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On 11 July 2022, 1 September 2022 and 1 November 2022, eligibility criteria for COVID-19 antiviral medicines were updated.
Please read our articles Changes to COVID-19 oral antiviral PBS eligibility criteria – July 2022 and COVID-19 oral antiviral PBS eligibility criteria update – September and November 2022 for more information, in conjunction with the article below.
On 1 May 2022, nirmatrelvir and ritonavir (Paxlovid), an oral combination antiviral medicine, was listed on the General Schedule (S85) as Authority Required (Streamlined) for specific patient groups with mild-to-moderate COVID-19 at high risk of progressing to severe disease.1-3
It is the second treatment listed on the PBS for COVID-19 after molnupiravir (Lagevrio) was listed on 1 March 2022.1,4
High-risk patient populations eligible for nirmatrelvir and ritonavir include people:1-3
See below for more information about vaccination status and high-risk patient populations.
Nirmatrelvir and ritonavir is not PBS-subsidised for pre-exposure or post-exposure prophylaxis for the prevention of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1
The eligibility criteria for PBS-subsidised supply of nirmatrelvir and ritonavir are the same as those for molnupiravir, including:
A difference between the PBS listings is a note for nirmatrelvir and ritonavir cautioning prescribers and dispensers about drug–drug interactions.1
See the Drug–drug interactions section for more details.
See the NPS MedicineWise RADAR article Molnupiravir (Lagevrio) for mild-to-moderate COVID-19 for more details about the molnupiravir PBS listing.
Authorised nurse practitioners may prescribe this medicine. See the PBS website for more information on nurse practitioner PBS prescribing.
For all included patient populations, the clinical criteria for PBS-subsidised nirmatrelvir and ritonavir are as follows.
COVID-19 diagnosis
Patients must have a:
The result, testing date, location and test provider (where relevant for the RAT) must be recorded on the patient record.
a The medical practitioner or nurse practitioner does not have to administer or supervise the test; the onus is on them to ensure the test is valid2
COVID-19 signs and symptoms
Patients must have at least one sign or symptom from the following list that is attributable to COVID-19:
Details of the patient’s medical condition necessitating use of nirmatrelvir and ritonavir must be recorded in their medical records.
COVID-19 treatment
Patients must:
Each high-risk population has additional clinical criteria that define ‘high risk of progressing to severe disease’ and determine access to PBS-subsidised nirmatrelvir and ritonavir. See Table 1 and Table 2.
Table 1: Factors for high risk of progressing to severe disease by patient population group
Patient population
Item number
Authority required (Streamlined) code
Number of risk factors
One or more
Two or more
Two or more
Risk factors
BMI = body mass index, COPD = chronic obstructive pulmonary disease, eGFR = estimated glomerular filtration rate, NYHA = New York Heart Association
Table 2: Definition of moderately to severely immunocompromised – patients aged ≥ 18 years with mild-to-moderate COVID-19 symptoms at risk of progression to severe disease
Patient population
Item number
Authority required (Streamlined) code
Moderately to severely immunocompromised includes:
Any primary or acquired immunodeficiency including:
Any significantly immunocompromising condition(s) where, in the last 3 months, the patient has received any of these treatments:
Others with very high-risk conditions, including:
Any significantly immunocompromising condition(s) where, in the last 12 months, the patient has received rituximab.
People with severe intellectual or physical disabilities requiring residential care.
BTK = Bruton’s tyrosine kinase, HIV/AIDS = human immunodeficiency virus/acquired immunodeficiency syndrome, JAK = Janus kinase
See the PBS website for complete details for the item and Authority required (Streamlined) codes.
Two or more doses
All people aged ≥ 18 years and moderately to severely immunocompromisedb can receive PBS-subsidised nirmatrelvir and ritonavir, even if they have had two or more doses of a SARS-CoV-2 vaccine.
Some people aged ≥ 65 years, or aged ≥ 50 years who identify as Aboriginal or Torres Strait Islanderb, can receive PBS-subsidised nirmatrelvir and ritonavir even if they have had two or more vaccine doses. To be eligible, people in these groups must have two or more of the other listed risk factors (one or more for people aged ≥ 75 years).
For more information, see the Why was the new listing made? section.
Unvaccinated or one dose
All unvaccinated and partially vaccinated people aged ≥ 18 years who are moderately to severely immunocompromisedb can receive PBS-subsidised nirmatrelvir and ritonavir.
Some unvaccinated and partially vaccinated people who are aged ≥ 65 years, or aged ≥ 50 years who identify as Aboriginal or Torres Strait Islanderb, can receive PBS-subsidised nirmatrelvir and ritonavir.
Unvaccinated and partially vaccinated people aged ≥ 75 yearsb do not need another risk factor to receive PBS-subsidised nirmatrelvir and ritonavir.
People aged 65–74 years, and those aged 50–74 years who identify as Aboriginal or Torres Strait Islanderb, need one more risk factor.
b and meet all other required clinical criteria
Prescribers and dispensers should:
See the Drug–drug interactions section for more details.
Nirmatrelvir and ritonavir is a combination antiviral medicine taken orally in tablet form.2,3,5
Nirmatrelvir is a peptidomimetic inhibitor of the SARS‑CoV‑2 main protease (Mpro). Inhibition of SARS-CoV-2 Mpro makes the protein incapable of processing polyprotein precursors, which prevents viral replication.5
Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir. This boosts plasma concentrations of nirmatrelvir. Ritonavir itself is inactive against SARS-CoV-2.5,6
Nirmatrelvir must be taken together with ritonavir. Failure to correctly take nirmatrelvir with ritonavir will result in plasma levels of nirmatrelvir that will be insufficient to achieve the desired therapeutic effect.5
The recommended dose is 300 mg nirmatrelvir (two 150 mg tablets) taken together with 100 mg ritonavir (one 100 mg tablet), every 12 hours for 5 days.5
The nirmatrelvir tablets are co-packaged with ritonavir tablets. The carton includes five blister cards, each marked with a ‘Morning Dose’ and ‘Evening Dose’ for tablets to be taken each morning and each evening. Each blister card contains four nirmatrelvir tablets and two ritonavir tablets.5
Nirmatrelvir and ritonavir has been provisionally approved by the Therapeutic Goods Administration (TGA) for the treatment of COVID-19 in Australian adults (≥ 18 years) who:5
For more information, see the What else should health professionals know? section below.
The Pharmaceutical Benefits Advisory Committee (PBAC) conducted an accelerated assessment of nirmatrelvir and ritonavir to help address the current urgent public health need for COVID-19 treatments and prevention of severe disease requiring hospitalisation.3
The PBAC was satisfied that, for some patients, nirmatrelvir and ritonavir is likely to be more efficacious than the current standard of care in reducing the risk of developing severe disease leading to hospital admission. The committee will continue to monitor the conditions for PBS access, considering new evidence for the effectiveness and safety of nirmatrelvir and ritonavir and the epidemiology of COVID-19.3
The PBAC considered whether the risk factors for the eligibility for PBS-subsidised oral antiviral medicines (molnupiravir, and nirmatrelvir and ritonavir) to treat mild-to-moderate COVID-19 should be updated. In particular, it noted the Australian Technical Advisory Group on Immunisation (ATAGI) has recently updated its vaccine recommendations.3
The PBAC considered the evidence continues to show that the highest risk for hospitalisation and death in older people with COVID-19 is associated with no or one vaccine dose(s). The PBAC decided not to make any changes to the risk factors at this time.3
The safety and efficacy of nirmatrelvir and ritonavir (300 mg of nirmatrelvir with 100 mg of ritonavir, twice daily for 5 days) has been assessed in a single phase II–III double-blind randomised control trial (EPIC-HR). Treatment was started within 5 days of the onset of signs or symptoms in 2246 nonhospitalised, unvaccinated adults with mild-to-moderate COVID-19 and at least one or more risk factors for progressing to severe disease.7
The risk factors for severe disease in the EPIC-HR trial were:7
COVID-19-related hospitalisation or death at 28 days was the most important efficacy endpoint in the trial. It was reported in:7,8
This represented an 88% relative risk reduction and absolute reduction of 5.62% (95% confidence interval [CI] -7.21 to -4.03 p < 0.001).7,9
Other results included:7
For more information about the EPIC-HR trial, see Australian Prescriber: Nirmatrelvir and ritonavir for COVID-19.
Prior to 1 May 2022, access to nirmatrelvir and ritonavir was primarily through state and territory governments. Each state and territory government was provided with allocations of nirmatrelvir and ritonavir via the National Medical Stockpile for distribution within their relevant jurisdiction. The mechanisms that were in place prior to 1 May 2022 will continue to provide access to nirmatrelvir and ritonavir.2
The prescribing criteria for accessing nirmatrelvir and ritonavir through these mechanisms may vary. Each state and territory may have their own specific eligibility form to complete. In general, these criteria are in alignment with the TGA-approved product information and National COVID-19 Clinical Evidence Taskforce Caring for people with COVID-19 Guidelines, and largely overlap with the PBS eligibility criteria.10-13
From 1 May 2022 the inclusion of nirmatrelvir and ritonavir on the PBS now also provides subsidised access for eligible patients through medicines dispensed in their local community pharmacy. The PBS is an appropriate mechanism to provide timely and equitable access to oral COVID-19 treatments. The Australian Government Department of Health is working with distributors and peak medical and pharmacy organisations to prioritise nirmatrelvir and ritonavir for patients at highest risk and to discourage private prescriptions.2
For people with mild-to-moderate COVID-19 symptoms who do not require oxygen and are living in residential care facilities or at home, the National COVID-19 Clinical Evidence Taskforce Caring for people with COVID-19 Guidelines also recommends four other COVID-19 treatments:14
The National COVID-19 Clinical Evidence Taskforce Caring for people with COVID-19 Guidelines notes that its recommendation for tixagevimab and cilgavimab is not a TGA-approved indication.14
It recommends that molnupiravir be prescribed when other treatments such as nirmatrelvir and ritonavir or sotrovimab are not suitable or available. For sotrovimab only, where infection with Omicron BA.2 is confirmed or considered likely, use should only be considered where other treatments are not suitable or available. For casirivimab and imdevimab only, where Omicron is the dominant variant, this medicine should not be routinely used unless there is reason to believe the patient has another variant.8,14
For more information comparing the three treatments, molnupiravir, nirmatrelvir and ritonavir and sotrovimab, see NPS MedicineWise Oral antivirals and sotrovimab for adults with mild-to-moderate COVID-19 who do not require oxygen.
Pharmacists will be able to access stock through the usual wholesalers.
It should be noted that the initial supply of nirmatrelvir and ritonavir in Australia has been manufactured overseas and the product has an international label. The TGA has assessed this international label, checked it contains key information to allow its safe use in Australia and provided the product with a labelling exemption.17
For some patients, nirmatrelvir and ritonavir is likely to be more efficacious than the current standard of care in reducing the risk of developing severe disease leading to hospital admission.3
However, the safety and efficacy of nirmatrelvir and ritonavir is based on a single clinical trial involving unvaccinated patients.7 The trial took place during a previous wave of the virus when Delta was the dominant COVID-19 strain. More understanding is needed on how nirmatrelvir and ritonavir performs in clinical practice, given the difference between the broader population and those involved in the trial.18
Use nirmatrelvir and ritonavir with caution because of its many contraindications and potential for significant drug–drug interactions.5 Management of these drug–drug interactions can be complex. However, there is good practical guidance about management strategies for these interactions.
Nirmatrelvir and ritonavir is contraindicated for patients with severe renal impairment (eGFR < 30 mL/min) or severe hepatic impairment, or for those who are allergic to the active ingredients or any of the excipients.5
Nirmatrelvir and ritonavir is contraindicated with medicines that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious or life-threatening reactions.5
It is also contraindicated with medicines that are potent CYP3A inducers where significant decreases in nirmatrelvir and ritonavir concentrations may be associated with loss of the therapeutic response and possible development of viral resistance.5 See Table 3.
Table 3: Medicines contraindicated for concomitant use with nirmatrelvir and ritonavir (Paxlovid)5
Contraindication
Medicines class
Medicines within class
Co-administration of medicines highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions are contraindicated
Alpha 1-adrenoreceptor antagonists
alfuzosin
Antianginal
ranolazine
Antiarrhythmics
amiodarone, flecainide
Anticancer
neratinib, venetoclax
Anti-gout
colchicine
Antipsychotics
lurasidone, clozapine
Ergot derivatives
ergometrine
HMG-CoA reductase inhibitors (statins)
simvastatin
Nonsteroidal anti-inflammatory drugs
piroxicam
Opioid analgesics
pethidine
PDE5 inhibitors
avanafil, sildenafil, vardenafil, tadalafil
Sedatives/hypnotics
diazepam
Co-administration of medicines that are potent CYP3A inducers where significant decreases in nirmatrelvir and ritonavir concentrations may be associated with a loss of response and possible resistance
Anticancer
apalutamide
Anticonvulsants
carbamazepine, phenobarbital, phenytoin
Antimycobacterials
rifampicin
Herbal products
St John’s Wort (hypericum perforatum)
Nirmatrelvir and ritonavir has established and potentially significant interactions with many medicines that may cause serious or life-threatening side effects or affect how the medicine works.5
Despite its short duration of therapy, drug–drug interactions can still occur as the maximal inhibition of CYP3A4 occurs within 48 hours of starting nirmatrelvir and ritonavir. This inhibition persists after stopping, resolving 3 days after stopping treatment in most young and elderly patients. There may be variability between patients.19
For a full list, see:
Management of drug–drug interactions with nirmatrelvir and ritonavir can be complex. In some cases, the recommendation is to avoid co-administration.5,19
The University of Liverpool COVID-19 Drug Interactions Checker is a useful tool for identifying and managing drug interactions. It categorises drug–drug interactions with essential medicines and nirmatrelvir and ritonavir into three categories:20
Management strategies may include:19,20
There may be times when dose adjustments are impractical, such as when:20
Consider alternative-day dosing of co-administered medicines in these situations.20 See Table 4.
Table 4: Management strategies for drug–drug interactions with common medicine classes and nirmatrelvir and ritonavir (note this is not an exhaustive list; see University of Liverpool COVID-19 Drug Interactions Checker and TGA-approved Product Information)5,21
Medicine class
Drug–drug interaction category
Red
(do not co-administer)
Amber/yellow
(potential interaction)
Green
(no interactions expected)
Anticoagulants and antiplatelets
apixaban, rivaroxaban
Management: consider the indication and whether it can be stopped safely for 8 days
clopidogrel
Management: consider whether a transient loss in clopidogrel efficacy during the short duration is acceptable; avoid co-administration in high-risk situations (eg, initial period at least 6 weeks post-coronary stenting)
dabigatran
Management: co-administer with nirmatrelvir and ritonavir; dabigatran dose may need to be reduced in mild or moderate renal impairment
warfarin
Management: warfarin concentration is expected to decrease; monitor the international normalised ratio
aspirin, dipyridamole
Antidepressants
amitriptyline, doxepin, fluoxetine, nortriptyline, paroxetine, venlafaxine
Management: potential for weak interaction; monitoring or dose adjustment is unlikely to be required
imipramine, mirtazapine
Management: monitor for the potential for increased drowsiness; effect is expected to disappear 3 days after the last dose of nirmatrelvir and ritonavir
citalopram, duloxetine, escitalopram, sertraline
Calcium channel blockers
amlodipine, diltiazem, felodipine, nifedipine, verapamil
Management: dose adjustment can be optional (eg, reduce dose by 50%) and monitor for side effects (eg, hypotension, flushing, oedema); effect is expected to disappear 3 days after the last dose of nirmatrelvir and ritonavir; temporarily stop medicine if needed
Cardiac glycosides
digoxin
Management: co-administration is expected to increase digoxin concentration; individualise dose or dosing schedule based on treatment indication, renal function and plasma concentration
HMG-CoA reductase inhibitors (statins)
simvastatin
Management: co-administration is expected to increase simvastatin concentration, which could result in serious reactions such as the risk of myopathy and rhabdomyolysis; stop and resume 3 days after the last dose of nirmatrelvir and ritonavir
atorvastatin, rosuvastatin
Management: stop and resume 3 days after the last dose of nirmatrelvir and ritonavir; if co-administration is necessary, reduce dose to 10 mg and resume usual dose 3 days after the last dose of nirmatrelvir and ritonavir
fluvastatin, pravastatin
Hormonal contraceptives
ethinylestradiol
Management: use an effective alternative contraceptive method or an additional barrier method of contraception during treatment with nirmatrelvir and ritonavir, and until one menstrual cycle after stopping
Long-acting beta-adrenoceptor agonist
salmeterol
Management: do not co-administer
formoterol, vilanterol
Anxiolytics, hypnotics and sedatives
diazepam, midazolam (oral/buccal)
Management: do not co-administer; if it is decided to stop during nirmatrelvir and ritonavir treatment, resume 3 days after the last dose
alprazolam
Management: consider a lower dose and monitor for side effects; effect is expected to disappear 3 days after the last dose of nirmatrelvir and ritonavir
zolpidem, zopiclone
Management: dose adjustment may not be necessary; monitor for enhanced sedative effects; effect is expected to disappear 3 days after the last dose of nirmatrelvir and ritonavir
lorazepam, temazepam
Nirmatrelvir must be taken together with ritonavir. Start as soon as possible after a diagnosis of COVID-19, within 5 days of symptom onset. The recommended dose for adults aged ≥ 18 years is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) every 12 hours for 5 days. The medicine can be taken with or without food.5
A lower dose is given to patients with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min). The dose should be reduced to 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) every 12 hours for 5 days. It is not recommended for patients with severe renal impairment (eGFR < 30 mL/min).5
The tablets should be swallowed whole and not chewed, broken or crushed.5 If the patient cannot swallow tablets whole, consider other treatment options. See Procedure for preparation of molnupiravir oral solution.
Patients with mild or moderate hepatic impairment do not need any dose adjustments. Nirmatrelvir and ritonavir is contraindicated for patients with severe hepatic impairment.5
The safety and efficacy of treatment for patients younger than 18 years have not yet been established.5
If a patient is hospitalised after starting treatment, the full treatment course should be completed at the prescriber’s discretion.5
Nirmatrelvir and ritonavir is not recommended during pregnancy (Category B3) and in people of childbearing potential who are not using contraception. Advise people of childbearing potential to use effective birth control (excluding combined hormonal contraceptives) during treatment and for 7 days after the last dose.5
Ritonavir reduces the efficacy of combined hormonal contraceptives. Advise patients to use an effective alternative method or an additional barrier during treatment and for one full menstrual cycle after stopping treatment.5
Breastfeeding is not recommended during treatment and for 7 days after the last dose. Due to limited data, risk to the newborn or infant cannot be excluded.5
Preliminary results from the EPIC-HR trial showed that the most common adverse effects reported during treatment and during the 34 days after the last dose were:5
Less common adverse effects reported were:5
Prescribers and pharmacists are encouraged to discuss the following with patients and carers:
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Patients at high risk of severe disease are eligible for treatment (Updated 2 May 2022)
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