On 11 July 2022, eligibility criteria for COVID-19 antiviral medicines were updated.  Please read our article Changes to COVID-19 oral antiviral PBS eligibility criteria – July 2022 for more information, in conjunction with the article below.

 

Key points

  • On 1 May 2022, nirmatrelvir and ritonavir (Paxlovid) was listed on the Pharmaceutical Benefits Scheme (PBS) for COVID-19. It is the second antiviral treatment to be PBS-listed for this indication. Molnupiravir (Lagevrio) was listed on 1 March 2022. 
    The eligibility criteria for access under the PBS are the same for both listings. It should be started within 5 days of symptom onset. It can be prescribed for adult patients with mild-to-moderate COVID-19 who are at high risk of progressing to severe disease.
  • High-risk patient populations include people aged ≥ 65 years, Aboriginal or Torres Strait Islander people aged ≥ 50 years and people aged ≥ 18 years who are moderately to severely immunocompromised.
    The definition of ‘high risk of progressing to severe disease’ varies for these patient populations, including the number of risk factors and conditions that define being moderately to severely immunocompromised.
  • A single phase II–III double-blind randomised control trial found nirmatrelvir and ritonavir had a relative risk reduction of 88% for COVID-19-related hospitalisation or death at 28 days among patients who commenced treatment within 5 days of symptom onset.
    This represented 8 per 1000 patients in the treatment group who were hospitalised or died compared to 63 per 1000 in the placebo group.
  • Prescribers and dispensers should be aware that nirmatrelvir and ritonavir has significant drug–drug interactions.
    Management of drug–drug interactions with nirmatrelvir and ritonavir can be complex. However, there is good practical guidance about management strategies for these interactions.
  • Nirmatrelvir and ritonavir can be used safely in patients with an estimated glomerular filtration rate (eGFR) > 30 mL/min. However, dose adjustment is required in patients with an eGFR of 30–60 mL/min.
    Patients should also receive adequate patient counselling to ensure they are clear on how to safely administer the medicine (including omitting one tablet of nirmatrelvir per dose).
 

What's new?

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

  • aged ≥ 65 years with two or more risk factors for severe disease (≥ 75 years with one or more risk factors)
  • aged ≥ 50 years who identify as Aboriginal or Torres Strait Islander and have two or more risk factors for severe disease
  • aged ≥ 18 years who are moderately to severely immunocompromised and at risk of progressing to severe disease due to their immunocompromised status. Access to treatment through this restriction is permitted regardless of vaccination status.

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 accessing nirmatrelvir and ritonavir on the PBS are the same as those for molnupiravir3

The eligibility criteria for PBS-subsidised supply of nirmatrelvir and ritonavir are the same as those for molnupiravir, including:

  • the requirements for COVID-19 diagnosis
  • COVID-19 signs and symptoms that must be present
  • specific patient populations and risk factors defining ‘high risk of progressing to severe disease’ for each patient population that determine who can receive treatment
  • that the medicine may be prescribed by nurse practitioners.1

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.

May be prescribed by nurse practitioners1

Authorised nurse practitioners may prescribe this medicine. See the PBS website for more information on nurse practitioner PBS prescribing.

Clinical criteria for all included patient populations1

For all included patient populations, the clinical criteria for PBS-subsidised nirmatrelvir and ritonavir are as follows.

COVID-19 diagnosis

Patients must have a:

  • positive polymerase chain reaction (PCR) test result, or
  • positive rapid antigen test (RAT) result verified by a medical practitioner or nurse practitionera.

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:

  • fever > 38 ºC, chills
  • cough, sore throat, shortness of breath or difficulty breathing with exertion
  • fatigue
  • nasal congestion, runny nose
  • headache, muscle or body aches
  • nausea, vomiting, diarrhoea
  • loss of taste, loss of smell.

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:

  • have the treatment initiated within 5 days of symptom onset, and
  • not require hospitalisation at the time of prescribing.

Clinical criteria defining ‘high risk of severe disease’ for specific patient populations1

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

  • aged ≥ 75 years
  • aged ≥ 65 years
  • aged ≥ 50 years, and
  • identify as Aboriginal or Torres Strait Islander

Item number

Authority required (Streamlined) code

  • 12996B

  • 12923
  • 12996B

  • 12936

Number of risk factors

One or more

Two or more

Two or more

Risk factors

  • unvaccinated or have received only one dose of a SARS-CoV-2 vaccine
  • lives in residential care (aged or disability)
  • neurological conditions, including stroke and dementia
  • respiratory compromise, including COPD, moderate or severe asthma (required inhaled steroids), and bronchiectasis
  • heart failure (NYHA Class II or greater)
  • obesity (BMI greater than 30 kg/m2)
  • diabetes type 1 or 2, requiring medication for glycaemic control
  • renal failure (eGFR less than 60 mL/min)
  • cirrhosis
  • reduced, or lack of, access to higher level healthcare and lives in an area of geographic remoteness classified by the Modified Monash Model as Category 5 or above.

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

  • aged ≥ 18 years, and
  • moderately to severely immunocompromised, and
  • at risk of severe disease due to immunocompromised status
  • eligible regardless of vaccination status.

Item number

Authority required (Streamlined) code

  • 12996B

  • 12839

Moderately to severely immunocompromised includes:

Any primary or acquired immunodeficiency including:

  • haematologic neoplasms: leukaemias, lymphomas, myelodysplastic syndromes, multiple myeloma and other plasma cell disorders
  • post-transplant: solid organ (on immunosuppressive therapy), haematopoietic stem cell transplant (within 24 months)
  • immunocompromised due to primary or acquired (HIV/AIDS) immunodeficiency.

Any significantly immunocompromising condition(s) where, in the last 3 months, the patient has received any of these treatments:

  • chemotherapy or whole-body radiotherapy
  • high-dose corticosteroids (≥ 20 mg of prednisone per day, or equivalent) for at least 14 days in 1 month, or pulse corticosteroid therapy
  • biological agents and other treatments that deplete or inhibit B- or T-cell function (anti-CD20 antibodies, BTK inhibitors, JAK inhibitors, sphingosine 1-phosphate receptor modulators, anti-CD52 antibodies, anti-complement antibodies, anti-thymocyte globulin)
  • selected conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) including mycophenolate, methotrexate (more than 0.4 mg/kg/week), leflunomide, azathioprine (at least 3 mg/kg/day), 6-mercaptopurine (at least 1.5 mg/kg/day), alkylating agents (eg, cyclophosphamide, chlorambucil), and systemic calcineurin inhibitors (eg, cyclosporin, tacrolimus).

Others with very high-risk conditions, including:

  • Down syndrome
  • cerebral palsy
  • congenital heart disease
  • thalassemia, sickle cell disease and other haemoglobinopathies.

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.

Vaccination status

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

Caution about drug–drug interactions1

Prescribers and dispensers should:

  • be aware that nirmatrelvir and ritonavir has significant drug–drug interactions
  • refer to the TGA-approved Product Information
  • carefully review a patient's concomitant medicines including over-the-counter medicines, herbal supplements and recreational drugs.

See the Drug–drug interactions section for more details.

 

What is it?

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

  • do not require initiation of supplemental oxygen due to COVID-19, and
  • are at increased risk for hospitalisation or death.

For more information, see the What else should health professionals know? section below.

 

Why was the new listing made?

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

 

Key clinical evidence

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

  • age ≥ 60 years
  • body mass index (BMI) > 25 kg/m2
  • smoking
  • immunosuppressive disease or prolonged use of immune-weakening medicines
  • chronic disease (lung, cardiovascular, kidney)
  • diabetes and sickle cell disease
  • neurodevelopmental disorders (eg, cerebral palsy, Down syndrome) or other conditions with medical complexity (eg, genetic or metabolic syndromes)
  • active cancer (except localised skin cancer)
  • medical-related technological dependence (eg, continuous positive airway pressure).

COVID-19-related hospitalisation or death at 28 days was the most important efficacy endpoint in the trial. It was reported in:7,8

  • 8 of 1039 (0.77%) participants in the treatment group = 8 per 1000 patients, and
  • 66 of 1046 (6.31%) participants in the placebo group = 63 per 1000 patients (p < 0.001).

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

  • 0 deaths in the treatment group vs 12 in the placebo group
  • adverse events reported in 22.6% of nirmatrelvir and ritonavir-treated participants vs 23.9% of participants given placebo.

For more information about the EPIC-HR trial, see Australian Prescriber: Nirmatrelvir and ritonavir for COVID-19.

 

Will the listing affect current prescribing?

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

Other COVID-19 treatments for people with mild-to-moderate COVID-19 living in the community

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

  • molnupiravir (Lagevrio), an antiviral oral tablet
  • sotrovimab (Xevudy), a monoclonal antibody given as a single-dose intravenous treatment
  • casirivimab and imdevimab (Ronapreve), a monoclonal antibody that may be given as a subcutaneous injection15
  • tixagevimab and cilgavimab (Evusheld), a combination of two monoclonal antibodies given as an intramuscular injection.16

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.

Supply

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

 

Where does it fit?

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.

 

Contraindications

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)

 

Drug–drug interactions

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

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

  • Red: do not co-administer (unless the medicine can be stopped safely for 8 days)
  • Amber/yellow: potential interaction (stop medicine temporarily or adjust dose to allow use with nirmatrelvir and ritonavir)
  • Green: no interaction expected (proceed with nirmatrelvir and ritonavir).

Management strategies may include:19,20

  • stopping the medicine and restarting 3 days after the last dose of nirmatrelvir and ritonavir (8 days in total)
  • adjusting the dose of the medicine and readjusting to the original dose 3 days after the last dose of nirmatrelvir and ritonavir
  • advising patients to monitor for side effects and on what to do if they occur
  • choosing an alternative COVID-19 treatment option.

There may be times when dose adjustments are impractical, such as when:20

  • a patient is using a compliance aid, such as a dosette box
  • a patient is taking a form of medicine in which dose adjustment is difficult or impractical, such as a capsule
  • there are concerns regarding patients misunderstanding instructions.

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

 

What else should health professionals know?

Dosing

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

Pregnancy and breastfeeding

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

Side effects

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

  • altered taste 5.6% (treatment); 0.3% (placebo)
  • diarrhoea (3.1%; 1.6%)
  • headache (1.4%; 1.3%)
  • vomiting (1.1%; 0.8%).

Less common adverse effects reported were:5

  • high blood pressure (0.6%; 0.2%)
  • painful or aching muscles (0.6%; 0.2%).
 

What should patients know?

Prescribers and pharmacists are encouraged to discuss the following with patients and carers:

  • Paxlovid has two medicines: nirmatrelvir and ritonavir. It comes in a carton of 30 tablets in five daily blister cards marked as ‘Morning Dose’ and ‘Evening Dose’. This will help remind you which tablets to take each morning and each evening.5
  • Take two tablets of nirmatrelvir and one tablet of ritonavir together every 12 hours for 5 days.5 You can take it at a convenient time, such as at 8 am and at 8 pm.
  • If you have kidney problems, your GP may tell you to only take one tablet of nirmatrelvir and one tablet of ritonavir together every 12 hours. This means there will be one tablet of nirmatrelvir left on each daily blister card.5
  • Swallow each tablet whole with some water. You can take it before, during or after a meal.5
  • Do not open, break or crush the tablets.5 Tell your GP or pharmacist if you cannot swallow the tablets whole.
  • If it has been less than 8 hours since the missed dose, take it as soon as you remember. You may take the next dose as normal. If it has been more than 8 hours, skip the missed dose and take the next dose at the scheduled time. Do not take a double dose to make up for the missed dose.22,23
  • You will need to ask someone to collect the medicine for you or arrange for a delivery if you are isolating.24
  • You may have leftover medicine. Take it to any pharmacy to dispose of it safely.5
  • If you are sexually active, or there is any chance of getting pregnant, discuss with your GP. You may need birth control or a pregnancy test before starting this medicine.5
  • Do not breastfeed your baby while taking this medicine and for 7 days after the last dose.5
  • Most side effects are minor and temporary. The most common side effects are changes in taste, loose or runny poo, headache and throwing up. Report any side effects to your GP and to the TGA.22
  • This medicine may raise or lower the effects of many medicines. Tell your GP or pharmacist about all the medicines you are taking or have recently taken. This includes medicines, vitamins and natural medicines you can buy without a script from your pharmacy or supermarket.5
  • Nirmatrelvir and ritonavir is not intended to be a replacement for vaccination against COVID-19.23
 

More information

 

References

  1. Pharmaceutical Benefits Scheme. PBS Schedule: Summary of Changes (May 2022). Canberra: Australian Government Department of Health, 2022 (accessed 14 April 2022).
  2. Pharmaceutical Benefits Scheme. Paxlovid® (nirmatrelvir and ritonavir) Pharmaceutical Benefits Scheme Factsheet. Canberra: Australian Government Department of Health, 2022 (accessed 11 April 2022).
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