Oral antivirals and sotrovimab for adults with mild-to-moderate COVID-19 who do not require oxygen

Clinical guidelines recommend the use of these three medicines to help manage at-risk people with mild–moderate COVID-19 symptoms in community settings. The tables below summarise key medicine information to support treatment decisions. Updated 13 July 2022

Updated to reflected changes to PBS listing for molnupiravir and nirmatrelvir plus ritonavir

There are a number of medicines provisionally approved by the Therapeutic Goods Administration (TGA) that can now be prescribed for adults with mild-to-moderate COVID-19 who do not require oxygen and where treatment can be started within 5 days of symptom onset, or as soon as possible after diagnosis is confirmed.

The oral antivirals molnupiravir (Lagevrio) and nirmatrelvir plus ritonavir (Paxlovid), are available for prescribing by medical and nurse practitioners through the PBS General Schedule - Authority Required (Streamlined), as well as though state and territory health departments for those patients who may not meet PBS criteria. The single-dose intravenous sotrovimab (Xevudy) is also available through state and territory health departments.
Prescribers can use the key medicine information in the tables below to support treatment decisions.

 

General prescribing information

Table 1: Information to support treatment decisions on oral antivirals or sotrovimab for people with mild-to-moderate COVID-19 who do not require oxygen1-7

Active ingredient (brand name)

Molnupiravir (Lagevrio)

Nirmatrelvir plus ritonavir (Paxlovid)

Sotrovimab (Xevudy)

Medicine type

Antiviral

Antiviral

Monoclonal antibody

Route of administration

Oral

Oral

Intravenous

Approved indication

Treatment of adults with COVID-19 who do not require initiation of oxygen due to COVID-19 and who are at increased risk for hospitalisation or death.

Treatment of coronavirus disease 2019 (COVID-19) in adults 18 years of age and older, who do not require initiation of supplemental oxygen due to COVID-19 and are at increased risk of progression to hospitalisation or death.

Treatment of adults and adolescents (aged 12 years and over and weighing at least 40 kg) with coronavirus disease 2019 (COVID-19) who do not require initiation of oxygen due to COVID-19 and who are at increased risk of progression to hospitalisation or death.

PBS listing (expanded on 11 July 2022 for molnupiravir and nirmatrelvir plus ritonavir - read more here)

Yes. Authority required (Streamlined)

For prescribing on the PBS, including clinical criteria, see this page.

People who may not meet the PBS clinical criteria may still be able to access the oral antiviral medicines or sotrovimab through state and territory health departments.

Primary care prescribers should follow the standard processes in their state or territory for access and approvals.

Read more about how medical professionals can access COVID-19 treatments through the National Medical Stockpile.

Yes. Authority required (Streamlined)

For prescribing on the PBS, including clinical criteria, see this page.

People who may not meet the PBS clinical criteria may still be able to access the oral antiviral medicines or sotrovimab through state and territory health departments.

Primary care prescribers should follow the standard processes in their state or territory for access and approvals.

Read more about how medical professionals can access COVID-19 treatments through the National Medical Stockpile.

No



National COVID-19 Clinical Evidence Taskforce guidance

Please Note: PBS clinical criteria for the prescribing of both oral antivirals, including risk factors for severe disease progression, are different to the guidance summarised below. 

Adults (≥ 18 years) diagnosed with mild-to-moderate COVID-19 who do not require oxygen due to COVID-19, and are:

  • unvaccinated with one or more risk factors for disease progression (see Table 2), or
  • immunosuppressed or not immunocompetent, regardless of vaccination status, or
  • vaccinated with one or two doses of a COVID-19 vaccine and at high risk of severe disease on the basis of age and multiple risk factors (see Table 2).
  • AND where other treatments such as nirmatrelvir plus ritonavir (Paxlovid) or sotrovimab (Xevudy) are not suitable or available.

Appropriateness of treatment should also be based on the patient’s time since vaccination. This is because the efficacy of these medicines in partially or fully vaccinated individuals or those who have received booster doses is unclear.

Commencement

Within 5 days of symptom onset.a

Dosing

800 mg (four 200 mg capsules) orally every 12 hours for 5 days, with or without food.b

300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) orally every 12 hours for 5 days.

Single 500 mg dose given as an IV infusion over 30 minutes.

Dose adjustment in kidney or liver impairment

No dose adjustment required

Kidney: Moderate renal impairment (GFR ≥ 30 to <60mL/min) reduce dose of nirmatrelvir/ritonavir to 150 mg/100 mg every 12 hours for 5 days.

Severe renal impairment (<30mL/min) contraindicated due to lack of available data.

Liver: No dosage adjustment required in mild or moderate liver impairment. Contraindicated in severe renal or liver impairment

No dose adjustment required

Efficacy

~ 30% reduction of disease progression leading to hospitalisation or death at 29 days compared with placebo.

88.9% relative risk reduction of disease progression leading to hospitalisation or death from any cause at 28 days compared with placebo.

Treatment reduced the risk of hospitalisation and death by 85% compared to those who didn’t receive treatment.

Adverse effects

Results from a single pivotal study show most common treatment-related adverse effects were mild–moderate, occurring at similar rates for treatment and placebo groups:

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

Results from a single pivotal study show most common treatment-related adverse effects were mild–moderate and included:

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

Results from a single pivotal study show most common treatment-related adverse effects were mild–moderate and included:

  • nausea < 1% (treatment); 2% (placebo)
  • diarrhoea (2%; < 1%)
  • headaches (< 1%; 2%).

Prescribing considerations

Contraindications

Hypersensitivity to the active substance or any of the excipients.

Hypersensitivity to the active substance or any of the excipients.

Contraindications corresponding to drug-drug interactions related to ritonavir. See Table 3

Hypersensitivity to the active substance or any of the excipients.

Drug-drug interactions

No drug interactions identified based on limited data available.

Drug interactions considered unlikely based on pharmacology.

No drug interaction studies yet.

Multiple interactions primarily related to ritonavir.

Before prescribing, use the Liverpool interaction checker or the Veterans’ MATES nirmatrelvir plus ritonavir interaction checker (for the Australian veteran population) to determine potential drug–drug interactions with medicines the patient is taking.

See Table 3 for identified interactions in the approved PI.

No formal interaction studies conducted yet.

Not renally excreted or metabolised by CYP P450 enzymes so interactions unlikely.

Pregnancy

Not recommended in pregnancy based on animal data.

Advise people of childbearing potential to use effective contraception during treatment and for 4 days after last dose.

It is unknown how molnupiravir may affect sperm. People who are sexually active with a partner of childbearing potential should use appropriate contraception during treatment and for 3 months after the last dose.

Not recommended in pregnancy.

Advise people of childbearing potential to use effective contraception (excluding combined hormonal contraceptives) during treatment and for 7 days after last dose

Ritonavir reduces the efficacy of combined hormonal contraceptives.  Advise to use an effective alternative method or an additional barrier during treatment and during a menstrual cycle after stopping treatment.

Category B2 (insufficient human data) – only use if the expected benefit justifies the potential risk to the foetus.

Breastfeeding

Not recommended during treatment and for 4 days after last dose based on potential adverse effects in infants.

Discontinue during treatment and for 7 days after last dose.

Insufficient data – consider the benefit of breastfeeding for the child and benefit of therapy for the mother.

a For molnupiravir (Lagevrio) and nirmatrelvir plus ritonavir (Paxlovid), treatment should be started as soon as possible after a diagnosis of COVID-19

b If swallowing capsules is not possible, and if alternative treatments are not available or not suitable, the manufacturer has advised a procedure that allows preparation of an oral solution. Please see this article for more information.

CI = confidence interval, IV = intravenous, PI = product information, RCT = randomised controlled trial.

 

Risk factors for disease progression

The table below outlines risk factors for severe disease progression that are used to inform recommendations made by the National COVID-19 Clinical Evidence Taskforce.4-6 The information is based on the inclusion criteria of pivotal studies for each medicine.8-10 

PBS clinical criteria for prescribing, including risk factors for severe disease progression, are different. Prescribers can read more about the current PBS listings and clinical criteria in this RADAR article or refer to the PBS website for further information. 

Table 2: Information based on inclusion criteria in pivotal studies to support treatment decisions on oral antivirals or sotrovimab for people with mild-to-moderate COVID-19 who do not require oxygen8-10

Molnupiravir (Lagevrio)

Nirmatrelvir plus ritonavir (Paxlovid)

Sotrovimab (Xevudy)

Age ≥ 60 years

Diabetes mellitus

Obesity (BMI ≥ 30 kg/m2)

Serious heart conditions such as heart failure, coronary artery disease or cardiomyopathies

Chronic obstructive pulmonary disease

Chronic kidney disease (ie, eGFR < 60 mL/min/1.73 m2 by MDRD), excluding patients on dialysis

Active cancer (excluding minor cancers not associated with immunosuppression, eg, basal cell carcinomas)

Immunocompromised state following solid organ transplant

Sickle cell disease

Age ≥ 60 years

Diabetes (requiring medication)

BMI ≥ 25 kg/m2

Cardiovascular disease

Hypertension

Chronic lung disease

Current smoker

Patients with the following conditions are also likely to benefit from treatment:

Chronic kidney disease (but where the eGFR ≥ 30mL/min)

Cancer (other than localised skin cancer)

Immunosuppressed

Prolonged iatrogenic immunosuppression

Sickle cell disease

Medical-related technological dependence (eg, CPAP not related to COVID-19)

HIV positive (CD4 cell count <200m3; viral load < 400 copies/mL)

Neurodevelopmental disorders (eg, cerebral palsy, Down’s syndrome)

Age ≥ 55 years

Diabetes (requiring medication)

Obesity (BMI ≥ 30 kg/m2)

Congestive heart failure (NYHA class II or greater)

COPD (history of chronic bronchitis, chronic obstructive lung disease, or emphysema with dyspnoea on physical exertion)

Moderate-to-severe asthma (requiring an inhaled steroid to control symptoms or prescribed a course of oral steroids in the previous 12 months)

Chronic kidney disease (ie, eGFR < 60 mL/min/ 1.73m2 by MDRD)

BMI = body mass index, COPD = chronic obstructive pulmonary disease, CPAP = continuous positive airway pressure, eGFR = estimated glomerular filtration rate, MDRD = modification of diet in renal disease

 

Contraindications and drug–drug interactions for nirmatrelvir plus ritonavir

Table 3: Information based on approved PI and pivotal trial data to support treatment decisions on the use of nirmatrelvir plus ritonavir for people with mild-to-moderate COVID-19 who do not require oxygen2,5,9

Contraindications

Drug interactions

Severe renal impairment (< 30 mL/min)

Severe hepatic impairment

Hypersensitivity to the active substance

Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption, due to lactose being one of the excipients

Nirmatrelvir is metabolised mainly by CYP3A. Ritonavir is an inhibitor of CYP3A. 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. This includes the following medicines:

Alpha 1-adrenoreceptor antagonists
  • alfuzosin
Antianginals
  • 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
Sedative/hypnotics
  • diazepam

Co-administration with, or starting immediately after discontinuation of, medicines that are potent CYP3A inducers, can significantly reduce nirmatrelvir or ritonavir plasma concentrations and may be associated with potential loss of virologic response and possible resistance. This includes the following medicines:
Anticancer

  • apalutamide
Anticonvulsant
  • carbamazepine
  • phenobarbital
  • phenytoin
Antimycobacterials
  • rifampicin
Herbal products
  • St John’s Wort (hypericum perforatum)
Drug interactions based on drug class that cause either ↑ (increased) or ↓ (decreased) concentrations of the concomitant medicine and require monitoring/actions.

These interactions correspond to drug-drug interactions related to ritonavir.

The Liverpool COVID-19 Drug Interactions website is a useful tool for identifying and managing drug interactions. Veterans’ MATES have developed annirmatrelvir plus ritonavir interaction checker for the Australian veteran population

Analgesics
  • ↑ fentanyl: monitor therapeutic and adverse effects (including potentially fatal respiratory depression)
  • ↓ methadone: monitor withdrawal effects and adjust the methadone dose
Antiarrhythmics
  • ↑ Iidocaine (systemic) antiarrhythmic: monitor therapeutic concentration
Anticancer
  • ↑ afatinib: caution should be exercised
  • ↑ abemaciclib: for monitoring and actions refer to respective product information (PI)
  • ↑ ceritinib: for monitoring and actions refer to respective PI 
  • ↑ dasatinib: for monitoring and actions refer to respective PI
  • ↑ encorafenib: avoid co-administration due to potential risk of serious adverse events such as QT interval prolongation
  • ↑ neratinib, venetoclax, ibrutinib: avoid use
  • ↑ vincristine: monitor for haematologic or gastrointestinal side effects
  • ↑ vinblastine: monitor for haematologic or gastrointestinal side effects
Anticoagulants
  • ↑↓ warfarin: closely monitor INR
  • ↑ rivaroxaban: monitor for bleeding
Anticonvulsants
  • ↓ lamotrigine: monitor serum levels for therapeutic effects
Antidepressants
  • ↑ amitriptyline, fluoxetine, imipramine, nortriptyline, paroxetine, sertraline: monitor therapeutic and adverse effects
Anti-HIV protease inhibitors
  • atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir ↑ protease inhibitor: continue medicine as indicated, monitor for increased nirmatrelvir plus ritonavir or protease inhibitor adverse effects
Anti-HIV
  • ↑ efavirenz ↑ maraviroc ↓ raltegravir ↓ zidovudine ↑ bictegravir ↔ emtricitabine ↑ tenofovir: for monitoring and actions refer to respective PI
Antihistamine
  • ↑ Loratadine; monitor therapeutic and adverse effects, use alternative where appropriate
Anti-infective
  • ↑ clarithromycin ↑ erythromycin: for monitoring and actions refer to respective PI
  • ↓ atovaquone: monitor serum levels or therapeutic effects
Antimycobacterial
  • ↑ rifabutin: for monitoring and actions refer to respective PI
Antipsychotics
  • ↑ quetiapine: reduce quetiapine dose and monitor for adverse effects
  • ↑ haloperidol: monitor therapeutic and adverse effects
  • ↑ risperidone: monitor therapeutic and adverse effects
Calcium channel blockers
  • amlodipine, diltiazem, felodipine, nifedipine, ↑ calcium channel blocker: clinical monitoring recommended, dose reduction required
Cardiac glycosides
  • ↑ digoxin: monitor serum levels
Endothelin receptor antagonists
  • ↑ bosentan: discontinue use 36 hours before prescribing nirmatrelvir plus ritonavir
  • ↑ riociguat: co-administration is not recommended; refer to riociguat product information
Hepatitis C direct acting antivirals
  • ↑ glecaprevir, ↑ pibrentasvir: not recommended to co-administer
  • sofosbuvir, velpatasvir, voxilaprevir ↑antiviral: for monitoring and actions refer to respective PI
HMG-CoA reductase inhibitors (statins)
  • ↑ atorvastatin: consider temporary discontinuation
  • ↑ rosuvastatin: consider temporary discontinuation
Hormonal contraceptive
  • ↓ ethinylestradiol: other contraceptive method should be considered
Immunosuppressants
  • ↑ciclosporin ↑ tacrolimus ↑ everolimus: refer to respective PI and monitor therapeutic concentration; if not possible, avoid use of nirmatrelvir plus ritonavir
Long-acting beta-adrenoceptor agonist (LABA)
  • ↑ salmeterol: not recommended; combination may result in increased risk of cardiovascular adverse events, including QT prolongation, palpitations, and sinus tachycardia.
Sedative/hypnotics
  • ↑ alprazolam: caution warranted during first several days of concomitant use with nirmatrelvir plus ritonavir
Sleeping agent
  • ↑ zolpidem: monitor excessive sedative effects
Smoking cessation
  • ↓ bupropion and active metabolite hydroxy-bupropion: monitor adequate clinical response
Systemic corticosteroids
  • betamethasone budesonide dexamethasone methylprednisolone prednisone triamcinolone ↑ corticosteroid: alternative corticosteroids including beclomethasone and prednisolone should be considered due to increased risk for Cushing’s syndrome and adrenal suppression

 

References

  1. Merck Sharp & Dohme (Australia) Pty Ltd. Lagevrio (molnupiravir) product information. Macquarie Park, NSW: Merck Sharp & Dohme (Australia) Pty Ltd, 2022. (accessed 22 February 2022).
  2. Pfizer Australia Pty Ltd. PAXLOVID (nirmatrelvir/ritonavir tablets) product information. Sydney, NSW: Pfizer Australia Pty Ltd, 2022. (accessed 22 February 2022).
  3. GlaxoSmithKline Australia Pty Ltd. XEVUDY (Sotrovimab) Concentrated injection solution for infusion product information. Abbotsford, Victoria. GlaxoSmithKline Australia Pty Ltd. (accessed 22 February 2022).
  4. Australian National COVID-19 Clinical Evidence Taskforce. Australian guidelines for the clinical care of people with COVID-19 - Molnupiravir (Lagevrio) for adults.
  5. Australian National COVID-19 Clinical Evidence Taskforce. Australian guidelines for the clinical care of people with COVID-19 - Nirmatrelvir plus ritonavir (Paxlovid) for adults.
  6. Australian National COVID-19 Clinical Evidence Taskforce. Australian guidelines for the clinical care of people with COVID-19 - sotrovimab (Xevudy) for adults.
  7. Pharmaceutical Benefits Scheme. Schedule of Pharmaceutical Benefits (Summary of changes). Canberra: Australian Government Department of Health, March 2022 (accessed 1 March 2022)
  8. Jayk Bernal A, Gomes da Silva MM, Musungaie DB,MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022 Feb 10;386(6):509-520. doi: 10.1056/NEJMoa2116044. Epub 2021 Dec 16. PMID: 34914868; PMCID: PMC8693688.
  9. Hammond J, Leister-Tebbe H, Gardner A,EPIC-HR Investigators. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022 Feb 16. doi: 10.1056/NEJMoa2118542. Epub ahead of print. PMID: 35172054.
  10. Gupta A, Gonzalez-Rojas Y, Juarez E, COMET-ICE Investigators. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med. 2021 Nov 18;385(21):1941-1950. doi: 10.1056/NEJMoa2107934. Epub 2021 Oct 27. PMID: 34706189.