Contraindications of nirmatrelvir and ritonavir

The nirmatrelvir and ritonavir combination is contraindicated in patients with severe renal or hepatic impairment.³The medicine may also interact with many different medicines, including herbal supplements.³ Interactions with medicinal products may lead to clinically significant adverse reactions, including severe, life-threatening or fatal events from greater exposures of concomitant medications. In some instances, it may lead to a loss of therapeutic effect of nirmatrelvir and ritonavir.

Although there may be drug interactions between nirmatrelvir and ritonavir and a wide range of medicines, only some of these drug interactions will mean nirmatrelvir and ritonavir is contraindicated.

Prescribers and dispensers should carefully review a patient’s concomitant medications including over-the-counter medications, herbal supplements, and recreational drug use before prescribing or dispensing nirmatrelvir and ritonavir to avoid significant adverse reactions.¹Where it is safe to do so, contraindications to nirmatrelvir and ritonavir can sometimes be managed by withholding the other medication or reducing its dose for the duration of treatment.

Additional tools are available to assist clinicians to identify and manage drug interactions, such as the Liverpool COVID-19 Drug interaction checker.

For complete details on drug interactions, please refer to the Product Information – Paxlovid® approved by the Therapeutic Goods Administration (TGA).

Table 1

PBS eligibility criteria nirmatrelvir and ritonavir, and molnupiravir from 1 March 2024 1,2

Patient population	PBS eligibility criteria for nirmatrelvir and ritonavir	PBS eligibility criteria for molnupiravir
Adults 70 years or older	Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised nirmatrelvir and ritonavir if: treatment is commenced within 5 days of onset of symptoms, or treatment is initiated as soon as possible after diagnosis is confirmed when asymptomatic, and they do not require hospitalisation for COVID-19 infection at the time of prescribing. No further risk factors for progression to severe disease are required for PBS eligibility.	Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised molnupiravir if: nirmatrelvir and ritonavir combination is contraindicated, treatment is commenced within 5 days of onset of symptoms, or treatment initiated as soon as possible after diagnosis is confirmed when asymptomatic, and they do not require hospitalisation for COVID-19 infection at the time of prescribing. No further risk factors for progression to severe disease are required for PBS eligibility.
Adults 50 – 69 years of age	Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised nirmatrelvir and ritonavir if: treatment is commenced within 5 days of onset of symptoms, and they have at least one sign or symptom attributable to COVID-19; and they do not require hospitalisation for COVID-19 infection at the time of prescribing, and they have two risk factors for developing severe disease. Please see Table 2 for a list of risk factors for developing severe disease.	Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised molnupiravir if: nirmatrelvir and ritonavir combination is contraindicated, and treatment is commenced within 5 days of onset of symptoms, and they have at least one sign or symptom attributable to COVID-19; and they do not require hospitalisation for COVID-19 infection at the time of prescribing, and they have two risk factors for developing severe disease. Please see Table 2 for a list of risk factors for developing severe disease.
Adults 30 years or older identifying as First Nations people	First Nations adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised nirmatrelvir and ritonavir if: treatment is commenced within 5 days of onset of symptoms, and they have at least one sign or symptom attributable to COVID-19; and they do not require hospitalisation for COVID-19 infection at the time of prescribing, and they have one risk factor for developing severe disease. Please see Table 2 for a list of risk factors for developing severe disease.	First Nations adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised molnupiravir if: nirmatrelvir and ritonavir combination is contraindicated, treatment is commenced within 5 days of onset of symptoms, and they have at least one sign or symptom attributable to COVID-19; and they do not require hospitalisation for COVID-19 infection at the time of prescribing, and they have one risk factor for developing severe disease. Please see Table 2 for a list of risk factors for developing severe disease.
Adults 18 years or older	Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised nirmatrelvir and ritonavir if: treatment is commenced within 5 days of onset of symptoms, and they have at least one sign or symptom attributable to COVID-19; and they do not require hospitalisation for COVID-19 infection at the time of prescribing. AND they are moderately to severely immunocompromised, or have been previously hospitalised from COVID-19 disease, and subsequently re-infected. Please see Table 3 for definition of moderately to severely immunocompromised patients for the purpose of PBS eligibility of nirmatrelvir and ritonavir.	Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised molnupiravir if: nirmatrelvir and ritonavir combination is contraindicated, treatment is commenced within 5 days of onset of symptoms, and they have at least one sign or symptom attributable to COVID-19; and they do not require hospitalisation for COVID-19 infection at the time of prescribing. AND they are moderately to severely immunocompromised, or have been previously hospitalised from COVID-19 disease, and subsequently re-infected. Please see Table 3 for definition of moderately to severely immunocompromised patients for the purpose of PBS eligibility of nirmatrelvir and ritonavir.

Patient population

PBS eligibility criteria for nirmatrelvir and ritonavir

PBS eligibility criteria for molnupiravir

Adults 70 years or older

Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised nirmatrelvir and ritonavir if:

treatment is commenced within 5 days of onset of symptoms, or
treatment is initiated as soon as possible after diagnosis is confirmed when asymptomatic, and
they do not require hospitalisation for COVID-19 infection at the time of prescribing.

No further risk factors for progression to severe disease are required for PBS eligibility.

Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised molnupiravir if:

nirmatrelvir and ritonavir combination is contraindicated,
treatment is commenced within 5 days of onset of symptoms, or
treatment initiated as soon as possible after diagnosis is confirmed when asymptomatic, and
they do not require hospitalisation for COVID-19 infection at the time of prescribing.

No further risk factors for progression to severe disease are required for PBS eligibility.

Adults 50 – 69 years of age

Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised nirmatrelvir and ritonavir if:

treatment is commenced within 5 days of onset of symptoms, and
they have at least one sign or symptom attributable to COVID-19; and
they do not require hospitalisation for COVID-19 infection at the time of prescribing, and
they have two risk factors for developing severe disease.

Please see Table 2 for a list of risk factors for developing severe disease.

Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised molnupiravir if:

nirmatrelvir and ritonavir combination is contraindicated, and
treatment is commenced within 5 days of onset of symptoms, and
they have at least one sign or symptom attributable to COVID-19; and
they do not require hospitalisation for COVID-19 infection at the time of prescribing, and
they have two risk factors for developing severe disease.

Please see Table 2 for a list of risk factors for developing severe disease.

Adults 30 years or older identifying as First Nations people

First Nations adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised nirmatrelvir and ritonavir if:

treatment is commenced within 5 days of onset of symptoms, and
they have at least one sign or symptom attributable to COVID-19; and
they do not require hospitalisation for COVID-19 infection at the time of prescribing, and
they have one risk factor for developing severe disease.

Please see Table 2 for a list of risk factors for developing severe disease.

First Nations adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised molnupiravir if:

nirmatrelvir and ritonavir combination is contraindicated,
treatment is commenced within 5 days of onset of symptoms, and
they have at least one sign or symptom attributable to COVID-19; and
they do not require hospitalisation for COVID-19 infection at the time of prescribing, and
they have one risk factor for developing severe disease.

Please see Table 2 for a list of risk factors for developing severe disease.

Adults 18 years or older

Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised nirmatrelvir and ritonavir if:

treatment is commenced within 5 days of onset of symptoms, and
they have at least one sign or symptom attributable to COVID-19; and
they do not require hospitalisation for COVID-19 infection at the time of prescribing.

AND

they are moderately to severely immunocompromised, or
have been previously hospitalised from COVID-19 disease, and subsequently re-infected.

Please see Table 3 for definition of moderately to severely immunocompromised patients for the purpose of PBS eligibility of nirmatrelvir and ritonavir.

Adults with COVID-19 confirmed by a PCR or RAT test can be prescribed PBS-subsidised molnupiravir if:

nirmatrelvir and ritonavir combination is contraindicated,
treatment is commenced within 5 days of onset of symptoms, and
they have at least one sign or symptom attributable to COVID-19; and they do not require hospitalisation for COVID-19 infection at the time of prescribing.

AND

they are moderately to severely immunocompromised, or
have been previously hospitalised from COVID-19 disease, and subsequently re-infected.

Please see Table 3 for definition of moderately to severely immunocompromised patients for the purpose of PBS eligibility of nirmatrelvir and ritonavir.

^{For complete information on the PBS listings for nirmatrelvir and ritonavir (Paxlovid®) and molnupiravir (Lagevrio®), including eligibility criteria, please refer to the PBS website at www.pbs.gov.au by using the search term “Paxlovid” or “Lagevrio” respectively.}

Table 2

List of risk factors contributing to the PBS definition of high risk for development of severe disease 1,2

Risk Factors
	The patient is in residential aged care
	The patient has disability with multiple comorbidities and/or frailty
	Neurological conditions, including stroke and dementia and demyelinating conditions
	Respiratory compromise, including COPD, moderate or severe asthma (required inhaled steroids), and bronchiectasis, or caused by neurological or musculoskeletal disease
	Heart failure, coronary artery disease, cardiomyopathies
	Obesity (BMI greater than 30 kg/m2)
	Diabetes type I or II, requiring medication for glycaemic control
	Renal impairment (eGFR less than 60mL/min)
	Cirrhosis
	The patient has 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
	Past COVID-19 infection episode resulting in hospitalisation

Table 3

Definition of moderately to severely immunocompromised adults at high risk of severe disease for the purpose of PBS eligibility 1,2

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 a month, or pulse corticosteroid therapy, Biological agents and other treatments that deplete or inhibit B cell or T cell function (abatacept, 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, leflunomide, azathioprine, 6 mercaptopurine (at least 1.5mg/kg/day), alkylating agents (e.g. cyclophosphamide, chlorambucil), and systemic calcineurin inhibitors (e.g. cyclosporin, tacrolimus).
Any significantly immunocompromising condition(s) where, in the last 12 months the patient has received anti-CD20 monoclonal antibody treatment, including rituximab, ocrelizumab, ofatumumab and obituzumab
Patients with very high-risk conditions including Down Syndrome, cerebral palsy, congenital heart disease, thalassemia, sickle cell disease and other haemoglobinopathies
People with disability with multiple comorbidities and/or frailty.

^{Paxlovid® (nirmatrelvir and ritonavir) Pharmaceutical Benefits Scheme. Canberra: Australian Government Department of Health and Aged Care; 2024 Available from:}^{https://www.pbs.gov.au/medicine/item/12996B 13147Y}^{(accessed 6 June 2024).}
^{Lagevrio® (molnupiravir) Pharmaceutical Benefits Scheme. Canberra: Australian Government Department of Health and Aged Care; 2024. Available from:}^{https://www.pbs.gov.au/medicine/item/12910L-13144T}^{(accessed 6 June 2024).}
^{Therapeutic Goods Administration. Australian Product Information – Paxlovid® (nirmatrelvir/ritonavir tablets) Available from:}^{https://www.tga.gov.au/resources/artg/377572}^{(accessed 30 April 2024)}