Knowledge Type: Clinical Articles

From 1 March 2022, eculizumab and ravulizumab are available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of paroxysmal nocturnal haemoglobinuria (PNH). This is an extension of indications for eculizumab which was listed on the PBS in 2014 for the treatment of atypical haemolytic uraemic syndrome. For ravulizumab, this is the first time it is available on the PBS. Both agents are supplied under the Section 100 Highly Specialised Drugs (HSD) program.

This new PBS listing changes the way that patients with PNH can access subsidised eculizumab. Eculizumab has previously been fully subsidised for patients with PNH via the Life Saving Drugs Program (LSDP). Access to eculizumab under the LSDP has now ceased for new patients. Existing patients may continue to receive their medication under the LSDP until they can transition to PBS supply or up to 31 May 2022 (whichever is sooner).

A fact sheet outlining these arrangements is available on the PBS website.

What is paroxysmal nocturnal haemoglobinuria?

Paroxysmal nocturnal haemoglobinuria is a rare and life-threatening disease of the blood. An acquired gene mutation leads to the production of defective haematopoietic stem cells, which go on to produce defective blood cells. These red blood cells are deficient in terminal complement inhibitors, making them highly susceptible to complement activation and intravascular haemolysis.

Haemolysis occurs throughout the day, not just at night as the name suggests. However, episodes of haemoglobinuria are typically more noticeable in the morning after the urine has concentrated overnight. This classic symptom of visible haemoglobin in the urine does not occur in all patients. Other signs and symptoms are variable but may include:

• Anaemia;
• Fatigue;
• Dark urine;
• Kidney disease;
• Bruising or bleeding easily;
• Shortness of breath;
• Recurring infections;
• Severe headache;
• Oesophageal spasms;
• Erectile dysfunction; and
• Thrombosis.

The complement inhibitor, eculizumab, is the mainstay of treatment. Supportive measures include iron and folic acid supplementation; transfusions may be required. Bone marrow transplantation can be curative. However, due to the significant complications associated with stem cell transplants, this approach is typically not a first-line option.

Eculizumab

Eculizumab is a terminal complement inhibitor. It specifically binds to the complement protein C5, preventing its cleavage to C5a and C5b. This blocks the subsequent formation of membrane attack complex (MAC) and intravascular haemolysis.

The double-blind TRIUMPH study investigated the safety and efficacy of eculizumab in patients with PNH. There was an immediate decline in lactate dehydrogenase levels (a marker of tissue damage) in the eculizumab group, while levels remained elevated in the placebo group. The primary efficacy endpoints were stabilisation of haemoglobin levels and the number of units of packed red cells transfused.

At the end of the 26-week treatment period, stabilisation of haemoglobin levels in the absence of transfusions occurred in 49% of eculizumab patients and 0% of placebo. The median number of units of packed cells transfused per patient was 0 in the eculizumab group and 10 in the placebo group. In comparison, the median number of units transfused per patient in the six-month period before the study was 9.0 in the eculizumab group and 8.5 in the placebo group. A long-term extension study demonstrated that this reduction in haemolysis was sustained and accompanied by a significant reduction in thromboembolic events.

Eculizumab is administered as an intravenous infusion. It is dosed on a weekly basis for the first five weeks, followed by maintenance dosing every two weeks. Patients should be monitored for signs and symptoms of infusion-related reactions for one hour after the completion of each infusion.

Adverse events reported in clinical trials include headache, fatigue, nausea, abdominal pain, oral herpes, upper respiratory tract infections, and dry skin.

Eculizumab is an effective therapy for PNH but does have some limitations. The frequent dosing schedule may be burdensome. In addition, some patients may experience breakthrough haemolysis due to insufficient complement inhibition in the 24-48 hours prior to their next dose. It is thought that up to 35% of patients treated with eculizumab will continue to require red cell transfusions.

Ravulizumab

Ravulizumab is a newer agent that has been engineered from eculizumab to address some of its limitations. The terminal half-life of ravulizumab is around four times longer than eculizumab, enabling an extended dosing interval. Two weeks after the initial loading dose, ravulizumab is dosed once every eight weeks. Patients switching to ravulizumab from eculizumab should receive the ravulizumab loading dose two weeks after their last eculizumab dose.

The 301 study assessed the non-inferiority of ravulizumab compared to eculizumab in complement inhibitor-naïve adults with PNH. Upon completion of the 26-week treatment period, ravulizumab achieved non-inferiority for all efficacy endpoints and a similar safety profile. The proportion of patients experiencing breakthrough haemolysis was 4.0% in the ravulizumab group and 10.7% in the eculizumab group. The study authors suggest that this positive result may be due to the sustained C5 inhibition achieved by ravulizumab.

In Australia, ravulizumab is currently only indicated for use in adult patients due to limited data in paediatric populations. However, interim results from a Phase III trial indicates that the efficacy and safety profile of ravulizumab in children is consistent with the profile observed in adults.

Precautions

While inhibition of MAC formation is desirable in PNH to prevent haemolysis, MAC also has an important role in the removal of pathogens. MAC is most effective against gram-negative bacteria and enveloped viruses, and is thought to be particularly important for the elimination of Neisseria species. Therefore, patients treated with complement inhibitors may be at higher risk of meningococcal and gonococcal infections.

Both eculizumab and ravulizumab are known to increase the risk of meningococcal infection/sepsis. All patients should be vaccinated against Neisseria meningitidis at least two weeks prior to their first dose unless the risk of delaying treatment outweighs the risk of meningococcal infection. If the monoclonal antibody is initiated less than two weeks after vaccination, prophylactic antibiotics are recommended until two weeks after administration of the vaccine. As infection can occur with any serogroup, vaccination against serogroup B as well as serogroups A, C, W135, and Y is advised. The Australian Immunisation Handbook provides guidelines for meningococcal vaccination.

Although vaccination reduces the risk of meningococcal infection, it does not eliminate the risk. Patients should be educated on the signs and symptoms of meningococcal infection and advised to seek immediate medical attention if infection is suspected.

Conclusions

Eculizumab and ravulizumab are effective therapies for the management of PNH and are now available on the PBS. Ravulizumab may offer an advantage for patients as it requires less frequent dosing. However, as it is a newer agent, there is less long-term safety data available.

Restrictive practice is an intervention or practice that restricts the rights or freedom of movement of the person. There are five restrictive practices in aged care – chemical restraint, environmental restraint, mechanical restraint, physical restraint and seclusion.

As per the new legislation introduced on 1 July 2021, chemical restraint is only to be used as a last resort. It should be implemented for the least amount of time possible and recorded, monitored and reviewed by providers. The amendments introduced in the new legislation are aimed at clarifying and strengthening the responsibilities of approved providers of residential aged care.

Chemical restraint involves medication use mainly to control a patient’s behaviour. It was a term not accepted by providers in aged care. Many accepted the high rates of psychotropic and benzodiazepine use in aged care, but justified their use to treat residents with dementia, anxiety or insomnia.

Medications classified as chemical restraint include antipsychotics, benzodiazepines, sedating antidepressants, anticonvulsants, opioids and Z drugs (zolpidem, zopiclone).

These medications are exempt from being classified as chemical restraint when used in:

• A diagnosed mental disorder;
• A physical illness;
• A physical condition; or
• End of life care

Regular or when needed use prescribing has no bearing on a medication being considered as chemical restraint.

The legislation details what residential aged care providers must do whenever chemical restraint is considered and used, including in an emergency.

Chemical restraint can only be used if the prescriber has assessed the person as being at risk of harming themselves or others. The assessment, decision to use restraint, and behaviours requiring restraint should be documented in the consumer’s care and services plan. Informed consent by the resident or, if they lack capacity, a substitute decision-maker, is necessary before administering chemical restraint. In an emergency situation, the resident or substitute decision-maker must be informed and reasons for use documented as soon as practical after administering chemical restraint.

Nearly 60% of aged care residents have at least one mental health disorder (46% depression, 15% phobia/anxiety and 10% psychosis). This does not mean that all their psychotropic use is exempt from being chemical restraint. When a medication is used to address behaviour (e.g. agitation, calling out, wandering, disinhibition, aggression, intrusive behaviour), then it is classified as a chemical restraint (unless it is used in end of life care or to enable medical or dental treatment). When used for psychosis associated with a mental disorder, then it is not a chemical restraint. However, antipsychotic use in dementia should be reserved for severe symptoms that have not responded to non-pharmacological strategies, e.g. the resident is extremely distressed and their safety or that of others is at risk. Psychotropic medications have a modest effect on many behavioural and psychological symptoms of dementia, but it needs to be weighed up against the significant adverse effects they can cause, e.g. increased risk of death, stroke, falls and movement disorders.

Prescribing a hypnotic for short term treatment (up to two weeks) after psychological and behavioural therapies have been trialled is not chemical restraint. But if it is used to stop a resident from disturbing others or fitting in with the aged care schedule, then it is chemical restraint. When a resident needs a benzodiazepine to allow them to comfortably undergo a medical or dental procedure, then its use is not classified as chemical restraint. In this instance, it is to enable treatment of a physical illness or condition.

After administering chemical restraint, monitoring for signs of distress, adverse effects, and changes to the person’s ability to engage in activities of daily living is necessary. Monitoring and reviewing ensure that chemical restraint is still needed and is the least restrictive form. It assesses effectiveness and, where possible, the use of alternative strategies.

In summary, aged care homes must assess residents to identify causes for behaviours and develop individualised behaviour support plans. They must consider whether the risk of harm can be managed using non-pharmacological strategies and use these options to their best effect before chemical restraint is used.

On 1 March 2022, molnupiravir became the first COVID-19 antiviral to be available on the Pharmaceutical Benefits Scheme (PBS). Molnupiravir is provisionally approved for the treatment of adults with COVID-19 who are at increased risk of hospitalisation or death.

To qualify for PBS-subsidised therapy, patients must meet all of the following criteria:

• Test positive for SARS-CoV-2 (either via polymerase chain reaction (PCR) test OR a rapid antigen test (RAT) verified by a medical practitioner);
• Have at least one sign or symptom attributable to COVID-19;
• Must not require hospitalisation at the time of prescribing; and
• Treatment must be initiated within five days of symptom onset.

In terms of population, patients must be:

• 65 years of age or older with two additional risk factors for severe disease;
• 50 years of age or older, identify as Aboriginal or Torres Strait Islander and have two additional risk factors for severe disease;
• 75 years of age or older with one additional risk factor for severe disease; or
• 18 years of age or older and at risk of progression to severe disease due to moderate to severe immunocompromise.

Molnupiravir is not PBS-subsidised for pre-exposure or post-exposure prophylaxis.

Risk factors

For the purposes of PBS subsidy, risk factors include:

• Having received less than two doses of a SARS-CoV-2 vaccine;
• Residing in a residential aged care or residential disability care facility;
• Neurological conditions (e.g. stroke, dementia);
• Respiratory compromise (e.g. chronic obstructive pulmonary disease, moderate or severe asthma requiring inhaled steroids, bronchiectasis);
• Congestive heart failure (NYHA Class II or greater);
• Obesity (BMI greater than 30 kg/m²);
• Diabetes Types I and II, requiring medication for glycaemic control;
• Renal failure;
• Cirrhosis; and
• Lack of, or reduced, access to higher-level healthcare (resides in an area of geographic remoteness classified by the Modified Monash Model as Category 5 or above).

Full details of the PBS restrictions are available on the PBS website.

Efficacy

Molnupiravir is a nucleoside analogue with activity against various viruses, including SARS-CoV-2. Following metabolism, it distributes into cells where it can be incorporated into viral RNA. This inhibits viral replication due to an accumulation of errors in the viral genome.

The safety and efficacy of molnupiravir were evaluated in a double-blind Phase III trial of at-risk unvaccinated adults diagnosed with COVID-19. Patients were randomly assigned to receive 800mg of molnupiravir or placebo twice daily for five days. The primary efficacy end point was the incidence of hospitalisation or death at day 29. At the interim analysis, this risk was lower in the molnupiravir group compared to the placebo group (7.3% versus 14.1%). One death was reported in the molnupiravir group and nine in the placebo group. Recruitment into the trial was stopped early due to these positive results. However, the efficacy shown in the final analysis was significantly lower at 6.8% for molnupiravir, compared to 9.7% for placebo. This translates to an adjusted relative risk reduction of 30% for molnupiravir compared to placebo (3% absolute reduction in risk).

There are many potential factors that may have contributed to this observed reduction in efficacy between the interim and final analyses, including regional differences in hospitalisation practices and capacity. In addition, the proportion of patients infected with the Delta variant increased significantly between the interim and final analyses, which may have affected the results. The efficacy of molnupiravir against the Omicron variant is not known.

Administration

Molnupiravir therapy should be initiated as soon as possible after a diagnosis of COVID-19, and within five days of symptom onset. It is administered orally, with a recommended dose of 800mg every 12 hours for five days. Each capsule contains 200mg of molnupiravir; doses may be taken with or without food. No dose adjustments are recommended for patients with renal or hepatic impairment.

Neither molnupiravir nor its metabolite inhibits or induces major drug metabolising enzymes or transporters. Although formal drug interaction trials have not been conducted, the potential for interactions is considered unlikely.

Adverse effects

The most frequently reported adverse effects considered to be related to the trial regimen were diarrhoea, nausea, and dizziness. However, rates of these adverse effects were similar to those seen in the placebo group. COVID-19 pneumonia was reported as an adverse effect in 6.3% of the molnupiravir group, compared to 9.6% of the placebo group. Worsening of COVID-19 was also reported in 7.9% of molnupiravir-treated patients and 9.8% of the placebo group.

As a new medication, molnupiravir is included in the Black Triangle Scheme. All potential adverse reactions should be reported to the Therapeutic Goods Administration (TGA).

Vaccination status

There is currently a lack of data on the efficacy of molnupiravir in partially or fully vaccinated patients as clinical trials were conducted in unvaccinated individuals. However, as vaccination confers a lower risk of deterioration, molnupiravir is considered unlikely to provide significant treatment benefits in immunocompetent patients who have received three vaccine doses.

The Pharmaceutical Benefits Advisory Committee (PBAC) considers receipt of zero or only one vaccine dose a risk factor for severe disease. While vaccine protection is not complete and does wane over time, the greatest risk of severe infection is currently found in patients who have received less than two doses of a COVID-19 vaccine.

The PBS criteria allow vaccinated older adults to access subsidised therapy if they have other risk factors for severe disease. For moderately to severely immunocompromised adults, subsidised access is not dependent upon vaccination status.

Place in therapy

The National COVID-19 Clinical Evidence Taskforce Living Guidelines recommend molnupiravir when other treatments (such as nirmatrelvir plus ritonavir) are not suitable or available.

Paxlovid® (nirmatrelvir plus ritonavir) is another orally administered antiviral for COVID-19. While there is currently no head-to-head trial evidence to compare its safety and efficacy with molnupiravir, studies suggest that Paxlovid® may offer a greater magnitude of benefit. Paxlovid® demonstrated an 88.9% relative reduction in the risk of hospitalisation or death (5.8% absolute risk reduction).

However, some factors may affect the appropriateness of Paxlovid® for individual patients, including:

• Paxlovid® is not currently subsidised on the PBS. This may limit the ability to initiate therapy in a timely manner;
• Paxlovid® has many clinically significant drug interactions due to its action as an inhibitor and substrate of the CYP3A enzyme (no interactions have been identified for molnupiravir);
• Paxlovid® requires dose adjustment in moderate renal impairment and is contraindicated in severe renal impairment (no dose adjustments required for molnupiravir); and
• Paxlovid® is contraindicated in severe hepatic impairment (hepatic impairment unlikely to affect exposure to molnupiravir).

Conclusions

Antiviral therapies that reduce the risk of COVID-19 progression may play a vital role in reducing hospitalisation and death, thereby easing pressure on the health system. As these therapies are most effective when initiated early, it is encouraging to see an oral agent readily available on the PBS. However, the availability of molnupiravir and other targeted therapies should not be considered a substitute for vaccination against COVID-19. Vaccination remains crucial for protecting individuals and the community.

The treatment of COVID-19 is a rapidly expanding area of research. The National COVID-19 Clinical Evidence Taskforce Living Guidelines are continually updated in response to new evidence. This resource can be freely accessed online for the latest recommendations.

The approved indications for empagliflozin have been updated to include the treatment of symptomatic heart failure with reduced ejection fraction, as an adjunct to standard of care therapy. Empagliflozin is now the second sodium-glucose co-transporter 2 (SGLT2) inhibitor approved for this indication, following the approval of dapagliflozin in 2020.

SGLT2 inhibitors were originally approved only for the treatment of type 2 diabetes. However, randomised clinical trials demonstrate that these agents may improve cardiovascular outcomes. The EMPA-REG OUTCOME trial investigated the effect of empagliflozin on cardiovascular morbidity and mortality in patients with diabetes and high cardiovascular risk. Compared to placebo, patients in the empagliflozin group showed a 38% relative risk reduction for cardiovascular death (3.7% versus 5.9%) and a 35% relative risk reduction for heart failure hospitalisation (2.7% versus 4.1%).

The reduction in risk of hospitalisation for heart failure is observed early after randomisation in clinical trials, suggesting that the mechanism may be independent of the glucose-lowering ability of these agents. While many trials have studied these cardioprotective effects in patients with diabetes, more recent studies have explored the use of SGLT2 inhibitors in patients without diabetes.

The EMPA-TROPISM study investigated the effect of empagliflozin on cardiovascular outcomes in people with heart failure with reduced ejection fraction (HFrEF) who do not have diabetes. Empagliflozin was associated with a significant reduction in left ventricular end-diastolic volume and left ventricular end-systolic volume, as well as improvements in peak oxygen consumption, 6-minute walk test, and quality of life.

The mechanism of the cardiac benefits associated with SGLT2 inhibitors is not completely understood. One theory relates to energy metabolism. Significant changes occur in energy metabolism in patients with heart failure. There is typically a progressive decline in mitochondrial oxidative metabolism, which can result in a cardiac energy deficit. In an animal model, SGLT2 inhibitors were shown to increase the utilisation of ketone bodies as a cardiac energy source. This may improve overall cardiac efficiency.

However, many other potential mechanisms have been proposed, including:

• Reduction in blood pressure (these effects are typically modest and thought unlikely to completely explain the magnitude of benefits seen);
• Diuretic effect (SGLT2 inhibitors more selectively target the interstitial volume and have less effect on intravascular volume than traditional diuretics. This limits reflex neurohormonal stimulation of the sympathetic nervous system and renin-angiotensin-aldosterone system);
• Weight loss (which is thought to improve myocardial insulin sensitivity. However, this is unable to completely explain the magnitude of effect as other weight loss strategies are not as effective in reducing heart failure severity);
• Inhibition of the sympathetic nervous system (may be secondary to a reduction in renal stress);
• Prevention of adverse cardiac remodelling (short-term exposure to SGLT2 inhibitors can promote reverse cardiac remodelling);
• Increased haematocrit (SGLT2 inhibitors may increase erythropoietin secretion leading to improved oxygen delivery);
• Reduced oxidative stress; and
• Improved vascular function.

Ongoing studies continue to investigate the mechanisms involved in the cardioprotective effects of SGLT2 inhibitors. These include studies on the effects of remodelling, lipolysis, myocardial calcium use, and ketone production. Improved understanding of the mechanisms involved may lead to further advances in the treatment of heart failure and the development of specific therapies to target these pathways.

A further two medicines have received provisional registration from the Therapeutic Goods Administration (TGA) for the treatment of coronavirus disease 2019 (COVID-19. The following seven medicines are now provisionally approved, with a further agent under evaluation.

Remdesivir

On 10 July 2020, remdesivir became the first COVID-19 treatment to be provisionally approved by the TGA. Remdesivir is indicated for the treatment of COVID-19 in patients 12 years of age and older (weighing at least 40kg) with pneumonia who require supplemental oxygen.

The ACTT-1 trial was conducted in patients hospitalised with COVID-19 who had evidence of lower respiratory tract infection. It provided efficacy data for remdesivir courses of up to ten days. Patients randomised to the remdesivir group had a median recovery time of ten days, compared to 15 days for the placebo group. The estimated mortality was 6.7% in the remdesivir group and 11.9% for placebo at day 15 (11.4% and 15.2% at day 29, respectively).

Remdesivir is administered daily as an intravenous infusion for five to ten days. It is recommended to test renal and liver function prior to initiating therapy and during treatment, as appropriate. During clinical trials, transaminase elevations have been observed in both healthy volunteers and patients with COVID-19. Severe renal toxicity has also been observed during animal studies of remdesivir, although the significance for humans is unknown. Remdesivir is not recommended for patients with an eGFR < 30mL/minute.

Sotrovimab

Sotrovimab was granted provisional approval in August 2021. This monoclonal antibody is indicated for the treatment of COVID-19 in patients 12 years of age and older (weighing at least 40kg) who are at increased risk of disease progression but do not require initiation of oxygen. It is not indicated for patients hospitalised due to COVID-19.

Sotrovimab binds to a highly conserved epitope on the spike protein receptor-binding domain of SARS-CoV-2, the virus that causes COVID-19. This blocks a step prior to viral and cell membrane fusion, which results in reduced viral replication.

The COMET-ICE trial investigated the efficacy of sotrovimab, the primary efficacy outcome being hospitalisation for more than 24 hours or death within 29 days after randomisation. Sotrovimab resulted in an 85% relative risk reduction for this primary outcome. In addition, no patients in the sotrovimab group were admitted to the intensive care unit compared to five in the placebo group.

Sotrovimab is administered as a single intravenous infusion that should be given within five days of symptom onset. No dosage adjustments are required in renal impairment, hepatic impairment, or the elderly.

Casirivimab + imdevimab

Casirivimab + imdevimab gained provisional approval in October 2021. These monoclonal antibodies are indicated for the treatment of COVID-19 in patients 12 years of age and older (weighing at least 40kg) who do not require supplemental oxygen but are at higher risk of progressing to severe disease. It is also indicated for post-exposure prophylaxis in patients who are not vaccinated against COVID-19 or have a medical condition that makes them unlikely to be adequately protected by vaccination. However, it is not intended to be a substitute for vaccination.

Casirivimab and imdevimab are supplied in separate vials that can be administered intravenously or subcutaneously. Both agents are administered together as a single infusion when given intravenously. When administered subcutaneously, the two medicines are given consecutively by separate injections. Intravenous use is highly recommended, with subcutaneous administration an alternative when an intravenous infusion is not appropriate or would lead to treatment delays.

These two antibodies block the spike protein receptor-binding domain of the virus, thereby preventing the virus from infecting healthy cells. For treatment, it should be initiated as soon as possible after a positive COVID-19 test and not later than seven days after symptom onset. For prophylaxis, it should be initiated as soon as possible after exposure to SARS-CoV-2.

The efficacy of this medicine for the treatment of COVID-19 was evaluated in the COV-2067 trial. The primary endpoint (hospitalisation or death) had a relative risk reduction of around 70% in the active group compared to placebo. For the prevention of COVID-19, the COV-2069 trial demonstrated an 81% risk reduction in the development of symptomatic COVID-19.

Tocilizumab

In December 2021, tocilizumab was granted provisional approval for the treatment of COVID-19 in hospitalised adults. Patients must be receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation.

In contrast to other agents approved for COVID-19, tocilizumab is not specific for the SARS-CoV-2 virus. Tocilizumab is a monoclonal antibody that blocks the interleukin-6 receptor. Interleukin-6 is thought to play a key pathogenic role in SARS-CoV-2-induced cytokine storm, an aggressive inflammatory response associated with very poor outcomes.

Studies demonstrate that tocilizumab reduces the duration of hospitalisation, risk of requiring mechanical ventilation, and risk of death for patients with severe COVID-19. Tocilizumab is available in both intravenous and subcutaneous presentations. Only the intravenous formulation is approved for the treatment of COVID-19.

Regdanvimab

Regdanvimab was also granted provisional approval in December 2021. It is indicated for the treatment of adults with COVID-19 who do not require supplemental oxygen but are at increased risk of progressing to severe disease.

This monoclonal antibody binds to the receptor-binding domain of the spike protein, thereby blocking its entry into cells. In a randomised, double-blind clinical trial, the proportion of patients with worsening disease (requiring hospitalisation, oxygen therapy, or resulting in death) was 3.1% in the regdanvimab group compared to 11.1% in the placebo group (72.3% relative risk reduction).

Regdanvimab is administered as a single intravenous infusion which should be given within seven days of symptom onset.

Nirmatrelvir + ritonavir

Nirmatrelvir + ritonavir was granted provisional approval in January 2022. It is indicated for the treatment of COVID-19 in patients 18 years of age and older who do not require supplemental oxygen but are at increased risk of progression to hospitalisation or death. While this product is not recommended to be initiated in patients requiring hospitalisation due to COVID-19, the full five-day course may be completed if the patient goes on to require hospitalisation.

Nirmatrelvir inhibits the SARS-CoV-2 main protease, an enzyme required for viral replication. Ritonavir is used to increase the plasma levels of nirmatrelvir by inhibiting its hepatic metabolism. The two agents are supplied as separate tablets that must be taken together.

The primary efficacy endpoint of the EPIC-HR trial was COVID-related hospitalisation or death. The nirmatrelvir + ritonavir group showed an absolute reduction of 5.81% for this endpoint and a relative reduction of 88.9% compared to placebo. No deaths were reported in the active drug group, compared to nine deaths in the placebo group.

This medication inhibits CYY3A. It is contraindicated with medicines highly dependent upon this pathway for clearance and for which elevated plasma concentrations may result in serious adverse effects (e.g. alfuzosin, amiodarone, flecainide, colchicine, simvastatin, and diazepam). Use is also contraindicated with potent CYP3A inducers due to a potential loss of virologic response and development of resistance. This includes apalutamide, carbamazepine, phenobarbital, phenytoin, rifampicin, and St John’s Wort. The product information contains a complete list of established and potentially significant drug interactions.

Molnupiravir

Molnupiravir is the latest treatment for COVID-19, gaining provisional approval on 18 January 2022. It is indicated for the treatment of COVID-19 in adults who do not require initiation of oxygen and who are at increased risk of hospitalisation or death.

Following metabolism to its active form, molnupiravir is incorporated into viral RNA to inhibit viral replication. This oral treatment is recommended to be given twice daily for five days. It should be initiated as soon as possible after diagnosis and within five days of symptom onset. Early trial results suggested that molnupiravir reduced the risk of hospitalisation by 50%. However, more recent data has produced an adjusted relative risk reduction of 30%.

The potential for molnupiravir to interact with concomitant medications is considered unlikely as it is not an inducer, inhibitor, or substrate of major drug metabolising enzymes or transporters.

Summary

A summary of the provisionally approved therapies is shown in Table 1. The National COVID-19 Clinical Evidence Taskforce provides clinical flowcharts on how these agents may fit into therapy for various populations.

Table 1. Summary of provisionally approved COVID-19 treatments

Medicine	Route	Therapy duration	Approved age	COIVD-19 indication
Remdesevir (Veklury®)	IV	5-10 days	≥ 12 years	Patients with pneumonia needing supplemental oxygen
Sotrovimab (Xevudy®)	IV	Single dose	≥ 12 years	Patients who do not need oxygen initiation
Casirivimab + imdevimab (Ronapreve®)	IV or SC	Single dose*	≥ 12 years	Patients who do not need supplemental oxygen. Post-exposure prophylaxis.
Tocilizumab (Actemra®)	IV	Single dose	≥ 18 years	Hospitalised patients receiving systemic corticosteroids + oxygen/mechanical ventilation
Regdanvimab (Regkirona®)	IV	Single dose	Adults	Patients who do not need supplemental oxygen
Nirmatrelvir + ritonavir (Paxlovid®)	Oral	5 days	≥ 18 years	Patients who do not need supplemental oxygen
Molnupiravir (Lagevrio®)	Oral	5 days	Adults	Patients who do not need supplemental oxygen

*Repeat doses for ongoing prophylaxis may be considered

It is worth noting that the provisional approval of these agents for the treatment and prophylaxis of COVID-19 is based on preliminary clinical data. The TGA continues to monitor the safety of these agents, and healthcare professionals are encouraged to report any suspected adverse effects.

Survivorship in Australia is a newly emerging area that refers to the stage at which patients have completed initial cancer treatment. Such patients can sometimes face a range of ongoing issues even after completing cancer treatment.  This area focuses on the health and life of a person with cancer following treatment and until the end of life. Survivorship includes the psychosocial, physical, and financial aspects of cancer, beyond the diagnosis and treatment phases. Survivorship includes issues related to the ability to access health care and follow-up treatment, the late effects of treatment, second cancers, and quality of life. Family members, friends, and caregivers are all considered part of the survivorship experience. The services and interventions required to support survivorship can vary, and care is an evolving process and requires further coordination.

Cancer survivorship is increasingly recognised as an important element of ongoing care for patients following diagnosis and treatment. As a patient group, cancer survivors have unique health needs due to the consequences of their diagnosis and treatment. These include dealing with the late-effects of chemotherapy and radiotherapy, such as specific cardiac issues, an increased risk of secondary cancers, persistent fatigue, chronic pain, lymphoedema, and infertility. Ongoing anxiety, depression and fear of recurrence may also be experienced. Specific cancer treatments may be associated with physical and psychosocial effects requiring multidisciplinary input in their management.

Australia has enjoyed marked improvements in cancer survival due to early detection and improved treatments of cancer. The five-year survival rose from 47% to 66% between the periods of 1982–87 and 2006–10, with survival rates now over 90% for several cancers. The median age of diagnosis of new cancer is 67 years of age. With an ageing population, there is a growing number of people requiring long term follow-up and management of the consequences of a cancer diagnosis and treatment. Furthermore, as there is an increase in the number of older people, then the prevalence of cancer survivors will increase, with this demographic also having age-related comorbidities and supportive care needs. This increasing number of cancer survivors places a greater burden on hospital oncology clinics and adds to the growing demand for more cancer services to be delivered in primary care (Role Redesign Shared Care, 2010).

The following factors have been identified as fundamental aspects of the survivor’s experience:

• Experiencing either positive or negative change
• Trying to stay healthy after treatment
• Handling practical issues such as work, study, finances, etc.
• Ongoing interaction with the health care system, e.g. for follow-up care or rehabilitation
• Coping with the fear of cancer returning
• Challenges in relation to resuming ‘normality’
• Handling the late effects and long-term effects of cancer treatment

A shared care model of survivorship care involves primary healthcare professionals working together with oncologists to result in effective communication and streamlined transition between services. Facilitation of this requires clear guidance for patients and primary care professionals about treatment and follow-up plans, as well as management of treatment adverse effects, and mechanisms for rapid referral and consultation to specialist advice if required. As treatments and in turn survival rates improve, there is emerging a further need to investigate models of care for these patients.

Side effects are unfortunately highly likely to be experienced by almost all patients receiving chemotherapy. Managing side effects effectively ultimately means optimisation of chemotherapy. Side effect management is influenced by a number of aspects such as:

• Other medical conditions the patient may have
• Concomitant medications being taken, including those as part of the treatment protocol, e.g. anti-emetics, etc.
• Whether the chemotherapy regimen is curative or palliative
• How many cycles, or if any other treatment modalities, e.g. radiotherapy, are intended
• The specific chemotherapy drug(s) prescribed and the dose(s)
• Whether the patient is receiving treatment as part of a clinical trial, which may require specific management of side effects

The following six side-effects are most commonly experienced by patients:

Chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is a common adverse effect of cancer treatment. Patients often report that this is a side effect that causes the greatest anxiety prior to commencing treatment, and it can negatively impact upon a patient’s quality of life. However, this adverse effect can be mostly circumvented by the application of international evidence-based guidelines and effective prophylaxis. Furthermore, the literature describes patient risk factors that can highlight those patients with a greater likelihood of experiencing CINV, such as youth, female gender, predisposition to motion sickness, morning sickness, low alcohol intake, and highly emetogenic chemotherapy protocols.

It has been identified by Vidal et al. (2011) that it is more probable that CINV will occur after the patient has left the outpatient clinic (where chemotherapy is most often administered). Accordingly, this can lead to the underreporting of CINV by the patient for several reasons. Such factors include: patients forgetting about such episodes or how their daily activities had been affected, not informing their doctor of CINV occurrences, or belittling the degree of CINV experienced for several reasons (e.g. fear that the onset of CINV may prompt a dosage decrease, postponement or cessation of treatment; or patients may consider that the incidence of CINV implies that the treatment is effective and therefore tolerate it).

A lack of CINV management can lead to increasing financial costs. Such costs include those incurred for hospital admission for intravenous rehydration, and costs that patients bear personally due to decreased function and productivity. The European CINV Forum recommends the following guidelines are followed:

• An emetogenicity calculation tool should be used to assess a patient’s risk of CINV;
• The emetogenicity of new chemotherapy drugs and protocols is in turn ascertained;
• Timely revision of local CINV protocols and guidelines as evidence-based international guidelines are updated;
• A “chemotherapy toxicity toolkit” including a patient diary, access to telephone support, and timely updates as new chemotherapy guidelines and protocols are made available, is devised to enhance the supportive care provided to address a spectrum of adverse effects;
• Provision of user-friendly patient information regarding CINV and its management;
• Undertake audits of CINV management at a local level.

Pharmacists can play an active role in the management of CINV by providing patient counselling, recording patient histories (including comorbidities and medication), and collaborating with oncologists in order to adapt anti-emetic medication regimes for individual patients. Collaborative efforts in the particular area of nausea and vomiting have led to measurement tools and anti-emetic guidelines that decrease the severity of nausea and vomiting on patient quality of life.

The mainstay of controlling CINV is typically prevention. Most chemotherapy protocols will be prescribed with prophylactic anti-emetic medicines, but unfortunately, various patients will still encounter CINV. Prior to suggesting any treatment, it is essential to assess the severity of the CINV since dehydration is a serious consequence. If this is the case, then the patient should be referred to the nearest hospital if the condition is critical. Anti-emetic medications that are prescribed typically include 5HT₃ antagonists, corticosteroids, dopamine antagonists, and antipsychotic agents. It is also important to consider the route of any anti-emetic, as some patients may not be able to accept oral administration. Various self-care tips can often benefit those experiencing CINV including:

• Eat dry food (e.g. toast or crackers)
• Eat small amounts when feeling able
• If cooking aromas trigger nausea, eat cold foods or foods that only require heating up
• Avoid fried and/or fatty foods
• Crystallised ginger, ginger tea or ginger biscuits can help with nausea
• Slowly sip soft drinks such as mineral water, lemonade, soda water, or ginger beer/ale

Fatigue

Fatigue is the most prevalent cancer symptom and is reported as the symptom that impacts quality of life to the greatest degree. The physiological disease or the treatments imposed can each cause fatigue, leading to loss of functionality, worsening symptoms and cognitive impairment. Anaemia can cause fatigue and is treatable, but in many cases, fatigue will arise in patients with a normal haemoglobin level. Mild exercise is considered to be of some benefit, but sufficient rest and support with household duties and childcare are often required. Assuring the patient that they can recover from fatigue after their treatment is essential.

 

Diarrhoea

Another common side effect is diarrhoea, which can be worse with certain drugs, including irinotecan, capecitabine and erlotinib. It is crucial to assess severity since, as for CINV, dehydration can develop rapidly and necessitates pre-emptive rehydration, often with intravenous fluids. Doctor referral is required for any patient experiencing more than four to six episodes of diarrhoea a day. Patients experiencing diarrhoea should be counselled to drink at least two litres of fluid per day. If the patient has a fever, then an infectious source for the diarrhoea should be assessed. Medications to treat diarrhoea include loperamide and codeine.

Mucositis

Mucositis is a common adverse effect involving complicated pathophysiology and treatment modalities. The pharmacist can play a role in devising protocols as well as effective patient management and the recommendation of methods of managing symptoms. It can be a troublesome complication leading to limitation of oral consumption and severe pain for the patient. There are several products available, including anti-inflammatory and antiseptic mouthwashes and oral gels, which are explicitly formulated for oncology patients. Treatment goals are normally to reduce pain and to continue oral consumption. Mucositis will generally resolve soon after chemotherapy. Infections of the oral cavity are often experienced, and oral thrush can be treated either systemically or topically subject to the degree of infection. Systemic analgesics can be used for oral pain, and sucking ice chips can relieve pain as well. It is recommended that good oral hygiene is continued, such as brushing teeth lightly using a soft toothbrush. Unless patients have thrombocytopaenia, then flossing is recommended, and lips are kept moisturised with lip balm. Patients should avoid foods that are salty, acidic or spicy.

Skin reactions

Chemotherapy can evoke dermatological reactions of varying severity, from minor to dose-restrictive. Depending on severity, the treatment required can range from using basic moisturisers or other topical preparations, but may require a doctor’s input to assess the need for antibiotics, steroids, or other agents. Self-care measures that can be recommended are as follow:

• Use sunscreen (SPF30+ or above)
• Use a moisturiser for dry skin and to protect nails (any radiotherapy patients should check with their doctor prior to using any topical products)
• Avoid wet shaving
• Use moisturiser
• Use gloves, as treatment may cause brittle nails
• Avoid false nails.

Myelosuppression

A particularly dangerous side-effect of chemotherapy is myelosuppression. This can in turn cause anaemia, and an increased risk of infection and bleeding. A chemotherapy patient who has a temperature over 38°C should be directed to immediately seek medical attention as they urgently require antibiotics. Many chemotherapy protocols indicate prophylactic antibiotics or GCSF (granulocyte colony-stimulating factor). Self-care tips in relation to decreasing the risk of developing an infection comprise:

• Avoid crowded places and people who may be unwell
• Make sure that food is cooked properly
• Avoid high-risk foods, such as raw animal products
• Wash hands well, particularly when undertaking food preparation and after visiting the toilet
• Seek medical assistance immediately if any anaemia symptoms, fever or bleeding arise

Further cancer information and resources are available from the PeterMacCallum Cancer Centre Victoria Australia website at https://www.petermac.org/services/cancer-information-resources.

There are three COVID-19 vaccines currently used in the Australian national rollout: Comirnaty®, Spikevax®, and Vaxzevria®. A primary course for each of these vaccines is two doses. However, booster doses have been recently introduced to mitigate against waning immunity and the emergence of new viral variants.

The Therapeutic Goods Administration (TGA) has given provisional approval to Comirnaty® and Spikevax® for use as a booster in individuals 18 years of age and older; booster doses for Vaxzevria® are currently under evaluation. An overview of available COVID-19 vaccines is shown in Table 1.

Table 1. COVID-19 vaccines available in Australia

Vaccine	Vaccine type	Approved age group	Booster
Comirnaty® (Pfizer)	mRNA	≥ 5 years	≥ 18 years of age
Spikevax® (Moderna)	mRNA	≥ 12 years	≥ 18 years of age
Vaxzevria® (AstraZeneca)	Viral vector	≥ 18 years	Under evaluation

Individuals 18 years of age and older are now eligible for a booster dose five months after completing a primary two-dose vaccination course. Based on the data for primary course completion, approximately 1.7 million people in Australia will be eligible for a booster dose by the end of 2021.

The Australian Technical Advisory Group on Immunisation (ATAGI) updated their recommendations regarding booster doses on 12 December 2021. This advice, which takes into account the likelihood of ongoing transmission of both Omicron and Delta variants, includes:

• A booster dose is now routinely recommended five months after completion of the primary course (previously six months);
• Comirnaty® and Spikevax® are considered equally acceptable and are the preferred vaccines for use as boosters in all eligible groups, including people who received Vaxzevria® for their primary course;
• When used as a booster, Spikevax® is given at half the dose used for the primary course;
• Vaxzevria® is not approved by the TGA as a booster. However, it may be considered for people who have a contraindication to other COVID-19 vaccines or received Vaxzevria® for their primary course; and
• Booster doses are not currently recommended for people younger than 18 years or for immunocompromised adults who have received a third dose as part of their primary course (the Department of Health provides further advice on dosing in people who are severely immunocompromised).

The evidence regarding booster doses is still limited. However, ATAGI advises that available data does support the benefits and safety of booster doses, particularly in high-risk groups. High-risk groups include people with risk factors for severe COVID-19 (e.g. 50 years of age and older, underlying medical conditions, residents of aged care and disability facilities, and Aboriginal and Torres Strait Islander adults) and people with an increased risk of exposure (e.g. occupational risk or outbreak areas).

The vaccine chosen for the booster dose can be different to the vaccine used for the primary course.  Clinical trials have investigated the safety and efficacy of heterologous COVID-19 vaccine schedules. Comirnaty® was studied following an initial dose of Vaxzevria®. In this trial, antibody levels were higher when Comirnaty® was used as a booster compared to Vaxzevria®.  Another study investigated the use of Spikevax® following an initial dose of Vaxzevria® or Comirnaty®. The Spikevax® booster was shown to be non-inferior to a homologous schedule in this trial. No safety concerns were raised in these studies.

Data is limited on the incidence of rare adverse events following booster doses. For example, myocarditis and pericarditis are rare adverse effects associated with mRNA COVID-19 vaccines. These events are most commonly reported in males under 30 years of age and mostly after the second dose. Preliminary data suggests that a booster dose of Comirnaty® does not further increase the risk of myocarditis.

The definition of ‘fully vaccinated’ for the purpose of compliance with public health orders remains unchanged in Australia. Boosters are not currently required to meet the definition of fully vaccinated as there is insufficient evidence to support a time or specific population in which this should be strictly required.

The advice on COVID-19 vaccine boosters is evolving as more evidence becomes available. Please refer to the Australian Government Department of Health and the TGA for further updates.

Glucagon-like peptide-1 (GLP-1) analogues are one of the newer medicine classes for the management of type 2 diabetes. This group includes the following agents:

• Dulaglutide;
• Exenatide;
• Liraglutide; and
• Semaglutide.

Glucagon-like peptide-1 is one of the main incretins and plays an important role in blood glucose regulation. This peptide functions to increase insulin secretion, inhibit glucagon release, reduce gastrointestinal motility, and enhance satiety. GLP-1 is secreted from the L-cells in the ileum and colon in response to nutrient ingestion.

While GLP-1 is effective at improving glucose-dependent insulin secretion, its short plasma half-life (around 2 minutes) limits its use as a therapeutic agent. This short half-life is due to rapid metabolism by dipeptidyl peptidase 4 (DPP4 – the enzyme targeted by the gliptin class of medicines). The GLP-1 analogues used therapeutically have been modified to prolong their half-life by increasing resistance to DPP4, slowing their absorption, and reducing their renal clearance.

A comparison of the GLP-1 analogues used in the management of type 2 diabetes is shown in Table 1.

Table 1. GLP-1 analogues available for the management of type 2 diabetes

	Dosing schedule	Administration	Presentation	Storage	PBS listed
Short-acting
Exenatide (Byetta®)	Twice daily	60 minutes before food	Multi-dose pen	2-8°C In use: < 25°C for up to 30 days	Yes
Intermediate-acting
Liraglutide (Victoza®)	Daily	Independent of food	Multi-dose pen	2-8°C In use: < 30°C (or refrigerate) for up to 1 month	No
Long-acting
Exenatide (Bydureon®)	Weekly	Independent of food	Single-dose pen (powder + solvent)	2- 8°C (< 30°C for up to 4 weeks)	Yes*
Dulaglutide (Trulicity®)	Weekly	Independent of food	Single-dose pen	2- 8°C (< 30°C for up to 14 days)	Yes
Semaglutide (Ozempic®)	Weekly	Independent of food	Multi-dose pen	2- 8°C In use: < 30°C (or refrigerate) for up to 42 days	Yes

*The modified-release formulation of exenatide (Bydureon®) has recently been discontinued, but is still listed on the PBS under ‘Supply Only’ arrangements.

 

Clinical benefits

Although there are no blinded direct comparative trials published for GLP-1 analogues, they have all demonstrated efficacy in reducing HbA_1c (around 5-20mmol/mol reduction expected). The short and intermediate-acting GLP-1 analogues have the greatest effect on postprandial glucose levels, while the long-acting agents have a more significant effect on fasting glucose levels.

Other clinical benefits of GLP-1 analogues may include:

• Modest weight loss (around 2-5kg over 30 weeks);
• Reduction in systolic blood pressure (1-5mmHg);
• Improved lipid levels (reduced LDL and total cholesterol);
• Prevention of cardiovascular events (evidence for liraglutide, semaglutide and dulaglutide); and
• Renal benefits (evidence for liraglutide, dulaglutide and semaglutide).

Adverse effects:

Hypoglycaemia is unlikely to occur with GLP-1 analogues, unless they are used in combination with a sulfonylurea or insulin. The most common adverse effects are gastrointestinal, with up to 50% of patients experiencing nausea and vomiting. However, these effects tend to improve with continued treatment. Initial dose titration is recommended for liraglutide, semaglutide and exenatide to improve gastrointestinal tolerability.

Other common adverse effects include:

• Dyspepsia;
• Abdominal pain;
• Diarrhoea;
• Constipation; and
• Injection site reactions.

Pancreatitis has been associated with GLP-1 analogues. However, studies suggest that any increased risk is likely to be very low. These agents should not be used in patients with a history of pancreatitis and should be ceased if pancreatitis occurs.

Drug interactions:

Owing to their ability to delay gastric emptying, it is theorised that GLP-1 analogues could affect the absorption of orally administered medicines. However, most studies demonstrate that this is not clinically relevant for dulaglutide, liraglutide, or semaglutide.

In the case of exenatide, consideration is recommended when co-administered with:

• Medicines that require rapid gastrointestinal absorption (e.g. some antibiotics);
• Medicines that are sensitive to degradation in the stomach (e.g. proton pump inhibitors); and
• Medicines associated with local gastrointestinal irritation (e.g. bisphosphonates, tetracyclines).

These interactions may be avoided by taking these other medicines at least one hour before or four hours after injecting exenatide. There have also been reports of raised INR when exenatide is administered with warfarin; monitoring is recommended.

As GLP-1 analogues stimulate insulin release, co-administration with insulin or a sulfonylurea significantly increases the risk of hypoglycaemia. A dose reduction of the insulin or sulfonylurea may be required.

Place in therapy

Lifestyle modification is central to the management of type 2 diabetes. The choice of antihyperglycaemic drug is dependent upon a range of patient and drug-related factors. Metformin is the usual first-line option, unless contraindicated or not tolerated; GLP-1 analogues are considered a second-line option.

All GLP-1 analogues approved in Australia must be administered by subcutaneous injection, which may limit their acceptability. Use of long-acting agents that only require weekly administration may improve adherence for some patients. An oral formulation of semaglutide has been approved in several countries. This product is formulated with an absorption enhancer (sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate) that increases the local pH to protect semaglutide against degradation and aid its absorption. Although this formulation is not yet approved for use in Australia, oral GLP-1 analogues may be an option in the future.

This coming week is ‘World Antimicrobial Awareness Week’. This global initiative aims to increase awareness of antimicrobial resistance and encourage best practices to reduce its spread. The theme for this year’s campaign is ‘Spread awareness, stop resistance.’

Antimicrobial resistance is one of the most significant healthcare challenges facing the world today. Antimicrobial-resistant infections are associated with a higher chance of a patient experiencing ineffective treatment, treatment toxicity, recurrent infection, delayed recovery, or death.

Antimicrobials include antibiotics, antivirals, antifungals, and antiparasitics. Resistance can develop to these agents when microbes change over time through mutation or gene transfer. These changes may enable the microbe to survive exposure to an antimicrobial that it was previously sensitive to. While antimicrobial resistance can develop naturally, the misuse and overuse of antimicrobials remains a significant contributory factor.

The COVID-19 pandemic appears to have had an interesting impact on antimicrobial use in Australia. The recently published AURA 2021 report (Antimicrobial Use and Resistance in Australia) reveals reduced dispensing rates for seven of the ten most commonly dispensed antibiotics. The greatest reduction was seen with amoxicillin (49% drop in use in April 2020). Significant reductions were also observed for amoxicillin with clavulanic acid, cefalexin, clarithromycin, doxycycline, phenoxymethylpenicillin, and roxithromycin. These agents are often used for the treatment of seasonal respiratory infections. The remaining three antibiotics that did not experience a significant decrease in use are those not typically used for upper respiratory tract infections (i.e., flucloxacillin, metronidazole, and trimethoprim).

The reduced dispensing of these antibiotics coincided with the implementation of pandemic control measures such as lockdown restrictions, an increased focus on hygiene and infection control, and increased use of telehealth services. It is thought that these efforts may have contributed to a decrease in seasonal respiratory infections. Data for the 2020 influenza season supports this hypothesis as laboratory-confirmed cases of influenza were around eight times lower in 2020 than the average for the preceding five years.

Some changes to the Pharmaceutical Benefits Scheme (PBS) listings may have also contributed to these results. In April 2020, the permissible number of repeat prescriptions reduced to zero for the five most commonly dispensed antibiotics: amoxicillin, amoxicillin with clavulanic acid, cefalexin, doxycycline and roxithromycin. Larger quantities of these agents are only available on authority prescription.

Similar reductions in antibiotic use over the pandemic have also been reported in other countries. This has highlighted the potential benefits of targeted interventions to maintain this trend. The Australian Commission on Safety and Quality in Health Care (the Commission) is currently exploring strategies to improve the appropriateness of antimicrobial use and maintain infection prevention and control measures. There will be a particular focus on upper respiratory tract infections, conditions that often do not require antimicrobial therapy.

The Therapeutic Guidelines: Antibiotic can be referred to for recommendations for the management of upper respiratory tract infections, including suggestions for symptomatic relief. For self-limiting viral illnesses, antibiotics are not indicated, although they are commonly used.

Further information on antimicrobial resistance and awareness initiatives can be found on the World Health Organization website.