Treating COVID-19 with Paxlovid in primary care

A number of treatments have become available, both in New Zealand and internationally, for the management of COVID-19. Early studies identified treatments, such as dexamethasone and tocilizumab, which reduced mortality for severely unwell patients admitted to hospital.

As the pandemic has continued, further treatments have been developed that are primarily intended to prevent early disease progression. These include parenteral treatments, such as casirivimab-imdevimab and remdesivir, which have operational and logistical barriers to their use in the primary care setting. Some novel therapeutics have been found to have reduced efficacy with variant shift, especially with anti-spike monoclonal antibodies and dramatic changes in binding domains.¹ The newer antiviral oral therapies such as nirmatrelvir/ritonavir (Paxlovid) provide an option for a more feasible and expedient access to treatment for eligible patients in a community setting. This article summarises the evidence and key considerations for use of nirmatrelvir/ritonavir for your patients.

A Science Brief from the Ontario COVID-19 Science Advisory Table is available and contains helpful advice, especially around managing drug–drug interactions. It should be noted that the Science Brief is developed for Canada and therefore some medicines available in New Zealand are not included. Access criteria may also differ due to differences in Canadian and New Zealand epidemiology, local risk factors, and supply.

To ensure safe prescribing and dispensing, it is paramount that clinicians are familiar with the medicine precautions, contraindications and interactions, and perform a thorough clinical assessment of each patient. This will require prescribers and pharmacists to work collaboratively on a case-by-case basis to ensure a full clinical evaluation and timely delivery of treatment.

Nirmatrelvir is a novel antiviral that inhibits the main protease enzyme (Mpro or 3CL-protease) of SARS-CoV-2. The Mpro is a critical enzyme for the virus that cleaves a number of proteins to enable viral replication.²

Nirmatrelvir has a relatively short half-life, so it requires combined use with ritonavir to maintain therapeutic concentrations sufficient to inhibit viral replication. Ritonavir has no activity against SARS-CoV-2 itself but is used as a pharmacokinetic “boosting” agent.³

Ritonavir is a known potent cytochrome P450 inhibitor that enables nirmatrelvir to be given only twice a day rather than multiple times a day. The key issue with ritonavir is that, in addition to reducing clearance (ie, increasing concentrations) of nirmatrelvir, it also does this to a number of other medicines that rely on the CYP3A4 and CYP2D6 clearance pathways.^2,3

There is a lot of experience in using ritonavir internationally, especially among HIV clinicians, as it has been a key component of antiretroviral therapies for many years.⁴

The treatment course of Paxlovid is 30 tablets: two 150mg tablets of nirmatrelvir and one 100mg tablet of ritonavir are to be taken together twice a day for five days.²

A dose reduction of nirmatrelvir is required for patients with moderate renal impairment (eGFR 30–59mL/min/1.73m²): one 150mg tablet of nirmatrelvir and one 100mg tablet of ritonavir are to be taken together twice a day for five days.^2a

The New Zealand data sheet for Paxlovid states it is contraindicated for patients with severe renal impairment (eGFR <30mL/min/1.73m²) due to a lack of data. However, recent changes to the Ontario treatment guideline supports consideration of reduced dosing in renal failure.^2,2a

Use of Paxlovid in severe renal impairment is not approved in New Zealand; the clinician is required to explain to the patient that there is limited evidence and gain informed consent before prescribing.

In severe renal impairment (<30mL/min/1.73m²) after careful risk-benefit assessment, prescribers could consider: two 150mg tablets of nirmatrelvir and one 100mg tablet of ritonavir daily on day 1, then one 150mg tablet of nirmatrelvir and one 100mg tablet of ritonavir daily for 4 days.^2a

As this regimen is off-label it can only be provided pursuant to a prescription from a registered prescriber; pharmacist-only supply cannot occur through the accredited scheme. Pharmacists dispensing reduced doses may refer to information provided by the supplier, or the tablets may be repackaged in a compliance pack.

Dosing of Paxlovid in patients on dialysis or with renal transplants should be discussed with a renal dialysis team or transplant specialist, respectively.^2a

The EPIC-HR study has demonstrated benefit of nirmatrelvir/ritonavir in early COVID-19 disease by preventing hospitalisation. This study, conducted in 2021, randomised symptomatic, unvaccinated, high-risk, non-hospitalised patients to either nirmatrelvir/ritonavir or placebo.⁵

In patients treated with nirmatrelvir/ritonavir within three to five days of symptom onset, 89 per cent less hospitalisation or death was seen compared to placebo (1 per cent vs 7 per cent). The earlier the treatment was given in illness the greater the effect size; the number needed to treat (NNT) was 18 if given within five days.⁵

While the studies were conducted in a Delta setting, in vitro laboratory testing has demonstrated sustained potency against the Omicron variant and clinical efficacy is expected to be preserved.⁶

It is also important to note that this research was undertaken in unvaccinated patients.⁵ While the antiviral effect is expected to occur whether or not someone has been vaccinated, the net effect on reduction in hospitalisation will be markedly reduced for vaccinated patients. In New Zealand as of mid-March 2022, the hospitalisation rate for unvaccinated patients is 4.5 per cent while for fully vaccinated patients it is 0.5 per cent.⁷ A 90 per cent reduction in hospitalisation therefore means that treating 1000 patients in each group might prevent 40 unvaccinated people and four or five vaccinated people from being admitted to hospital.

The rate of hospitalisation is greater for those people with more co-morbidities, older age and severe immunosuppressing disorders that limit their ability to mount an adequate vaccine response. Māori and Pacific peoples have also been disproportionately affected by COVID-19 and are more likely to progress to severe disease due to disparate rates of co-morbidities, increased barriers to vaccination, and social determinants of health.⁸ Therefore, prioritising these groups for treatment is expected to have the greatest benefit for both these communities and the New Zealand health system.

For most fully vaccinated people, it is likely that treatment with nirmatrelvir/ritonavir will offer little benefit.

As such, Pharmac has set access criteria following advice from their Therapeutic Advisory Committee and public consultation.

Ritonavir may cause liver damage, so caution should be exercised when giving Paxlovid to patients with pre-existing liver disease, liver enzyme abnormalities or hepatitis. No pharmacokinetic or safety data are available regarding the use of nirmatrelvir/ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, Paxlovid is contraindicated in patients with severe hepatic impairment.² Refer to the Paxlovid Medsafe data sheet for a full description of contraindications.

Common side effects of Paxlovid include impaired sense of taste, diarrhoea, vomiting and headache. Less commonly high blood pressure and muscle aches are reported.²

As a new medicine in New Zealand any adverse events must be reported to the Centre for Adverse Reactions Monitoring (CARM).