucose-dependent manner. Semaglutide can produce significant clinical benefits in diabetes management, including reduced HbA1c and lower fasting and postprandial glucose levels.

Glucagon-like peptide 1 agonists are also associated with weight loss due to an increase in satiety and a slowing of gastric emptying. As weight loss with these agents can be significant, semaglutide has been used off-label as a weight loss therapy. An unfortunate consequence of this is a long-term supply interruption as manufacturers struggled to meet the increased demand. The supply interruption for Ozempic® (semaglutide) is anticipated to continue until the end of 2024. However, a new brand of semaglutide is now marketed and available in Australia.

Wegovy® (semaglutide) is indicated for weight management as an adjunct to diet and exercise. While Wegovy® and Ozempic® contain the same active ingredient, they have different dosages and administration devices and should not be considered interchangeable. A comparison of the two presentations is shown in Table 1.

Table 1. Comparison of Ozempic® and Wegovy®

  Ozempic® Wegovy®
Indications Type II diabetes Weight management
Dose frequency Weekly
Initial dose 0.25mg
Maintenance dose 0.5mg or 1mg 2.4mg
PBS listed Yes No

 Semaglutide for weight management

Use and administration:

In adults, Wegovy® is indicated for chronic weight management (including weight loss and weight maintenance) in people with an initial body mass index (BMI) of:

  • ≥30 kg/m2 (obesity); or
  • ≥27 kg/m2 to <30 kg/m2 (overweight) who have at least one weight-related comorbidity.

In adolescents, Wegovy® is indicated for weight management in people 12 years and above with initial obesity (BMI ≥ 95th percentile) and a body weight above 60 kg. The manufacturer recommends discontinuation of treatment in adolescent patients if the BMI does not reduce by at least 5% after 12 weeks on the 2.4mg dose (or the maximum tolerated dose).

Presentation and use:

Wegovy® is presented in a FlexTouch® pen device for subcutaneous injection. A pack contains one pen, with each pen containing four doses. Wegovy® should be refrigerated before use but may be stored at room temperature (up to 30°C) after first use for up to 42 days. The pen should always be stored without the needle attached.

For weight management, the recommended maintenance dose of semaglutide is 2.4mg weekly. To minimise the impact of gastrointestinal adverse effects, gradual dose escalation is required. Wegovy® is available in five strengths to aid this dose escalation process. The dosing schedule recommended by the manufacturer is shown in Table 2.

Table 2. Wegovy® dose escalation schedule

Weeks Weekly dose
1-4 0.25mg
5-8 0.5mg
9-12 1mg
13-16 1.7mg
17 + onwards 2.4mg

 Efficacy:

A double-blind, double-dummy study investigated the efficacy of semaglutide for weight management in adults with overweight or obesity and type 2 diabetes. Semaglutide 1mg weekly (i.e. the usual maintenance dose for type 2 diabetes) and semaglutide 2.4mg weekly (i.e. the recommended maintenance dose for weight management) were compared with placebo.

Patients in the semaglutide 2.4mg group achieved a 9.6% reduction in body weight over the 68-week trial period. This is in comparison to a 6.99% reduction in the semaglutide 1mg group and a 3.42% reduction in the placebo group.

Both semaglutide doses demonstrated superiority over placebo for various metabolic parameters. Semaglutide 2.4mg and 1mg doses delivered similar HbA1c reductions (1.6% vs 1.5%, respectively) that were superior to the placebo group (0.4% reduction). Semaglutide was also associated with improved blood lipid profiles and reduced systolic blood pressure.

Adverse effects

All GLP-1 agonists are associated with gastrointestinal adverse effects. Nausea, vomiting, diarrhoea, constipation, and abdominal pain are very common with semaglutide. These adverse effects are typically mild to moderate in severity and transient in nature. The median duration of nausea, vomiting, and diarrhoea in clinical trials was between two and eight days. Constipation may persist for longer, with trials reporting a median duration of 47 days. Gastrointestinal adverse effects led to permanent discontinuation in only 4.3% of trial participants.

Patients should be counselled on the likelihood of experiencing these adverse effects and given strategies on how to manage them. General counselling points to minimise the impact of gastrointestinal adverse effects may include advice on the following:

  • Eating habits
    • Eat slowly
    • Only eat when hungry
    • Eat smaller portions more frequently
    • Avoid lying down immediately after a meal
  • Food composition
    • Choose low-fat, easy-to-digest foods
    • Increase fluid intake (i.e. small, regular sips of clear drinks)
  • Food diary
    • May help to identify foods or eating habits that contribute to the condition.

More specific advice may also be required for patients experiencing particular adverse effects. For example, patients experiencing constipation should ensure they have adequate fibre in their diet, increase their physical activity, and be encouraged to remain well hydrated. On the other hand, patients experiencing diarrhoea may need to temporarily reduce their fibre intake.

Providing patients with realistic expectations and strategies to minimise adverse effects may help improve adherence to therapy. However, patients should be encouraged to speak to their prescriber if adverse effects are persistent or particularly troublesome.

Medication-Induced Taste Disorders

Food

Food

Taste disorders are relatively common and can significantly affect quality of life. There are many types of taste disorders, including:

  • Dysgeusia – distortion of normal taste;
  • Hypogeusia – reduced or diminished sense of taste;
  • Ageusia – a complete loss of taste;
  • Aliageusia – when a typically pleasant-tasting food or drink begins to taste unpleasant; and
  • Phantogeusia – tasting something that is not actually there, also known as phantom taste perception.

While the exact prevalence is unknown, the literature reports rates ranging from 0.6% up to 20%. The prevalence may be much higher in some patient groups, with up to 76% of people receiving cancer treatment reporting some disorder of taste. These disorders are particularly common in cancer patients undergoing radiotherapy of the head and neck.

However, a wide range of other factors can contribute to taste disturbances. This includes xerostomia, heavy smoking, nutritional deficiencies, COVID-19, and various other medical conditions. As taste and smell are closely linked, patients may report a taste disorder when the primary dysfunction is actually olfactory.

It is important to consider the potential for medications to affect taste. One report found that medications were responsible for around a quarter of all cases of taste disturbance.

Implicated medications:

When thinking of medications that affect taste, anticholinergics may be the first that come to mind due to their propensity to cause dry mouth. The number of medications with anticholinergic properties is large, and their effects are additive. Many other medications can also cause taste disturbances via different mechanisms; in many cases, the precise mechanism for their effect on taste is not known.

A small sample of medications associated with taste disturbances is shown in Table 1.

Table 1. Medications associated with taste disturbances

Medication Effect Reported incidence Comments

Antimicrobials

Doxycycline Hypogeusia Uncommon
Maribavir Taste disturbance 46% May resolve during continued therapy
Micafungin Hypogeusia Uncommon
Metronidazole Taste alteration (metallic) Common
Terbinafine Hypogeusia Uncommon Usually reversible within weeks of discontinuation

Cardiovascular

Amiodarone Dysgeusia Rare
Atorvastatin Dysgeusia Uncommon
Captopril Hypogeusia / ageusia 1.6% – 7.3% Dose-dependent; usually self-limited to 2-3 months (even with continuation of therapy)
Diltiazem Dysgeusia / dry mouth Rare

Oncology

Capecitabine Hypogeusia Common
Anastrozole Hypogeusia Common
Dasatinib Dysgeusia Common
Everolimus Dysgeusia Very common
Cisplatin Loss of taste Common
Methotrexate Dysgeusia Common

Other

Acetazolamide Dysgeusia Common Likely dose-dependent
Allopurinol Taste disturbances Infrequent
Auranofin Metallic taste Considered warning sign of impending gold toxicity
Baclofen Dysgeusia Rare
Carbamazepine Dysgeusia Very rare
Carbimazole Loss of taste Uncommon
Dexamfetamine Hypogeusia Rare or very rare
Levodopa Bitter taste / dry mouth Unknown
Lithium Taste alteration (metallic) Common
Phenytoin Hypogeusia Unknown
Zopiclone Taste alteration (bitter) Common
Topiramate Dysgeusia 2.3% – 5.9% Dose-dependent

Potential consequences of taste disturbances:

Taste disturbances may not seem like a particularly significant issue beyond reducing the enjoyment of food. However, there are some potentially serious consequences that should be considered.

Patients affected by this condition may end up reducing their food intake due to decreased enjoyment of eating. This may lead to nutritional deficiencies and unintended weight loss. Other patients may attempt to improve the flavour of their food by adding large amounts of salt or sugar or significantly increasing their fluid intake to mask unpleasant tastes or soothe a dry mouth. These coping strategies could result in increased urinary frequency (which could potentially contribute to urinary incontinence or increased falls risk) or exacerbate underlying conditions such as hypertension and diabetes. The onset of taste disturbances may also affect medication compliance, which can interfere with the management of chronic conditions.

The elderly are more likely to experience medication-induced taste disturbance due to higher rates of polypharmacy in this population. The potential consequences may also be more serious in this group due to higher rates of underlying frailty and comorbid conditions.

Taste disturbances and related disturbances of smell can also have more acute consequences. For example, taste disturbances may reduce the ability to detect if a food is spoiled, while smell disturbances may make it difficult to detect airborne dangers such as smoke and gas leaks.

Management of taste disturbances

Understanding the potential for medications to cause disorders of taste is important when considering a management strategy. Ceasing the drug responsible for the condition is likely to resolve the problem, but may not provide immediate relief. However, it is not always appropriate to cease a therapy. Changing to a different medication from the same class may be an option. For example, enalapril is less likely to affect taste than captopril.

If changes to the medication therapy are not possible, consideration of other options may be required. Unfortunately, there is not a lot of evidence to guide treatment in this area, but options that could be explored include improving oral hygiene, zinc supplementation, and saliva substitutes. There is trial data to support the use of the antioxidant, alpha lipoic acid. However, further studies have produced mixed results for this therapy.

For therapies that are highly associated with taste disturbances, such as cancer therapies, it is useful to provide patients with clear information about the risks and potential management strategies. The Cancer Council Australia provide patient information on how to manage taste and smell changes during cancer therapy. Early referral to a dietician may be required for patients at particular risk of nutritional deficiencies.

 

Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is a common virus that can infect people of all ages. It is highly contagious, and it is thought that almost all children will be infected with RSV by two years of age. While RSV can cause a range of respiratory conditions, it typically presents as a mild cold. However, it can cause severe illness in infants, young children, and older adults.

Infection with RSV can develop into pneumonia. In infants, RSV is a significant cause of morbidity and mortality and the main pathogen responsible for bronchiolitis. Studies demonstrate that RSV bronchiolitis has a more severe clinical course than non-RSV bronchiolitis in children. The duration of hospitalisation tends to be longer, and there is an increased need for supplemental oxygen, admission to paediatric intensive care units, and mechanical ventilation. There is also some evidence to suggest that a lower respiratory tract infection (LRTI) with RSV in early childhood is associated with ongoing morbidity, including asthma and impaired lung function.

The incidence of RSV varies throughout the year. In most temperate regions of Australia, outbreaks tend to occur during autumn and winter, with a peak in June and July. Seasonality is often less distinct in tropical parts of the country but may coincide with rainy seasons.

Three new preventative medicines have recently become available in Australia: two vaccines and one monoclonal antibody. As RSV is most likely to be serious in the very young and older adults, preventative therapies focus on these populations.

Vaccines

There are two RSV vaccines available: Arexvy® and Abrysvo®. These are both non-live vaccines containing protein subunits that target the pre-fusion F protein. This protein is highly conserved among different RSV strains and has a vital role in viral entry, making it an ideal vaccine target. Abrysvo® is a bivalent vaccine containing antigens from both RSV subgroup A and subgroup B. Arexvy® is a single valent vaccine but contains an adjuvant to improve immunogenicity.

Both vaccines are indicated for use in patients 60 years of age and older to prevent lower respiratory tract disease caused by RSV. There is no brand preference in this population and either product can be used. Vaccination can occur at any time of year, but preferably before the start of the RSV season.

Abrysvo® is also indicated for active immunisation of pregnant women for the prevention of RSV disease in infants from birth to six months of age. The Australian Technical Advisory Group on Immunisation (ATAGI) recommends that administration occur between 28 and 36 weeks of gestation. If the vaccine is not administered before 36 weeks gestation, it may be given as soon as possible. However, adequate protection may not develop in the newborn if given less than two weeks before delivery. Studies demonstrate that maternal immunisation reduces the risk of severe RSV disease in infants less than six months of age by around 70%. The pregnant woman may also receive protection, although studies have not evaluated this as RSV disease is typically mild in women of childbearing age. Arexvy® is not recommended for use during pregnancy.

The Australian Immunisation Handbook recommendations for RSV vaccination are summarised below:

  • Adults ≥ 75 years
    • Single dose of Arexvy® or Abrysvo® recommended
  • 60-64 years (no risk factors for severe RSV disease)
    • Single dose of Arexvy® or Abrysvo® may be considered
    • This age group has a lower risk of severe RSV disease than people ≥ 75 years; therefore, the benefits may be lower.
  • Aboriginal and Torres Strait Islander people
    • Single dose of Arexvy® or Abrysvo® recommended for those ≥ 60 years
  • People with risk factors for severe RSV disease
    • Single dose of Arexvy® or Abrysvo® recommended for those ≥ 60 years
    • Risk factors include some cardiac conditions, chronic respiratory conditions, immunocompromising conditions, chronic metabolic conditions, chronic kidney disease (stage 4 or 5), chronic neurological conditions, and obesity (BMI ≥ 30).
  • Pregnancy and lactation
    • Single dose of Abrysvo® recommended at 28-36 weeks gestation
    • Not recommended during lactation as there is no evidence that vaccination would protect the infant via breastfeeding alone.

Both Arexvy® and Abrysvo® are only indicated for administration to adults. When administered during pregnancy, Abrysvo® protects infants via passive immunity. There are currently no vaccines available for infants that provide active immunity against RSV.

Nirsevimab

Nirsevimab is a new long-acting monoclonal antibody that is specific for the RSV F protein. This medication is also a form of passive immunity, providing antibodies that neutralise the virus and block cell-to-cell function. Nirsevimab is indicated for the prevention of RSV lower respiratory tract disease in neonates and infants born during or entering their first RSV season and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.

The Australian Immunisation Handbook recommends its administration in the following cases:

  • Infants born to women who did not receive the RSV vaccine during pregnancy or where the vaccine was administered within two weeks of delivery;
  • Infants with a condition that increases the risk of severe RSV disease (regardless of maternal vaccination). Risk factors include;
    • Preterm birth <32 weeks gestational age
    • Haemodynamically significant congenital heart disease
    • Significant immunosuppression
    • Chronic lung disease requiring ongoing oxygen or respiratory support
    • Neurological conditions that impair respiratory function
    • Cystic fibrosis with severe lung disease or weight for length <10th percentile
    • Genetic condition that increases the risk of severe RSV disease (e.g. Trisomy 21)
  • Infants born to mothers with a severe immunocompromising condition that may have impaired the maternal response to the RSV vaccine; and
  • Infants born to mothers who received the RSV vaccine but subsequently underwent a treatment causing loss of maternal antibodies (e.g. cardiopulmonary bypass or extracorporeal membrane oxygenation).

A pooled analysis of randomised controlled trials demonstrates consistent efficacy across disease severity over the 150 days following a dose. A single nirsevimab dose was associated with a relative risk reduction of 79.5% for medically attended RSV LRTI and 86.0% for very severe RSV LRTI. The efficacy of nirsevimab is likely to be greatest when administered soon after birth for infants born just before or during the RSV season. For infants born outside of the RSV season, it is recommended to administer nirsevimab once before the start of the RSV season.

Nirsevimab is administered as an intramuscular injection. For neonates and infants born during or entering the RSV season, the usual recommended dose is a single injection (50mg for patients weighing less than 5kg and 100mg for patients weighing 5kg or more). There is no clinical data for infants with a body weight of less than 1kg or a postmenstrual age of less than 32 weeks. For children up to 24 months of age who remain at increased risk of severe RSV disease in their second RSV season, a single 200mg dose is recommended.

Nirsevimab is currently only available through state-managed programs in New South Wales, Queensland, and Western Australia. The National Centre for Immunisation Research and Surveillance Australia regularly updates its website with details of current availability.

Palivizumab

Palivizumab is another monoclonal antibody that neutralises RSV. This is an older medication that was first approved in Australia in 2015.

Like nirsevimab, palvizumab also provides passive immunity. It is indicated for the prevention of serious lower respiratory tract disease caused by RSV in children at high risk. However, unlike nirsevimab, palvizumab is a short-acting agent and must be administered monthly to maintain protection. It is given as an intramuscular injection with a recommended dose of 15mg/kg. Patients may receive up to five monthly doses during the RSV season.

Compared to placebo, palivizumab is associated with a relative risk reduction of 49% for RSV hospitalisation. Nirsevimab is generally preferred over palivizumab due to its longer duration of action. However, palivizumab is recommended where nirsevimab is not available.

A summary of RSV preventative therapies is shown in Table 1.

Table 1. Summary of RSV preventative therapies

Medication Immunity provided Population for administration Dose frequency
≥ 60 years Pregnant women ≤ 24 months
Arexvy® Active Yes No No Once
Abrysvo® Active Yes Yes No Once
Nirsevimab Passive No No Yes Once
Palivizumab Passive No No Yes Monthly

 

Additional considerations:

While infants receive specific anti-RSV antibodies prior to birth via transplacental transfer, breastfeeding provides continuing transfer after birth. One study demonstrates that breastfeeding halves the risk of hospitalisation for RSV bronchiolitis during the first 12 months of life in moderately preterm infants. This finding is supported by many other studies that demonstrate the importance of breastfeeding in the prevention of RSV.

Hygiene is also an important consideration to reduce exposure to RSV. As RSV can be transmitted via direct and indirect contact with infectious droplets, hand hygiene and avoiding crowded places may be useful strategies. Interestingly, considerable data shows that the public health measures introduced during the COVID-19 pandemic may have significantly reduced the incidence of RSV disease.

Multiple studies demonstrate the negative impact of passive smoking on the frequency and severity of LRTI. Avoiding exposure to cigarette smoke should also form part of RSV prevention strategies.

Overview of cephalosporins

Cephalosporins are a large group of beta-lactam antimicrobials used in the treatment and prophylaxis of a range of bacterial infections.

Cephalosporins exert a bactericidal action in a similar manner to penicillins. They bind to penicillin-binding proteins (PBP), an enzyme found in many bacteria that is essential for cell wall synthesis. Binding of a cephalosporin to the PBP inactivates the enzyme, making the bacteria unable to synthesise peptidoglycan, the main component of the cell wall.

Categorisation

All cephalosporins have a central beta-lactam ring structure. The side chains of individual agents are what give each cephalosporin its unique antibacterial, pharmacologic, and pharmacokinetic properties.

Cephalosporins are sometimes grouped into generations based on their spectrum of activity and date of introduction. However, this categorisation system is not always precise and may differ slightly between sources.

1st generation:

Cefazolin and cefalexin have a similar spectrum of activity:

  • Gram-positive
    • Active against streptococci and staphylococci (including beta–lactamase–producing staphylococci).
    • Inactive against methicillin-resistant Staphylococcus aureus (MRSA), enterococci and Listeria monocytogenes.
  • Gram-negative
    • Active against a narrow range of aerobic bacteria, including wild-type Escherichia coli and some Klebsiella species.
    • Inactive against anaerobic Gram-negative bacteria, including Bacteroides fragilis.

 2nd generation:

Cefuroxime and cefaclor:

  • Slightly broader activity against Gram-negative bacteria compared to first-generation cephalosporins.
  • More active against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis compared to cefaclor.

Cefoxitin:

  • Significant activity against anaerobic bacteria (although not as great as metronidazole)

 3rd generation:

Cefotaxime and ceftriaxone:

  • Broad spectrum
  • No activity against Pseudomonas aeruginosa
  • Less active against staphylococci compared to cefazolin
  • Inactive against MRSA
  • Anti-staphylococcal activity is dose-dependent (sometimes co-administered with flucloxacillin)
  • No clinically useful activity against enterococci
  • Can be used for meningitis as they achieve therapeutic concentrations in the cerebrospinal fluid in the presence of meningeal inflammation

Ceftazidime:

  • Extended-spectrum
  • Active against most Enterobacteriaceae and P. aeruginosa.
  • Also available in combination with avibactam, a beta-lactamase inhibitor. This further extends the spectrum of ceftazidime to include organisms that produce beta-lactamase.

4th generation:

Cefepime:

  • Extended-spectrum
  • Active against most Enterobacteriaceae and P. aeruginosa
  • Greater Gram-positive activity compared to ceftazidime.

 5th generation:

Ceftaroline:

  • Good activity against aerobic Gram-positive bacteria
  • Only cephalosporin that is active against MRSA
  • Active against vancomycin-intermediate S. aureus (VISA) and heterogeneous VISA (hVISA)
  • Active against penicillin-intermediate and penicillin‑resistant S. pneumoniae.
  • Variable activity against Gram-negative and anaerobic bacteria
  • Inactive against Pseudomonas spp.

Ceftolozane:

  • Activity against P. aeruginosa and E. coli
  • Only available in combination with tazobactam, a potent and irreversible inhibitor of class A broad-spectrum and extended-spectrum beta-lactamases and class C cephalosporinases.
  • Inactive against bacteria that produce Klebsiella pneumoniae carbapenemases (KPCs), metallo–beta-lactamases or OXA-carbapenemases.

Administration

Parenteral:

Many cephalosporins are available in parenteral formulations that can be given intravenously (IV) or intramuscularly (IM). Cephalosporins not approved for IM use are cefuroxime, ceftaroline, ceftolozane, and ceftazidime when formulated with avibactam. The IM route is often avoided for cefazolin, cefoxitin, and cefotaxime, as it can be painful.

Mixing cephalosporins with other drugs should be avoided due to a large number of physical incompatibilities.

Oral

Only cefalexin, cefuroxime, and cefaclor are available for oral administration. Cefalexin can be given without regard to food. Optimal absorption of cefuroxime occurs when administered after a light meal. While cefaclor is well absorbed orally, total absorption is increased when given within one hour after a meal.

Cefuroxime oral liquid has been discontinued in Australia. However, the Therapeutic Goods Administration (TGA) has approved the import and supply of an internationally registered cefuroxime oral liquid under Section 19A of the Therapeutic Goods Act. This approval is currently valid until end June 2025. Cefalexin and cefaclor are both still available in an oral liquid in addition to capsule/tablet presentations.

An overview of the use of cephalosporins via oral and parenteral routes is shown in Table 1.

Table 1. Administration of cephalosporins

Drug Oral Parenteral Usual dosing interval

1st generation

Cefazolin x 6-8 hourly
Cefalexin x 6-12 hourly

2nd generation

Cefoxitin x 8 hourly (severe infections: 4 hourly)
Cefuroxime 12 hourly
Cefaclor x 8-hourly (controlled release: 12-hourly)

3rd generation

Ceftazidime x 8-12 hourly
Ceftriaxone x Daily (Meningitis: 12 hourly)
Cefotaxime x 6-12 hourly

4th generation

Cefepime x 12 hourly

5th generation

Ceftaroline x 8-12 hourly
Ceftolozane x 8 hourly

Resistance

Resistance to cephalosporins can occur by different mechanisms, including changes to the PBP or the production of beta-lactamase enzymes.

As an example, S. aureus can develop resistance to cephalosporins by changing the structure of its PBP. This prevents the beta-lactam ring of the cephalosporin from inactivating the protein. Altered PBPs are found in MRSA, and most cephalosporins are ineffective against MRSA. Ceftaroline is unique in that it inhibits the altered PBP produced by MRSA.

Beta-lactamase is an enzyme some bacteria produce that inactivates beta-lactam antibiotics by cleaving the beta-lactam ring. Cephalosporins are less susceptible to these enzymes than other beta-lactam antibiotics (such as penicillins); however, this is still an important resistance mechanism.

Cephalosporin and beta-lactamase inhibitor combinations are available, e.g. ceftazidime + avibactam, ceftolozane + tazobactam. This extends the spectrum of the cephalosporin to cover bacteria that produce beta-lactamase.

Allergies

Cephalosporins can induce IgE-mediated allergic reactions. Symptoms can include urticaria, angioedema, rhinitis, and bronchospasm. Immediate reactions to cephalosporins have been reported to occur in up to 3% of the population, while anaphylactic reactions are rare, with a reported incidence of 0.0001–0.1%.

For some time, cross-reactivity between penicillin and cephalosporins was thought to be common (i.e. around 10%). However, much of the cross-reactivity found in early studies is now known to be related to penicillin contamination of the cephalosporin preparations tested.

Studies demonstrate that it is the side chains that are responsible for beta-lactam allergies rather than the beta-lactam ring itself. Penicillins have an R1 side chain, while cephalosporins have an R1 and R2. The R1 side chain is thought to be the major factor in cross-reactivity between penicillins and cephalosporins. Some penicillins and cephalosporins have the same or similar side chains, which makes cross-reactivity more likely.

The following antibiotics have the same or similar side chains:

  • Ampicillin + amoxicillin + cefalexin + cefaclor;
  • Penicillin G + cefoxitin;
  • Cefotaxime + cefalotin;
  • Cefuroxime + cefoxitin.

Cefazolin has a unique side chain which confers a very low risk of cross-reactivity with penicillins.

More recent evidence suggests that the rate of cross-reactivity between penicillins and cephalosporins is much lower than originally thought. It is now thought that less than 2% of patients with a confirmed penicillin allergy have a cephalosporin allergy. In many cases, a cephalosporin can be safely administered to a patient with a reported penicillin allergy. However, consideration of the severity of the reaction and the specific penicillin involved should occur. E.g. an allergy to ampicillin or amoxicillin makes a reaction to cefalexin or cefaclor more likely due to the side chain similarity.

Adverse effects

Cephalosporins are generally well-tolerated. The most common adverse reactions include nausea, vomiting, diarrhoea, and pain and inflammation at the injection site.

Superinfection can occur, including Candida and Enterococcus spp. This is more likely to occur during prolonged treatment and when agents with a broader spectrum of activity are used. Clostridioides difficile-associated disease has also been reported, particularly with broad-spectrum cephalosporins. C. difficile is the most common cause of infectious diarrhoea in the healthcare setting, and its incidence has increased over the past decade. While any antibiotic may theoretically increase the risk of C. difficile-associated disease, studies suggest that the first-generation cephalosporin cefalexin carries a low risk.

Neurotoxicity is rarely reported. This may be characterised by encephalopathy, myoclonus, and/or seizures. One study suggests that these effects may be most common with cefepime, followed by ceftriaxone and ceftazidime. Factors that may increase the risk of central nervous system effects include older age (>65 years), renal impairment, history of CNS disease, and other medications. The majority of these reactions occurred following IV administration. Attention should be paid to the rate of IV administration, particularly if the patient has renal impairment or high doses are used.

 

Iron Infusions

Iron is an essential micronutrient that is required for the production of haemoglobin and a range of other proteins, including enzymes. This makes iron important in the transport of oxygen, oxidative metabolism, cellular proliferation, and many catalytic reactions. Iron is obtained from the diet, with the average adult absorbing around 1-2mg per day from an average daily intake of 10-15mg. Iron is highly conserved in the body, and daily losses are small in the absence of bleeding or pregnancy.

However, iron deficiency is common in Australia and may be related to:

  • Inadequate dietary intake;
  • Malabsorption; and
  • Increased iron requirements (e.g. pregnancy or breastfeeding, rapid growth, heavy menstrual loss, chronic gastrointestinal loss).

Iron deficiency can lead to iron deficiency anaemia. While some patients may be asymptomatic, symptoms can include breathlessness, angina, claudication, and fatigue.

Iron deficiency

The cause of iron deficiency should be treated as appropriate. Supplementation should be initiated for patients with iron deficiency anaemia. An iron supplement may also be considered to improve symptoms for patients with iron deficiency without anaemia.

Iron supplements may be administered orally or parenterally. Oral iron is more commonly used and is effective at increasing haemoglobin levels. Oral iron has the advantage of being a cheap and convenient option for patients, and is safe when taken as recommended. However, gastrointestinal adverse effects are common and may affect adherence. These adverse effects may be minimised by starting with a low dose and gradually increasing, dosing on alternate days, or taking the supplement with food (although this may reduce absorption from ferrous salts).

Intravenous iron supplementation may be more appropriate in some cases, including:

  • When rapid replacement is required (e.g. highly symptomatic patients or patients scheduled for elective surgery that is associated with significant blood loss);
  • Anaemia associated with malignancy;
  • When oral iron is not tolerated or absorbed effectively (e.g. following gastrectomy);
  • Chronic kidney disease; and
  • Inflammatory bowel disease.

When iron is administered intravenously, the absorption from oral iron products is significantly reduced. Therefore, it is not recommended to take oral iron supplements with intravenous iron. Oral iron is generally not required after an infusion as the infusion is intended to replete iron stores. However, if oral iron is considered necessary, it should be started at least a week after the last IV iron dose.

Intravenous iron preparations

There has been a significant increase in the use of iron infusions in the last decade, largely due to the introduction of newer iron salts that are better tolerated and faster to administer.

There are four iron salts available in Australia for parenteral use:

  • Ferric carboxymaltose;
  • Ferric derisomaltose;
  • Iron polymaltose; and
  • Iron sucrose.

While oral iron may require a course of around six months, intravenous iron supplementation may allow iron levels to be corrected with a single infusion (depending on the severity of iron deficiency).

Ferric carboxymaltose (Ferinject®)

Ferric carboxymaltose has some advantages over other salts. It can be infused rapidly, making it more attractive for use in the primary care setting. In many cases, the total iron requirement can be given as a single dose (up to 1,000mg of elemental iron can be given in one infusion over 15 minutes). If repeat doses are required, it is recommended to wait at least seven days between doses.

Ferric carboxymaltose may be administered undiluted for IV injection, but must be diluted in 0.9% sodium chloride when administered via IV infusion. To ensure stability, the final concentration should not be less than 2mg iron/mL. Doses of 200-500mg are usually diluted in a maximum of 100mL, and doses of 500-1000mg are diluted in a maximum of 250mL.

Ferric derisomaltose (Monofer®)

Ferric derisomaltose may also allow the total iron requirement to be given as a single dose. Up to 20mg of iron per kg body weight can be given at once, although single doses over 1,500mg are not recommended. If the total iron dose exceeds this, the dose can be split into two and given at least a week apart. Administration is also reasonably fast, with doses less than 1,000mg able to be given over 20 minutes and higher doses given over at least 30 minutes.

Ferric derisomaltose may be diluted in 0.9% sodium chloride. To ensure stability, it should not be diluted to less than 1mg iron/mL and never diluted in more than 500mL.

Ferric derisomaltose may also be given as an IV injection, either undiluted or diluted in up to 20mL of 0.9% sodium chloride.

Iron polymaltose (Ferrosig®)

Iron polymaltose allows the total iron requirement to be given as a single dose. Up to 2,500mg can be given in 500mL of 0.9% sodium chloride.

A potential disadvantage of iron polymaltose is the longer infusion time. The product information recommends slow infusion (5-10 drops/minute) for the first 50mL, increased to 30 drops/minute if well tolerated. Therefore, an infusion may take around five hours, making this a very resource intensive option. However, there is some evidence to support a rapid infusion for doses up to 1,500mg.

Iron polymaltose is approved for intramuscular injection. However, this is not generally recommended as iron is poorly absorbed by this route, can be painful, and increases the risk of permanent skin staining.

Iron sucrose (Venofer®)

Iron sucrose is indicated for use in patients undergoing chronic haemodialysis who are also receiving supplemental erythropoietin therapy. The recommended dose for these patients is 100mg of iron (one 5mL ampoule) given intravenously during the dialysis session up to three times per week. In most cases, patients require at least 1,000mg iron, which can be administered over ten consecutive dialysis sessions. Following this, dosing may continue at the lowest dose required to maintain target haemoglobin, haematocrit, and iron storage parameters.

Iron sucrose can be administered by intravenous drip infusion or by slow injection directly into the venous line of the dialysis machine. The solution is strongly alkaline and must not be administered by the intramuscular or subcutaneous route.

When given by infusion, the ampoules are diluted in 0.9% sodium chloride up to a maximum of 100mL. It is then infused at a rate of 100mg of iron over at least 15 minutes. When injected into the venous line of the dialysis machine, it can be used undiluted. An ampoule can be given over five minutes, i.e. 1mL (equivalent to 20mg iron) per minute.

Table 1. Summary of IV iron preparations

  Ferric carboxymaltose Ferric derisomaltose Iron polymaltose Iron sucrose
Brand Ferinject® Monofer® Ferrosig® Venofer®
Iron concentration 50mg/mL 100mg/mL 50mg/mL 20mg/mL
Presentation 2mL, 10mL, 20mL vials 5mL, 10mL vials 2mL ampoules 5mL ampoule
Indication Iron deficiency (≥14 years old):

– Oral agents ineffective or cannot be used

– Need for rapid iron delivery

Iron deficiency anaemia (1-13 years):

– Oral agents ineffective or cannot be used

Iron deficiency in adults:

– Oral agents ineffective or cannot be used

– Need for rapid iron delivery

Iron deficiency:

– Oral therapy impractical or contraindicated

– Defective enteric iron absorption

Iron deficiency in haemodialysis patients receiving erythropoietin
Max recommended dose 1,000mg (20mg/kg) 20mg/kg

Single doses > 1500mg not recommended

2,500mg 100mg during dialysis up to 3x a week
Rate of IV injection* >200-500mg at 100mg/min

>500-1000mg over 15 minutes

Up to 250mg/min (doses up to 500mg 3x weekly)
Rate of IV infusion* 100-200mg over 3 minutes

>200-500mg over 6 minutes

>500-1000mg over 15 minutes

<1000mg over 20 minutes

>1000mg over 30 minutes or longer

The first 50 mL infused slowly (5-10 drops/minute).

If tolerated, may increase to 30 drops/minute.

100mg over at least 15 minutes
Compatible fluids

0.9% sodium chloride

TGA pregnancy category B3 B3 A B3

*Rates given per manufacturer’s recommendations. Local protocols may differ.

Adverse effects

Iron infusions are generally well tolerated but can cause minor adverse events such as headache and taste disturbance. The following adverse effects may also occur.

Flushing

Some patients may experience flushing or feel dizzy or light-headed during the first few minutes of the infusion. This is thought to be caused by unbound labile iron interacting with the endothelium. Preparing the infusion according to directions helps minimise this effect. Changes in pH and concentration during dilution can destabilise iron complexes, potentially increasing the amount of labile iron. Therefore, it is important not to dilute iron further than what is recommended.

These reactions may occur less frequently when the iron complex binds the elemental iron more strongly, as is the case with ferric carboxymaltose and ferric derisomaltose. Iron sucrose does not bind elemental iron as strongly and releases larger amounts of labile iron into the blood. Therefore, the maximum single dose is considerably lower for iron sucrose compared to the other IV iron salts.

If these effects occur, the infusion can be stopped until the symptoms subside and then restarted at a slower rate or as advised by the prescriber.

Skin staining

Iron can stain the skin if extravasation occurs during administration. This is not a common event; clinical trials have reported rates of 0.68% to 1.3%.

Skin discolouration that occurs as a result of iron can be long-lasting and potentially even permanent. Patients should be informed of the risk of skin staining prior to receiving an iron infusion and advised to report any adverse reactions during the infusion.

The general principles of minimising the risk of iron stains are to ensure that there is an appropriate indication for parenteral iron, ensure the correct injection site and administration technique is used, and monitor the patient closely for signs and symptoms of extravasation (e.g. pain, swelling, feelings of pressure at the infusion site). If extravasation occurs, the infusion should be stopped immediately to minimise the amount of solution entering the tissues and the prescriber contacted for assessment.

If skin staining occurs, it may be localised around the injection site or extend along the length of the arm. It is typically brownish in colour, but may also appear black, bluish, purple, or grey. While this discolouration is often permanent, it can fade with time. Some patients have also achieved good cosmetic results from laser therapy.

Hypersensitivity

All iron infusions can cause hypersensitivity, including anaphylactic and anaphylactoid reactions. Severe reactions have been reported, even in patients who tolerated a previous dose. Therefore, infusions should only be administered by staff trained in the management of anaphylaxis, and adrenaline should be on hand. The number of infusions administered to a patient should also be kept to a minimum. Severe reactions are rare. Studies suggest that the rate of anaphylaxis to currently used IV iron products is around 1 in 200,000.

It is recommended that patients be monitored during each infusion and for at least 30 minutes after.

Factors that may increase the risk of allergic reactions include a history of asthma, eczema, or other atopic allergy, or a previous allergic reaction to another parenteral iron preparation. The concomitant use of beta-blockers or angiotensin-converting enzyme (ACE) inhibitors may also increase the risk of hypersensitivity reactions. Beta-blockers include atenolol, bisoprolol, and metoprolol; ACE inhibitors include enalapril, perindopril, ramipril, and trandolapril.

Influenza-like symptoms

Patients should be advised that they may develop influenza-like symptoms a few days after their iron infusion. This may include body aches and raised temperature that typically subsides within 24-48 hours. These reactions are common, with some studies suggesting up to a third of patients may be affected to some degree. Patients should be reassured that this is not an allergic reaction.

Hypophosphataemia

Hypophosphataemia has been reported in patients receiving ferric carboxymaltose and ferric derisomaltose. This may be asymptomatic or present with fatigue, muscular weakness, bone pain, breathlessness, and tachycardia.

The incidence, severity and duration of this adverse effect is highest with ferric carboxymaltose. A large meta-analysis found a pooled incidence of 47% in patients treated with ferric carboxymaltose compared to 4% in patients receiving ferric derisomaltose. Only ferric carboxymaltose was associated with severe hypophosphataemia (11% of patients); evidence suggests that hypophosphataemia can persist for six months in around 5% of patients.

This adverse effect is related to an increased urinary excretion of phosphate. Patients with impaired renal function are at a significantly lower risk of developing this adverse effect. Patients at higher risk of this effect include those receiving multiple high doses who also have risk factors for hypophosphataemia (e.g. vitamin D deficiency, calcium and phosphate malabsorption, secondary hypoparathyroidism, inflammatory bowel disease, and osteoporosis).

Summary

There are four different formulations available for the intravenous administration of iron. The dosage and rate of administration are not interchangeable between these products. The product information provides dosing information, although local protocols may also be in place.

While intravenous iron is generally well tolerated, it is associated with serious adverse effects. Therefore, it is important that patients only receive intravenous iron when oral supplementation is inappropriate.

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

Route Product*
Topical Some eye drops (e.g. Prednefrin Forte®)
Some topical creams and cosmetics
Oral Curam® and Curam® Duo suspension
Chlorpromazine syrup
Phenergan® elixir
Tryzan® (ramipril) capsules
Movicol® chocolate
Injectables Adrenaline (epinephrine)
Isoprenaline
Phenylephrine
Chlorpromazine
Dexamethasone
Dopamine
Local anaesthetics containing adrenaline
Amikacin
Gentamicin
Tobramycin

*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.

 

Potentially Inappropriate Medicines in the Australian Setting

A list of potentially inappropriate medicines (PIMs) specific to the Australian setting has recently been published. Potentially inappropriate medicines can be defined as medications with risks that may outweigh their benefits in older adults. This includes medicines with a high risk of severe adverse effects and drug interactions, as well as an increased risk of falls.

The use of PIMs in older people should be avoided unless there is a clear therapeutic need and an absence of effective and lower-risk alternatives. Avoiding PIMs is an important part of the quality use of medicines, as demonstrated by the 2020 report Medicine Safety: Aged Care. This report showed that the use of PIMs is common, with over half of all people living in aged care facilities prescribed a PIM. Furthermore, one in five unplanned hospital admissions among this population is a result of taking a PIM. Admissions related to PIMs include falls, heart failure, confusion, constipation, and gastrointestinal bleeds. Studies suggest that PIMs also cause up to 39% of all cases of delirium.

Older patients may be more susceptible to medication-related harm due to physiological changes associated with the ageing process. A medicine’s pharmacokinetic and pharmacodynamic properties can be affected by changes in body composition and reductions in renal and hepatic function. Furthermore, older patients are more likely to have multiple comorbidities and polypharmacy, thereby increasing the risk of drug interactions.

The newly published list of Australian-specific PIMs is significant for two reasons. Firstly, it may be more relevant than international lists due to differences in medication availability and clinical practice guidelines in Australia. Secondly, this new list also includes recommendations for potentially safer alternatives.

Table 1 contains the medicines and medicine classes that achieved consensus agreement for inclusion in the Australian list of PIMs.

Table 1. PIMs and possible alternatives (adapted from Wang et al. 2024)

PIM or medicine class Avoid these drugs in older people Avoid this medicine or medicine class in older people with these conditions Alternatives that may be considered
Alpha-adrenoreceptor antagonists (prazosin) Prazosin
  • Risk of hypotension
  • Taking other antihypertensive
  • Frailty
  • Risk of falls
  • Initial dose adverse effects
  • ACE inhibitors
  • Sartans
  • Calcium channel blockers
  • Silodosin
  • Tamsulosin
Antiemetics – dopamine antagonist Chlorpromazine

Prochlorperazine

  • Parkinson disease
  • Polypharmacy
  • Lewy body dementia
  • Neurodegenerative diseases
  • Frailty
  • High risk of falls
  • Ondansetron
  • Domperidone
Antihypertensives, centrally acting (methyldopa, clonidine and moxonidine) Methyldopa
  • Risk of hypotension
  • Risk of falls
  • Taking other antihypertensive
  • Frailty
  • ACE inhibitors
  • Sartans
  • Thiazide diuretics
Antipsychotics (haloperidol, zuclopenthixol, trifluoperazine, thioridazine, periciazine and flupenthixol) Haloperidol

Zuclopenthixol

Trifluoperazine

Thioridazine

Periciazine

Flupenthixol

  • Risk of extrapyramidal reactions
  • Taking anticholinergic medications
  • Polypharmacy
  • Frailty
  • Neurodegenerative diseases
  • Cognitive impairment
  • Cardiovascular diseases
  • Cerebrovascular diseases
  • Risk of falls
  • Atypical antipsychotics (e.g. quetiapine)
  • Risperidone
  • Non-pharmacological strategies (e.g. yoga)
Antipsychotics (olanzapine, quetiapine, amisulpride, ziprasidone, lurasidone, risperidone, aripiprazole and paliperidone) Olanzapine
  • Cardiometabolic syndrome
  • Risk of falls
  • Polypharmacy
  • When a non-pharmacological option has not been adequately tried
  • Neurodegenerative diseases
  • Long-term use
  • Quetiapine
  • Risperidone
Benzodiazepine, long-acting (clobazam, clonazepam, diazepam, flunitrazepam and nitrazepam) Clonazepam

Flunitrazepam

  • Dependence
  • Other medications with sedative properties
  • Polypharmacy
  • Frailty
  • Neurodegenerative diseases
  • Cognitive impairment
  • Poor renal function
  • Long-term use
  • Risk of falls
  • Short-acting benzodiazepine
  • Melatonin (for indication of sleep)
  • Non-pharmacological strategies

 

Benzodiazepines, medium-acting (bromazepam and lorazepam) Bromazepam

Lorazepam

  • Falls
  • With other sedating medications
  • Polypharmacy
  • Frailty
  • Neurodegenerative diseases
  • Cognitive impairment
Benzodiazepines, short-acting (alprazolam, oxazepam and temazepam) Alprazolam
  • Falls
  • With other sedating medications
  • Polypharmacy
  • Frailty
  • Neurodegenerative diseases
  • Dependency
  • Renal impairment
  • Long-term use
  • Oxazepam
  • Temazepam
  • Melatonin (for indication of sleep)
  • Non-pharmacological strategies
Genito-urinary anticholinergics (oxybutynin, propantheline, tolterodine and solifenacin) Oxybutynin
  • With other anticholinergics
  • Frailty
  • Polypharmacy
  • Risk of falls
  • Neurodegenerative diseases
  • Constipation
  • Cognitive impairment
N/A
Non-selective NSAIDs, (indomethacin, diclofenac, ketorolac, piroxicam, meloxicam, ibuprofen, naproxen, ketoprofen and mefenamic acid) Diclofenac

Indomethacin

Ibuprofen

Ketoprofen

Piroxicam

Meloxicam

Ketorolac

  • History of gastrointestinal bleeding
  • ↑ bleeding risks
  • Frailty
  • Poor renal function
  • Peptic ulcer disease
  • Multimorbidity
  • Chronic kidney disease
  • Heart failure
  • Cardiovascular diseases
Paracetamol
Selective NSAIDs (celecoxib and etoricoxib) N/A
  • History of gastrointestinal bleeding
  • ↑ bleeding risks
  • Frailty
  • Poor renal function
  • Heart failure
  • Cardiovascular disease
  • Chronic kidney disease
  • Long-term use
  • Taking ACE inhibitors or diuretics
  • Paracetamol
  • Celecoxib
Opioids (morphine, pethidine, fentanyl, dextropropoxyphene, hydromorphone, buprenorphine, oxycodone and codeine) Pethidine

Fentanyl

Codeine

Hydromorphone

Dextropropoxyphene

  • Polypharmacy
  • Risk of falls
  • Frailty
  • Poor renal function
  • Neurodegenerative diseases
  • Constipation
  • Opioid dependency
  • Long-term use
  • Impaired cognition
  • Chronic pain
  • Physiotherapy
  • Paracetamol
  • Oxycodone
  • Buprenorphine
Oral anticoagulants – direct thrombin inhibitors (dabigatran) Dabigatran
  • ↑ bleeding risk
  • Multimorbidity
  • Peptic ulcer disease
  • Frailty
  • Risk of falls
  • Poor blood pressure control
  • Chronic kidney disease
  • Poor renal function
N/A
Oral anticoagulants – Factor Xa inhibitors (apixaban and rivaroxaban) Rivaroxaban
  • Peptic ulcer disease
  • ↑ bleeding risk
  • Risk of falls
  • Multimorbidity
  • Polypharmacy
  • Poor renal function
  • Chronic kidney disease
N/A
Sedating antihistamines Promethazine
  • Taking other sedating medications
  • Cognitive impairment
  • Taking anticholinergics
  • Frailty
  • Neurodegenerative diseases
  • Risk of falls
  • Polypharmacy
Non-sedating antihistamines (e.g. fexofenadine)
Sulfonylureas Glibenclamide

Glimepiride

  • With other glucose-lowering medications
  • High risk of falls
  • Frailty
  • Chronic kidney diseases
  • Polypharmacy
  • Multimorbidity
  • Renal impairment
  • Irregular diet
  • Dehydration
  • Metformin
  • Gliclazide
  • DPP-4 inhibitors (sitagliptin, saxagliptin)
  • SGLT2 inhibitor (dapagliflozin)
Tramadol N/A
  • Multimorbidity
  • Frailty
  • Neurodegenerative diseases
  • Risk of falls
  • Polypharmacy
  • Poor renal function
  • Cognitive impairment
  • Long-term use
  • Taking antidepressant medications
  • Epilepsy
  • Risk of seizures
  • Paracetamol
  • NSAIDs
Tricyclic antidepressants Doxepin

Dosulepin (dothiepin)

  • With other anticholinergics
  • Frailty
  • Polypharmacy
  • Risk of falls
  • Neurodegenerative diseases (e.g. delirium)
  • Constipation
  • Cognitive impairment
  • With other sedating medications
  • Risk of postural hypotension
  • Benign prostatic hyperplasia
  • SSRIs (e.g. citalopram, paroxetine)
  • SNRIs (e.g. duloxetine)
  • Mirtazapine
Zolpidem and zopiclone N/A
  • Dependency
  • Taking other sedating medications
  • Frailty
  • Neurodegenerative diseases
  • Risk of falls
  • Polypharmacy
  • Cognitive impairment
  • Long-term use
  • Melatonin
  • Nonpharmacological strategies (e.g. sleep hygiene)

Abbreviations: ACE, angiotensin converting enzyme; DPP4 inhibitor, dipeptidyl peptidase-4; SSRI, selective serotonin reuptake inhibitor; SNRIs, serotonin and noradrenaline reuptake inhibitors; NSAID, non-steroidal anti-inflammatory drug; SGLT2, sodium-glucose transport protein 2

This list of PIMs was obtained by consensus agreement of 33 experts with specialties across 15 areas. One limitation of the study is that participants were not asked to provide sources of evidence to support their recommendations. Therefore, it is possible that the recommendations reflect clinical practice rather than current scientific evidence. Other factors not considered include medication dosage, frequency, and route of administration. It is also worth highlighting that the medications suggested as potentially safer alternatives may not have the same level of evidence to support their efficacy for all indications. For example, paracetamol is suggested as an alternative to opioids and NSAIDs, although paracetamol may not be an effective alternative in all clinical scenarios.

The harm related to PIMs contributes to loss of independence and poorer quality of life for older adults. It is also responsible for a significant amount of healthcare resource utilisation. Lists of PIMs may be useful as decision-support tools when assessing the appropriateness of a medication for an older person. However, they do not replace clinical judgment in individual cases. In some cases, a PIM may be the most appropriate option for an older individual after accounting for allergies, drug interactions, and other medical conditions. Wherever a PIM is used in an older patient, regular medication review is vital to ensure the benefit continues to outweigh the potential risks.

Intranasal Corticosteroids in Allergic Rhinitis

Rhinitis is an inflammation of the lining of the nose, causing congestion, rhinorrhoea, sneezing and itching. It is classified as allergic (hay fever) or non-allergic (including drug-induced, irritant, occupational) rhinitis.

Allergic rhinitis is a major respiratory disease due to its increasing prevalence and major impacts on quality of life. It is a major risk factor for asthma. Uncontrolled moderate to severe allergic rhinitis can affect asthma control. Asthma occurs in 30% of patients with allergic rhinitis, and allergic rhinitis occurs in more than 80% of patients with asthma.

Effective treatment of allergic rhinitis can improve asthma symptoms. Sleep disorders and sleep apnoea may also develop from chronic nasal congestion due to allergic rhinitis. Sleep apnoea may result in increased cardiovascular risk, diabetes, depression, and accidents.

Allergic rhinitis is associated with an immunoglobulin E (IgE)-mediated immune response to environmental allergens. These allergens can be seasonal (e.g. pollens) or perennial (e.g. dust mites, pet dander). Chemical irritants, such as cigarette smoke, can further exacerbate symptoms. Allergens should be identified and avoided where possible. Environmental controls, such as general measures to reduce house dust mites, may help improve symptoms.

Intranasal corticosteroids are administered directly to the nasal mucosa in the form of a nasal spray to manage allergic rhinitis, rhinosinusitis (infectious rhinitis) and nasal polyps. INCS reduce the influx of inflammatory cells into the nasal mucosa in response to allergic stimuli. This reduces the release of inflammatory mediators and the development of nasal hyperresponsiveness.

Intranasal corticosteroids are the treatment of choice in patients with moderate to severe allergic rhinitis symptoms and in patients with mild, persistent symptoms. Optimal improvement in symptoms is reached after several days of regular use, although some symptoms may start to improve within a few days. They are still effective if used on an as-needed basis for episodic symptoms.

Sodium chloride 0.9% nasal irrigation may help clear nasal passages by washing out allergens and sticky mucus and reduce congestion and irritation.

Common adverse effects of INCS are:

  • Nasal stinging
  • Itching
  • Nosebleed
  • Sneezing
  • Sore throat
  • Dry mouth and cough

Intranasal corticosteroids rarely cause systemic adverse effects when used at recommended doses. They should be used with caution in patients with glaucoma or cataracts. They are generally considered safe to use in pregnancy. Budesonide, mometasone and fluticasone are preferred in the first trimester as there is greater experience with these agents.

The recommended minimum age for the available INCS are:

  • Beclomethasone 50mcg/spray – from age 12 and older
  • Budesonide 32mcg/spray or 64mcg/spray – from age 6 and older
  • Ciclesonide 50mcg/spray – from age 6 and older
  • Fluticasone furoate 27.5mcg/spray – from age 2 and older
  • Fluticasone propionate 50mcg/spray – from age 12 and older
  • Mometasone 50mcg/spray – from age 3 and over.

General patient counselling points:

  • Shake the bottle well before each use.
  • Prime the spray before initial use or if it has not been used recently.
  • Gently blow nose to clear the nasal passages (or use a saline rinse to clear nasal obstruction and then waiting for 10 minutes before using the nasal spray).
  • Tilt head slightly forward.
  • Gently insert the nozzle into the left nostril, aiming towards the left ear, away from the septum. Use your right hand for the left nostril and left hand for the right nostril. This reduces the amount of drug deposited onto the septum.
  • Press to spray (do not sniff hard, as this can force the dose into the throat).
  • Repeat for the other nostril.
  • Wipe the tip of the spray device with a dry tissue and put the cap back on.
  • Optimal effects may be seen after 7 days of continual use.
  • For intermittent symptoms, consider using 2-4 weeks before exposure to know allergens (e.g. pollen) to prevent symptoms.
  • If two different nasal sprays are used, there should be an interval of at least 10 minutes between sprays.

Combination products containing an INCS and intranasal antihistamine (INAH) are also available. These formulations are used in patients with allergic rhinitis with moderate to severe symptoms, those with mild, persistent symptoms, and those with mild symptoms not responding to antihistamines. Combination treatments offer the advantages of both medications and are more efficacious and faster acting than monotherapy.

The minimum recommended age for use of INCS/INAH formulations is:

  • Azelastine 125mcg/fluticasone propionate 50mcg (Pharmacy Only medicine) – age 12 and older. Offers nasal symptom relief from 5 minutes and ocular symptom relief from 10 minutes.
  • Olopatadine 600mcg/spray/mometasone furoate 25mcg (Prescription Only medicine) – age 6 and older. Offers nasal symptom relief from 10 minutes.

Counselling points:

The information that should be provided to patients is much the same as per INCS products.

If the patient is already taking an oral antihistamine, it should be stopped before starting the combination nasal spray. Combining an oral and intranasal antihistamine does not provide additional benefit.

Although the efficacy of each INCS is thought to be similar, choice may be affected by many factors including dosing, cost and tolerability.