Knowledge Type: Clinical Articles

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.

1^st 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.

 2^nd 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)

 3^rd 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.

4^th generation:

Cefepime:

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

 5^th 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 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 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.

 

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.

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.

While COVID-19 may no longer be considered a public health emergency, it continues to have a significant impact on health services and the community. Residential aged care homes (RACH) continue to experience outbreaks. As of 11 April 2024, there were 209 active outbreaks in RACHs across the country. Outbreaks are highest in New South Wales and Victoria, with these states recording 29 and 27 new outbreaks in the previous seven days, respectively. In Australia, over 100,000 infections have already been reported this year. However, given the reduced volume of testing, this figure likely underestimates the actual number of cases.

Over 70.7 million COVID-19 vaccine doses have been administered in Australia since the vaccination program began in early 2021. Vaccination remains the most important measure to protect people at risk of severe disease. However, only 22.9% of people aged 65-74 and 38.1% of those over 75 have received a booster in the last six months.

The Australian Technical Advisory Group on Immunisation (ATAGI) has recently updated its advice on the use of COVID-19 vaccines. This advice contains important information regarding:

• Recommendations for additional doses of COVID-19 vaccine;
• Timing of vaccination; and
• The preferred COVID-19 vaccines for various age groups.

Table 1 provides an overview of the COVID-19 vaccines used in Australia.

Table 1. COVID-19 vaccines registered in Australia (adapted from ATAGI 2024)

Vaccines	Omicron XBB.1.5				Bivalent	Original
	Comirnaty® Omicron XBB.1.5 (raxtozinameran)			Spikevax® XBB.1.5 (Andusomeran)	Comirnaty® Original/Omicron BA.4-5 (tozinameran/ famtozinameran)	Comirnaty® (tozinameran)
Formulations	6 month – <5 year*	5 – <12 years	≥ 12 years	≥ 12 years	≥ 12 years	6 month – <5 year	5 – <12 years
Presentation	Maroon or yellow cap	Blue cap	Grey cap	Pre-filled syringe	Grey cap	Maroon cap	Orange cap
Dose	3 mcg	10 mcg	30 mcg	50 mcg	15/15 mcg	3 mcg	10 mcg

*Not yet available

The Omicron XBB.1.5 vaccines are currently preferred as they provide a better immune response against Omicron variants. Early data suggests that these newer vaccines are as well tolerated as the original and bivalent formulations of Spikevax® and Comirnaty®. In the three days after receiving an XBB.1.5 COVID-19 vaccine, no adverse effects were reported for 73% of Comirnaty® recipients and 54% of Spikevax® recipients. For each XBB.1.5 vaccine, local reactions were the most common adverse effects, followed by fatigue, muscle or joint pain, and headache. The rate of reported medical attendance following vaccination with Comirnaty® XBB.1.5 and Spikevax® XBB.1.5 was low at 0.3% and 0.4%, respectively. The AusVax Safety website provides additional safety data for each vaccine.

An Omicron XBB.1.5 vaccine is not yet available for infants and children under five years of age. However, Comirnaty® Omicron XBB.1.5 (6 months – 5 years formulation) has been approved by the Therapeutic Goods Administration (TGA). Once this product is available, it will be the preferred vaccine for this age group. Until then, the age-appropriate original Comirnaty® vaccine should be used in this population, where indicated.

Vaccine timing:

A primary vaccination course is recommended for all adults 18 years of age or older, and from six months of age for children with risk factors for severe disease or death from COVID-19. A primary course is now considered one dose for most people. However, for people with severe immunocompromise, a primary course is two or three doses.

The current ATAGI recommendations for the administration of additional COVID-19 vaccine doses include:

• Every six months for adults ≥ 75 years;
• Every 12 months (with consideration of six-monthly dosing) for adults aged 65-74 years;
• Every 12 months (with consideration of six-monthly dosing) for adults aged 18-64 years with severe immunocompromise;
• Consideration of an annual dose for all other adults; and
• Consideration of an annual dose for children aged 5 to <18 years with severe immunocompromise.

Examples of severe immunocompromise for which additional doses of COVID-19 vaccine may be required can be found in the Australian Immunisation Handbook. These include:

• Haematological malignancies (treated and untreated);
• Malignancy, solid organ transplantation, autoimmune and inflammatory conditions currently treated with therapies such as conventional chemotherapy, significant doses of conventional immunosuppressants, and some monoclonal antibodies;
• HIV with a CD4+ cell count below 200;
• Primary immunodeficiency (e.g. complement defects); and
• Chronic kidney disease requiring dialysis.

The recommended timing of additional vaccine doses is summarised in Table 2. Where it is stated that additional doses may be considered, this should include an individual risk-benefit assessment.

Table 2. Recommended timing of COVID-19 vaccine doses following primary course (adapted from ATAGI 2024)

Age	Severe immunocompromise	Without severe immunocompromise
≥ 75 years	Every 6 months
65 – 75 years	Annual (may consider 6-monthly dosing)
18 – 64 years	Annual (may consider 6-monthly dosing)	Consider annual dosing
5 – 17 years	Consider annual dosing	Not recommended
< 5 years	Not recommended

ATAGI advises that COVID-19 vaccines may be administered at the same time as any other vaccine for people five years of age or older.

Treatment:

Most cases of COVID-19 are mild and can be managed symptomatically at home. Specific antiviral treatments are available for higher-risk groups.

Two oral treatments for COVID-19 are available: Lagevrio® (molnupiravir) and Paxlovid® (nirmatrelvir and ritonavir). From 1 March 2024, the Pharmaceutical Benefits Scheme (PBS) eligibility criteria were modified for these therapies. People who test positive for COVID-19 may now be eligible for PBS-subsidised therapies if they meet the following criteria:

• Are 70 years of age or older (regardless of risk factors and presence of symptoms);
• Are 50 years of age or older and have two additional risk factors for developing severe disease;
• Are a First Nations person aged 30 years or older with one additional risk factor for developing severe disease; or
• Are 18 years of age or older and moderately to severely immunocompromised or have previously been hospitalised for COVID-19.

For the purpose of PBS eligibility, risk factors include:

• Residing in an aged care facility;
• Living with disability with multiple conditions and/or frailty;
• Neurological conditions (e.g. stroke, dementia) and demyelinating conditions (e.g. multiple sclerosis);
• Chronic respiratory conditions (e.g. COPD, moderate or severe asthma);
• Obesity or diabetes (type I or II requiring medication);
• Heart failure, coronary artery disease, cardiomyopathies;
• Kidney failure or cirrhosis; and
• Living remotely with reduced access to higher level healthcare.

Paxlovid® remains the preferred oral antiviral for COVID-19. Current evidence suggests that it is superior to Lagevrio® in terms of hospitalisation and mortality rates. However, Paxlovid® is contraindicated in severe renal or hepatic impairment and with some medications that are highly dependent on CYP3A for clearance. Lagevrio® is only PBS-subsidised when Paxlovid® is contraindicated.

Summary

The recommendations for COVID-19 vaccination have recently been updated. Some of the more significant points include the preference for the Omicron XBB.1.5 vaccines and changes to the definition of a primary dose. Vaccination continues to be an important measure to reduce the risk of severe disease and death from COVID-19.

Medication-overuse headache is a neurologic disorder that can cause significant disability and suffering. This condition typically only occurs in patients with migraine or tension headaches and is associated with overuse of medications for the treatment of the primary headache. Responsiveness to prophylactic therapies may also be reduced, leading to a cycle of increased medication use and increasing headache frequency and intensity. Alternative names for this condition include analgesic rebound headache, drug-induced headaches, and medication misuse headaches.

The International Classification of Headache Disorders (ICHD) defines medication-overuse headache as: “Headache occurring on 15 or more days/month in a patient with a pre-existing primary headache and developing as a consequence of regular overuse of acute or symptomatic headache medication (on 10 or more or 15 or more days/month, depending on the medication) for more than 3 months. It usually, but not invariably, resolves after the overuse is stopped.”

The prevalence of medication-overuse headache is estimated to be around 1% in the general population but may be up to 50% in specialised headache clinics.

While the pathophysiology of medication-overuse headache is not fully understood, it is thought to be related to central sensitisation. Some evidence suggests that there may also be a behavioural component, with some studies finding a higher prevalence of substance use disorders in people with medication overuse headache. Some neurobiological pathways may be common to both substance-related disorders and medication-overuse headache.

Animal models demonstrate that chronic analgesia exposure causes increased excitability in parts of the nervous system related to headache pathogenesis. This includes upregulation of calcitonin gene-related peptide (CGRP), substance P, and nitric oxide synthase in trigeminal ganglia; reduced nociceptive threshold of central trigeminal neurons; and increased susceptibility to develop cortical spreading depression.

Medications that are considered potent inducers of medication overuse headache include opioids, triptans, and ergot alkaloids. Patients may be at risk if they are taking these medications more than ten days per month. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) can also induce this disorder if taken for more than 15 days per month. Medication overuse headache can also develop in headache-prone individuals when acute headache medications are taken for other indications.

Other potential risk factors for medication-overuse headache include:

• High headache frequency at baseline;
• Age <50 years;
• Female sex;
• Anxiety or depression;
• Physical inactivity;
• Chronic musculoskeletal complaints;
• Smoking; and
• Metabolic syndrome.

Management:

The management of medication-overuse headache typically involves withdrawal of the overused medication. Patients may experience unpleasant withdrawal symptoms during this period. Symptoms will vary depending on the medicine but may include increased headache, vomiting, restlessness, sleep disturbances, and anxiety. The duration of withdrawal symptoms is typically up to four days for triptans, seven days for ergotamine, and up to ten days for analgesics. Simple analgesics, triptans, and ergot alkaloids can be discontinued abruptly without dose tapering. However, gradual dose reduction may be required for patients taking opioids or benzodiazepines.

Medications that have been overused should be avoided during the withdrawal period. However, bridging therapy may be considered, particularly for patients with severe symptoms. The Therapeutic Guidelines recommend a long-acting NSAID or a short course of prednisolone for bridging therapy, as follows:

• Naproxen modified-release tablets 750mg once daily for five days in the first week, then three to four days per week in the next two weeks, then stop; or
• Prednisolone or prednisone 50mg once daily for three days, then reduce gradually over seven to ten days to zero.

Following this, the guidelines advise that the usual acute medication may be restarted with restrictions on dose frequency (i.e. opioids and triptans to be used less than ten days a month, non-opioid analgesics for less than 15 days per month). However, it is important that these patients receive education and appropriate follow-up to reduce the risk of recurrence.

Studies support the addition of prophylactic medications for patients with primary migraine or tension headaches to return to an episodic pattern. Preventative medications with significant evidence to support them in this setting include:

• Topiramate;
• Onabotulinumtoxin A; and
• Monoclonal antibodies against CGRP (e.g. erenumab, fremanezumab).

Other prophylactic medications, such as beta-blockers, may also be considered as appropriate.

Summary

Medication overuse headache can have a significant impact on a patient’s quality of life. The accurate diagnosis of this condition is important as patients often improve following discontinuation of the overused medication. Follow-up care is important for these patients as relapse and recurrence are common.

Hormone receptor-positive and HER2 receptor-negative (HR+/HER2-) breast cancer can be treated with CDK4/6 inhibitors. When cyclin-dependent kinase (CDK) cellular biology becomes dysregulated, cell proliferation occurs, and this has led to the discovery of three current CDK4/6 inhibitor drugs to treat HR-positive HER2-negative breast cancer: palbociclib, ribociclib and abemaciclib (1).

All CDK4/6 inhibitors (CDK4/6i) used for HR+/HER2- breast cancer should be used in combination with an endocrine inhibitor such as an aromatase inhibitor or Fulvestrant. (2) If using palbociclib in endocrine pre-treated patients, then fulvestrant would be the recommended endocrine inhibitor of choice (2).

Seven pivotal trials have determined the efficacy of all three current CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer. Although one should be prudent when directly translating across three different trials, the progression-free survival (PFS) hazard ratios are similar between the three molecules (3).

It should also be noted that in pre-treated patients, the combination of ribociclib or abemaciclib with fulvestrant produced greater overall survival (OS) than with fulvestrant alone. Although statistical significance wasn’t seen with palbociclib in combination with fulvestrant for OS in pre-treated patients, the population studied received significantly more pre-therapy than trials with ribociclib or abemaciclib (3).

Overall survival was a secondary endpoint in the first-line metastatic trials. Abemaciclib did not reach statistical significance for OS after 70.2 months of follow-up. A recent presentation of 8 years of follow-up in the abemaciclib MONARCH-3 study showed an increase in overall survival of 13 months (66.8 months vs 53.7 months). Although this effect unfortunately did not quite reach statistical significance, it is worth noting (4). Ribociclib reached statistical significance for OS in several trials compared to endocrine therapy alone for first-line metastatic HR+/HER2- breast cancer. Palbociclib did not reach statistical significance. However, there is controversy in regard to the veracity of this finding for palbociclib. Survival data was missing, and post-progression therapy in the control arm was higher in the palbociclib trial (3). After 7.5 years, 10% of patients are still on palbociclib, and real-world data outside of a trial setting showed an OS benefit (3).

The disparate results in OS and the very similar results in PFS between the three molecules have caused some debate as to the reasons behind this. Overall survival was a secondary endpoint in each of the studies, and this highlights the importance of primary and secondary endpoints when analysing the results of trials. In fact, it has been suggested both the MONALEESA trial and PALOMA-2 trial were only powered to <70% for OS and the differences could very well be attributed to chance. As discussed previously, the post-progression treatment rates were different and, as palbociclib underwent regulatory approval, those on ribociclib in the MONALEESA trials who progressed received palbociclib, a different drug to the treatment arm. In the palbociclib (PALOMA-2 trial) trial, those who progressed received the same drug palbociclib post-progression. There were also differences in disease-free intervals in the exclusion criteria for the trial designs that may possibly imply differences in endocrine sensitivities. Other differences existed in patient recruitment across trials and there is debate if they were a potential cause of difference. This is always a factor to consider with no head-to-head trials to draw from (3).

The Monarch-E trial combined abemaciclib with endocrine therapy for HR-positive, HER2-negative early breast cancer that was node-positive and at high risk of recurrence (5). This phase III open-label trial assigned patients to receive either abemaciclib for two years combined with anti-estrogen therapy for five years or anti-estrogen therapy alone for five years. At the initial follow-up of 27 months, the results were statistically significant in favour of the treatment arm (2). At an additional follow-up of 42 months, this statistically significant result was maintained, and data presented at the ASCO conference showed a statistically significant five-year invasive disease-free survival (IDFS) benefit (6).

The NATALEE trial is investigating ribociclib 400mg daily using the 21-day treatment and seven-day rest protocol for three years for early breast cancer. Patients were included who had stage IIA, IIB, or III hormone receptor–positive, HER2-negative breast cancer and were at risk of recurrence. The final analysis has been done, and the results are positive for ribociclib for this new indication and even for patients with node-negative disease. (7) Upon publication, there is anticipated much discussion about the pros and cons of abemaciclib vs ribociclib for the treatment of high-risk HR+/HER2- early breast cancer.

One of the most important aspects for pharmacists managing CDK4/6 inhibitors is interpreting the adverse effect profile of the three current agents in use for individual patients. This will be even more important with TGA approval and PBS approval for early breast cancer. It is easier to be less cautious in the metastatic setting than in those with quite likely curable early breast cancer.

The differing adverse effect profiles are due to the difference in affinity for each of the two receptors amongst the three molecules. Neutropenia and other haematological adverse effects are more common with ribociclib and palbociclib. The neutropenia seen with CDK4/6 inhibitors is distinct from that seen with other cytotoxic agents in that it is easily reversible, reflecting a cytostatic effect on the bone marrow and rarely associated with febrile neutropenia. Ribociclib is associated with QT prolongation, and baseline ECG should be done and monitored during treatment. Diarrhoea is mostly associated with abemaciclib and it is important to discuss this with patients at the start of treatment to come up with a plan as to how to treat with loperamide and electrolytes and when to seek medical or emergency help. (7) Liver toxicities are associated with the CDK4/6 inhibitors abemaciclib and ribociclib, and liver enzymes should be monitored (3).

Patient counselling on the rare but serious side effect of interstitial lung disease should occur, and patients should be cognizant of cough or shortness of breath. Blood clots are also rare but serious potential side effects, and although rare, one has to consider this in particular in the early breast cancer setting as to whether the risk outweighs the potential reward for those at particular risk of VTE and potential prophylactic anticoagulation. (7) There is also an increase in hypertension and other cardiovascular events amongst patients treated with CDK4/6 inhibitors (8).

There are potential drug interactions associated with all three molecules, both metabolic in terms of CYP3A4 inhibition or induction. P-gp drug interactions and pharmacodynamic drug interactions, particularly with QT prolongation for ribociclib are also possible.

The CDK4/6 inhibition and the resulting choice of drugs are an exciting development in the treatment of both metastatic and now early breast cancer. Pharmacists must strive to play a pivotal role in the management of these medications to ensure to get the most out of these exciting new treatment protocols.

The Therapeutic Goods Administration (TGA) has announced plans to transition Special Access Scheme (SAS) and Authorised Prescriber (AP) submissions to a fully digital model. Once this is implemented, paper-based submissions (including faxed and emailed submissions) will no longer be accepted.

The online system has been designed to allow real-time access to notifications and submission data across multiple platforms, e.g. computer, smart phone, tablet, etc. Transition to this system is intended to improve the security of interactions between the TGA and healthcare practitioners and simplify these processes.

The transition process will be occurring in two stages, with the TGA providing the following proposed timeline:

• 1 April 2024 (Phase 1)
  • Submissions for SAS Category B pathway and AP scheme will only be accepted via the SAS/AP Online System.
• 1 July 2024 (Phase 2)
  • Submissions for SAS Category A and C pathways will only be accepted via the SAS/AP Online System.

In 2023, 84% of SAS and AP submissions were received via the online system. Of the submissions that utilised a paper-based method, the majority were for SAS Category A and C pathways and generally originated from tertiary hospitals. The longer transition time for moving these pathways to the online system is hoped to provide hospitals with adequate time to change their processes.

Pathways for accessing unapproved therapeutic goods

The TGA encourages the use of TGA-approved medications, i.e. medications entered on the Australian Register of Therapeutic Goods (ARTG). This ensures that the therapeutic good has been evaluated by the TGA for quality, safety, and effectiveness. However, there may be times when a therapeutic good is required that is not on the ARTG. In these cases, the SAS or AP pathways may be considered.

The SAS can be used to access unapproved medications for individual patients. The SAS is divided into three categories:

• Category A
  • The patient must be seriously ill with a condition from which death is reasonably likely to occur within months or premature death is reasonably likely in the absence of early treatment
  • Unapproved products can be accessed immediately
  • The TGA must be notified within 28 days of use
  • The prescriber must be a medical practitioner
• Category B
  • The TGA must be provided with a brief clinical justification to support the use of the good for the medical condition in question
  • TGA approval is required before the therapeutic good can be supplied
  • This category may be used by medical practitioners and other health practitioners
  • Goods that may be accessed depend upon the health professional’s scope of practice, qualifications, condition being treated, and state/territory requirements
• Category C
  • Includes a range of unapproved therapeutic goods that the TGA deems to have an established history of use
  • Unapproved products can be accessed immediately
  • The TGA must be notified within 28 days of use
  • All listed criteria must be met in order to prescribe a product listed in Category C.

Medical practitioners can use the AP pathway to access unapproved medications for multiple patients with the same condition. Authorised prescribers do not need to seek approval for each individual patient but must provide the TGA with a report every six months of how many patients have been treated with each unapproved product.

The prescriber is responsible for deciding which pathway should be used in each case. An interactive tool is available on the TGA website to guide decision making. Suspected adverse events or defects must be reported to the TGA within 15 days of learning of the issue.

Background to transition

In 2015, the Medicines and Medical Devices Regulation (MMDR) review recommended the TGA create an online system to improve access to unapproved goods. The TGA launched their online system in 2018 with the intention of fully transitioning to digital submissions by July 2019. However, user feedback suggested that further improvements were required before the online system could be used exclusively.

Since then, the TGA has made a significant investment in improving the system, including:

• Improvements to the user registration process;
• Streamlined navigation of the application process;
• Redistribution of the TGA workforce to improve internal efficiencies in processing submissions;
• A streamlined process for therapeutic vape submissions;
• Improved functionality of AP reporting to reduce administrative burden; and
• The ability for pharmacists to validate the application and notification status in real-time.

Additional upgrades are planned for this year to improve security and efficiency. For example, health practitioner registration status will be automatically validated against the Australian Health Practitioner Regulation Agency (AHPRA) registry to prevent the creation of fraudulent accounts. Ways to optimise how information is managed and shared within organisations are also being investigated. The TGA will continue to review and seek feedback on the system to optimise efficiency.

Further information

• The TGA provides guidance for the SAS and AP Online System
• The TGA can also provide direct assistance in transitioning to the online system by emailing [email protected]

There are currently four pneumococcal vaccines available in Australia. These vaccines protect against disease caused by Streptococcus pneumoniae. While asymptomatic nasopharyngeal carriage can occur, S. pneumoniae is thought to be responsible for at least one million deaths around the world each year. S. pneumoniae can cause severe invasive disease, including meningitis, pneumonia and bacteraemia, as well as non-invasive disease, such as otitis media.

The polysaccharide capsule of S. pneumoniae is a major virulence factor which allows the bacteria to evade host immune responses. While there are over 100 known serotypes, only a small number of these are responsible for the majority of pneumococcal disease. Serotypes 1 and 19A are the predominant causes of invasive disease, although serotypes 4, 5, 7F, 8, 12F, 14, and 18C are also commonly implicated. Non-bacteraemic pneumonia in adults is most commonly associated with serotype 14.

The introduction of vaccines against the most clinically relevant serotypes has led to a significant reduction in pneumococcal disease globally. However, this has led to a relative increase in the prevalence of non-vaccine serotypes.

The Australian Immunisation Handbook recommends pneumococcal vaccination for the following groups:

• Infants and children;
• Non-indigenous adults ≥ 70 years of age
• Aboriginal and Torres Strait Islander adults ≥ 50 years of age; and
• Children, adolescents and adults with risk factors for pneumococcal disease.

Risk conditions for pneumococcal disease include a previous episode of invasive pneumococcal disease, immunocompromising conditions, cerebrospinal fluid (CSF) leak, chronic respiratory disease, chronic kidney disease, chronic liver disease, cardiac disease, extremely premature birth, trisomy 21, diabetes, smoking, and harmful use of alcohol. Not all individuals with a risk condition for pneumococcal disease are eligible to receive a dose funded by the National Immunisation Program (NIP).

Pneumococcal vaccines can be divided into two types: pneumococcal conjugate vaccines (PCV) and pneumococcal polysaccharide vaccines (PPV). Both vaccine types contain antigenic polysaccharides from pneumococcal serotypes that commonly cause disease.

Pneumococcal conjugate vaccines

The polysaccharides in PCVs are attached to a carrier protein in order to increase their immunogenicity. The carrier protein used is a non-toxic variant of diphtheria toxin known as CRM₁₉₇ protein. A single mutation of the diphtheria toxin eliminates its toxicity while retaining its immunostimulant properties.

The immune response to the bacterial polysaccharide is a T-cell-independent process. However, conjugation to the CRM₁₉₇ protein modifies this response to be T-cell-dependent. This results in a stronger immune response and the generation of memory B-cells. Pneumococcal conjugate vaccines also reduce asymptomatic carriage of the vaccine serotypes, which may provide indirect protection for unvaccinated people.

The PCVs available are:

• Prevenar® 13
  • 13-valent (13vPCV)
  • 2.2µg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F
  • 4.4µg of pneumococcal purified capsular polysaccharides for serotype 6B
  • Indicated for use in people from 6 weeks of age and older
• Prevenar® 20
  • 20-valent (20vPCV)
  • 2.2µg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F
  • 4.4µg of pneumococcal purified capsular polysaccharides for serotype 6B
  • Approved indication has recently been extended to include infants and children from 6 weeks of age
• Vaxneuvance®
  • 15-valent (15vPCV)
  • 2.0µg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F
  • 4.0µg of pneumococcal purified capsular polysaccharides for serotype 6B
  • Indicated for use in people from 6 weeks of age and older

Prevenar® 20 and Vaxneuvance® are considered extended valency vaccines as they cover more serotypes than Prevenar® 13. However, these newer vaccines are not currently covered on the NIP.

Pneumococcal polysaccharide vaccine

Pneumovax® 23 contains the purified capsular polysaccharides from 23 of the most prevalent or invasive S. pneumoniae types, including the six serotypes most commonly responsible for antibiotic-resistant pneumococcal infections. According to surveillance data from the United States, this vaccine covers at least 90% of pneumococcal blood isolates and around 85% of all pneumococcal isolates found at sites generally considered sterile.

The immune response to this vaccine is primarily an IgM response with some contribution from IgG. Protective antibodies are generated without the involvement of T-cells, resulting in a less robust response and a shorter duration of immunity compared to conjugated vaccines. Immunocompromised adults and children younger than two years of age are also likely to respond poorly to this vaccine. However, when a PCV is used as the priming vaccine, the immunologic response to subsequent doses of a PPV is significantly greater.

Pneumovax® 23:

• 23-valent (23vPPV)
• Serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F
• May be used in people ≥ 2 years of age (poor immune response in younger individuals)
• May be given by intramuscular or subcutaneous injection. The intramuscular route is preferred to minimise injection site reactions.

The recommendations for 23vPPV administration have changed and it is no longer recommended for healthy non-Indigenous adults aged 70 years or older. This vaccine is still recommended for Aboriginal and Torres Strait Islander adults aged 50 years or older and adults with risk conditions. This advice follows trial data showing that conjugate vaccines are effective in older adults for the prevention of vaccine-type pneumococcal pneumonia and invasive pneumococcal disease. According to Australian data, most disease caused by the additional serotypes contained in 23vPPV occurs in Indigenous adults and individuals with risk conditions. Therefore, the 23vPPV is now only offered to those groups.

The serotypes contained in each of these vaccines are shown in Table 1.

Table 1. Serotypes covered by each pneumococcal vaccine

Vaccine	Shared serotypes	Additional serotypes
Prevenar® 13	1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F	6A
Vaxneuvance®		6A, 22F, 33F
Prevenar® 20		6A, 8, 10A, 11A, 12F, 15B, 22F, 33F
Pneumovax® 23		2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F

Vaccine recommendations:

While the optimal vaccine schedule is presently under review in Australia, the current recommendations from the Australian Immunisation Handbook are:

• Universal childhood schedule
  • All non-Indigenous children, and Aboriginal and Torres Strait Islander children living in ACT, NSW, Tasmania and Victoria
  • Three doses of pneumococcal conjugate vaccine
  • Doses at age 2 months, 4 months and 12 months.
• At-risk children 12 months or under
  • All children with risk conditions, and Aboriginal and Torres Strait Islander children living in NT, Qld, SA and WA
  • Four doses of pneumococcal conjugate vaccine and two doses of 23vPPV
  • Conjugate vaccine at 2 months, 4 months, 6 months and 12 months.
  • 23vPPV at 4 years with a second dose at least 5 years later.
• Children over 12 months, adolescents and adults of any age diagnosed with a risk condition
  • Single dose of conjugate vaccine at diagnosis
  • Then two doses of 23vPPV (first dose 12 months after 13vPCV or at age 4 years, whichever is later, then second dose at least 5 years later).
• Aboriginal and Torres Strait Islander adults aged ≥ 50 years
  • Single dose of conjugate vaccine and 2 doses of 23vPPV (first dose 12 months after conjugate vaccine, and second dose at least 5 years later).
• Non-Indigenous adults aged ≥ 70 years
  • Single dose of conjugate vaccine

Additional resources:

• Australian Immunisation Handbook
• National Immunisation Program schedule
• Department of Health and Aged Care – risk conditions for pneumococcal disease and their eligibility for NIP funding