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

  • Molnupiravir is the first medicine to be listed on the Pharmaceutical Benefits Scheme (PBS) for COVID-19.
    It is an oral antiviral that should be started within 5 days of symptom onset. It can be prescribed for patients with mild-to-moderate COVID-19 who are at high risk of 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 severe disease’ varies for these patient populations, including the number of risk factors and conditions that define moderately to severely immunocompromised.
  • A single phase III randomised controlled trial found molnupiravir had an adjusted relative risk reduction of 30% for hospitalisation or death at 29 days.
    The most common adverse effects were mild to moderate, occurring at similar rates for treatment and placebo groups. Contraindications and drug interactions were minimal.
  • Molnupiravir is not recommended during pregnancy and while breastfeeding. Effective birth control is recommended for people of childbearing potential.

    While it is unknown how molnupiravir affects sperm, sexually active people with a partner of childbearing potential should use a reliable contraception method during treatment and for 3 months after the last dose.
  • This PBS-listing adds to the existing access mechanism for molnupiravir that has been pre-placed in community settings through the National Medical Stockpile.
    People with mild-to-moderate COVID-19 at high risk of severe disease but not eligible for PBS-subsidised molnupiravir may have access to this mechanism if clinically appropriate.
 

What’s new?

On 1 March 2022 molnupiravir (Lagevrio), an oral 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 severe disease. It is the first treatment listed on the PBS for COVID-19.1,2

High-risk patient populations include people:1,3

  • aged ≥ 65 years with two or more risk factors for severe disease
    (≥ 75 years only require 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 progression to severe disease due to their immunocompromised status. Access to molnupiravir through this restriction is permitted regardless of vaccination status.

See below for more information about vaccination status and the high-risk patient populations.

Molnupiravir is not PBS-subsidised for pre-exposure or post-exposure prophylaxis for the prevention of SARS-CoV-2 infection.

May be prescribed by nurse practitioners

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 molnupiravir are:

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 valid4

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 molnupiravir 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 severe disease' and determine access to PBS-subsidised molnupiravir. See Table 1 and Table 2.

Table 1: Factors for high risk of 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

  • 12910L
  • 12582

  • 12910L
  • 12584

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

  • 12910L
  • 12583

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 molnupiravir, 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 molnupiravir 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 molnupiravir.

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 molnupiravir.

Unvaccinated and partially vaccinated people aged ≥ 75 yearsb do not need another risk factor to receive PBS-subsidised molnupiravir.

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

 

What is it?

Molnupiravir is an antiviral medicine taken orally in capsule form. It is a prodrug of N-hydroxycytidine, a ribonucleoside analogue that is incorporated into viral RNA, resulting in the inhibition of SARS-CoV-2 replication.2

Molnupiravir has been provisionally approved by the Therapeutic Goods Administration (TGA) for the treatment of Australian adults (≥ 18 years) with COVID-19 who:2

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

The recommended dose is 800 mg (four 200 mg capsules) every 12 hours for 5 days.2

For more information about dosing, oral solution, contraindications, drug interactions, pregnancy and breastfeeding and side effects, 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 the sponsor submission of molnupiravir to help address the current urgent public health need for accessible COVID-19 treatments and prevention of severe disease requiring hospitalisation.3

The PBAC was satisfied that, for some patients, molnupiravir 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 molnupiravir and the epidemiology of COVID-19.3

The PBAC acknowledged that most antivirals for COVID-19 have only been evaluated in unvaccinated people and currently most recommendations are confined to people who are unvaccinated or have had only one dose of a COVID-19 vaccine, and those with a high risk of primary vaccine failure such as people who are immunocompromised.3

It found that the current greatest risk of severe infection is for people who have had no or one vaccine dose. As a result, it concluded that being unvaccinated or having one vaccine dose is a risk factor.3

At the same time, the PBAC acknowledged that vaccine protection wanes and vaccination is not fully protective against severe COVID-19 disease. It considered PBS-subsidised molnupiravir for older patient populations (see Table 1) who have had two or more vaccine doses and have risk factors that don’t relate to vaccination status (eg, living in residential care, type 2 diabetes) strikes an appropriate balance. This decision was based on what is known about vaccine protection against COVID-19 and the mechanism of action of molnupiravir.3

Key clinical evidence

The safety and efficacy of molnupiravir (800 mg twice daily for 5 days) was assessed in a single phase III double-blind randomised control trial (MOVe-OUT). Treatment was started within 5 days of the onset of signs or symptoms in 1433 non-hospitalised, unvaccinated adults with mild-to-moderate COVID-19 and at least one risk factor for severe disease.5

The risk factors for severe disease in MOVeOUT were:5,6

  • age > 60 years
  • active cancer (excluding minor cancers not associated with immunosuppression, eg, basal cell carcinomas)
  • chronic kidney disease (estimated glomerular filtration rate 30–60 mL/min, excluding people on dialysis)
  • COPD
  • obesity (body mass index ≥ 30 kg/m2)
  • serious heart conditions (heart failure, coronary artery disease or cardiomyopathies), and
  • type 2 diabetes and sickle cell disease.

The primary efficacy end point was a composite of hospitalisation (defined as ≥ 24 hours of acute care in a hospital or any similar facility) or death at 29 days, and was reported in:5

  • 48 of 709 (6.8%) participants from the treatment group, and
  • 68 of 699 (9.7%) participants in the placebo group (95% confidence interval [CI] −5.9 to −0.1).

This represented an adjusted relative risk reduction of 30% (95% CI 1%, 51%) and an absolute reduction of 2.9%.2

Other results included:5

  • one death in the molnupiravir group vs nine for placebo
  • adverse events reported in 30.4% of molnupiravir-treated participants vs 33.0% for placebo.

For more information about the MOVe-OUT trial, see Australian Prescriber: Molnupiravir for COVID-19.

 

Will the listing affect current prescribing?

Prior to 1 March 2022, access to molnupiravir was through pre-placement in residential aged care facilities, Aboriginal Controlled Community Health Organisations, the Royal Flying Doctor Service and through the state and territory health departments via the National Medical Stockpile (NMS). These mechanisms will continue to provide access in cases where a prescriber considers treatment is clinically indicated but the patient is not eligible under the PBS. There is usually no cost to the patient associated with prescription of molnupiravir under these pathways.

Inclusion of molnupiravir on the PBS provides subsidised access for patients through medicines dispensed in the community. The PBAC noted that integration with general practice prescribing processes means that all eligible Australians will be able to access treatment in a timely and equitable way.3

The prescribing criteria for accessing molnupiravir through the NMS (including pre-placement in residential aged care facilities) is primarily based on the National COVID-19 Clinical Evidence Taskforce Caring for people with COVID-19 Guidelines.7

These criteria mainly overlap with the PBS clinical criteria with regards to patient populations and risk factors for severe disease, but there are some differences. For example, risk factors for severe disease outlined in the Guidelines are based on the MOVe-OUT trial inclusion criteria. 

The risk factors in the PBS listing were developed, taking into account a range of factors including the effectiveness and cost of a medicine when considering it for PBS subsidy. The PBAC developed the eligibility criteria for PBS access to molnupiravir based on what is known about COVID-19 and the mechanism of action of molnupiravir.1,4-6

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

Nirmatrelvir plus ritonavir (Paxlovid), an antiviral oral tablet, and sotrovimab (Xevudy), a monoclonal antibody given as a single-dose intravenous treatment, are two other treatments available 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 recommend that molnupiravir be prescribed when other treatments such as nirmatrelvir plus ritonavir or sotrovimab are not suitable or available.6

For more information comparing the three treatments, molnupiravir, nirmatrelvir plus 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. Stock in community pharmacies is designated to be used for PBS prescriptions.

It should be noted that the initial supply of molnupiravir 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.8

 

What else should health professionals know?

Dosing

Start molnupiravir 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 800 mg (four 200 mg capsules) every 12 hours for 5 days. The medicine can be taken with or without food.2

Elderly patients, or those with kidney or liver impairment do not need any dose adjustments.2

The safety and efficacy of treatment for longer than 5 days or for patients younger than 18 years has not yet been established.2

If a patient is hospitalised after starting treatment, the full treatment course can be completed at the prescriber’s discretion.9

Oral solution

While the recommendation is to swallow the molnupiravir capsule whole, preparation of an oral solution may be considered if:10

  • the patient cannot swallow the capsule, and
  • alternative treatments are not available or not suitable.

When considering the oral solution, please note that:10

  • the advice from the manufacturer is based on preliminary data and should be limited to cases where there is no other option
  • there is limited experience with administering molnupiravir via nasogastric/orogastric (NG/OG) tube
  • it is regarded as an ’off label‘ use
  • it is important to document your decision in the patient record
  • consent should be obtained from the patient or their carer for use of treatment in this way
  • anyone preparing the solution should consider the risks of exposure (see Pregnancy and breastfeeding below).

Table 3: Procedure for preparation of molnupiravir oral solution10

Dose preparation

  1. Open four capsules and transfer contents into a cup or syringe. Discard empty capsules per local procedures.
  2. Add approximately 40 mL of water to the cup or syringe.
  3. Mix/stir the capsule contents and water for 3 minutes.
    1. Note: insoluble capsule contents may not dissolve properly.
    2. Reconstituted solutions prepared according to directions may have visible undissolved particulates and are acceptable for oral administration.
  4. Administration should occur as soon as possible after the preparation and no later than 2 hours after the preparation.

Administration procedure

  1. Oral dose should be administered by staff wearing personal protective equipment required per local standards.
  2. Stir the solution for 1 minute prior to administration to re-mix the suspension.
  3. Follow local procedures for disposal of hazardous and/or biohazardous waste.
  4. Wash hands following dose administration.

Specific NG/OG guidance

  1. Mix/shake the administration syringe for 1 minute prior to administration to re-mix the suspension.
  2. Flush NG/OG tube with 5 mL of water prior to administration.
  3. Administer entire volume from the administration syringe.
  4. Flush tube with 5 mL of water TWICE (10 mL in total) after administration of the solution.

Contraindications

Molnupiravir is contraindicated for patients allergic to the active substance or any of the excipients.2

Drug interactions

Molnupiravir does not interact with any other medicines based on limited data. No drug interaction studies are available. The way our body metabolises molnupiravir makes it unlikely for it to interact with medicines taken at the same time.2

Pregnancy and breastfeeding

Molnupiravir is not recommended during pregnancy (Category D) based on animal studies. It may cause fetal harm. Advise people of childbearing potential to use effective birth control during treatment and for 4 days after the last dose.2

It is unknown how molnupiravir may affect sperm. Advise sexually active people with a partner of childbearing potential to use a reliable method of contraception during treatment and for 3 months after the last dose.2

Molnupiravir may have the potential for adverse reactions on the infant. Breastfeeding is not recommended during treatment and for 4 days after the last dose.2

Side effects

Results from the MOVe-OUT study showed that the most common treatment-related adverse effects were mild to moderate, occurring at similar rates for treatment and placebo groups:2,5

  • diarrhoea 1.7% (treatment); 2.1% (placebo)
  • nausea (1.4%; 0.7%)
  • dizziness (1.0%; 0.7%).

Closely monitor frail and elderly patients as these side effects can lead to significant morbidity, including dehydration, delirium and increased falls risk.11

 

What should patients know?

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

  • Take four capsules of molnupiravir every 12 hours at a convenient time, such as at 8 am and at 8 pm, for 5 days.2
  • Swallow each capsule whole with some water. It can be taken before, during or after a meal.2
  • Do not open, break, or crush the capsules.12 Contact the GP or pharmacist if you cannot swallow the capsules whole.
  • If it has been less than 10 hours since the missed dose, take it as soon as you remember and then take the next dose as normal. If it has been more than 10 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.2
  • If you are sexually active, or there is any possibility of getting pregnant, discuss contraception needs with your GP including if a pregnancy test is required prior to starting these medications.2
  • Most side effects are minor and temporary. The most common side effects are diarrhoea, nausea and dizziness. Report any side effects to the TGA.2
  • Molnupiravir is not intended to be a replacement for vaccination against COVID-19.13
 

More information

 

References

  1. Pharmaceutical Benefits Scheme. PBS Schedule: Summary of Changes (March 2022). Canberra: Australian Government Department of Health, 2022 (accessed 25 February 2022).
  2. Merck Sharp & Dohme (Australia) Pty Ltd. Molnupiravir (Lagevrio) product information. 2022 (accessed 27 February 2022).
  3. Pharmaceutical Benefits Scheme. PBAC web outcome statement: Molnupiravir. Canberra: Australian Government Department of Health, 2022 (accessed 25 February 2022).
  4. Pharmaceutical Benefits Scheme. Lagevrio® (molnupiravir) PBS Factsheet. Canberra: Australian Government Department of Health, 2022 (accessed 4 March 2022).
  5. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med 2022;386:509-20.
  6. National COVID-19 Clinical Evidence Taskforce. Disease-modifying treatments for adults with COVID-19. Melbourne, Australia: National COVID-19 Clinical Evidence Taskforce, 2022 (accessed 28 February 2022).
  7. NPS MedicineWise. FAQs about the use of COVID-19 oral antiviral medicines in residential aged care. Sydney: NPS MedicineWise, 2022 (accessed 28 February 2022).
  8. Therapeutic Goods Administration. Labels for COVID-19 treatments. Canberra: Australian Government Department of Health, 2022 (accessed 7 March 2022).
  9. National Institutes of Health. Therapeutic management of nonhospitalized adults with COVID-19. USA: NIH, 2022 (accessed 27 February 2022).
  10. Data on File. Kenilworth, NJ, USA: Merck & Co Inc, 2022 (accessed 28 February 2022).
  11. Royal Australian College of General Practitioners. Oral antiviral treatments for COVID-19. East Melbourne, VIC: RACGP, 2022 (accessed 27 February 2022).
  12. Merck Sharp & Dohme (Australia) Pty Ltd. Molnupiravir (Lagevrio) consumer medicine information summary. 2022 (accessed 27 February 2022).
  13. NSW Therapeutic Advisory Group Inc and Clinical Excellence Commission. Information for patients, family and carers: Use of molnupiravir (Lagevrio®) for the treatment of COVID-19 in adults. NSW: NSW Government, 2022 (accessed 27 February 2022).

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