Treating COVID-19 with Paxlovid in primary care

8 minutes to Read + 7 minutes to Delve
Contributor
Eamon Duffy
31 March 2022
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Introduction to nirmatrelvir/ritonavir (Paxlovid)

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 like 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.

Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) is listed on the pharmaceutical schedule from 1 April 2022 and will be available from nominated pharmacies in early April.

It is indicated for:

  • treatment of acute symptomatic 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.2

In patients who:

Treatment should be initiated as early as possible and within five days of symptom onset.2

A Science Brief from the Ontario COVID-19 Science Advisory Table is also linked 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.


Activity and dosing

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

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 – 60mL/min/1.73m2). Paxlovid is not currently recommended for patients with eGFR below 30mL/min/1.73m2.2 Pharmacists adjusting the dose for this purpose may refer to information provided by the supplier, or the tablets may be repackaged in a compliance pack.

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. It was initially used as a direct-acting antiviral at much higher doses and is used now as a pharmacokinetic booster.4


Evidence base – clinical effect

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.


Drug–drug interactions

For many eligible patients with multiple co-morbidities, careful management of drug-drug interactions will be necessary.

Ritonavir is a strong inhibitor of CYP3A4, CYP2D6, p-glycoprotein (PGP) and some other transporter proteins (BRCP, OATP-C and MRP). The effect is almost immediate on starting and lasts for several days after stopping. The effect on other cytochrome enzymes (eg, CYP2C19 or 1A2) is less concerning due to a weaker inhibition and a more prolonged onset of action, so with a five-day course there is minimal clinical impact.

Potential drug interactions need to be carefully considered ideally by a clinician familiar with the patient and their comorbidities. A careful patient history should be taken to identify current medicines, natural or complementary therapies and recreational drug use (especially methamphetamine).

To assess the risk of interactions, the University of Liverpool’s COVID-19 interaction checker should be used and then the Ontario Science Brief should be consulted for specific advice on management of interactions.

Other useful pages that can be found on the Liverpool website include a flow chart "Assessing a patient for treatment with Paxlovid" and drug interaction tables "Interactions with selected WHO essential medicines and Paxlovid". The Medsafe data sheet and New Zealand Formulary are also reliable resources but may not be updated as quickly and frequently as the Liverpool and Ontario websites.

Interactions are generally displayed in a tiered manner:

  • RED (Do not co-administer/avoid combination)
  • ORANGE (Potential interaction; modify dose or monitor)
  • GREEN (No interaction expected)

Red level interactions are simple to manage; nirmatrelvir/ritonavir cannot be used. This is either because a co-medication reduces nirmatrelvir to sub-therapeutic concentrations by CYP3A4 induction or because ritonavir will change the concentration of the co-medicine that cannot be easily withheld or safely adjusted. Another COVID-19 treatment should be considered instead. Examples of red level interactions include:

  • CYP3A4 inducers: rifampicin, phenytoin, St John’s wort and carbamazepine
  • CYP3A4 or 2D6 substrates (increased by ritonavir): amiodarone, clozapine, tacrolimus, cyclosporin, flecainide, rivaroxaban.

Orange level interactions may produce significant toxicity or impaired efficacy of either drug. Careful considerations need to be made and communicated clearly with the patient. The patient, prescriber and pharmacist should all be involved in the medicine management plan. These interactions can be managed in one of four ways:

  1. Withhold/pause the interacting medicine.
  2. Adjust the dose of the interacting medicine (usually not feasible – see below).
  3. Counsel patients to monitor for side effects and advise to call if they occur.
  4. Choose an alternative COVID-19 treatment.

Consider if the medicine can be withheld without causing any patient harm. A good example is simvastatin. Concentrations are markedly increased with ritonavir and put the patient at high risk of rhabdomyolysis. Simvastatin should be withheld and restarted two to three days after stopping Paxlovid (ie, stop simvastatin for a week).

Adjusting the dose of the interacting medicine is often not feasible unless the half-life is very short and it has a wide therapeutic window. Examples of medicines where dose adjustment is not usually feasible include amiodarone due to its long half-life and tacrolimus due its narrow therapeutic window. Amlodipine is a good example of a medicine that could be dose-reduced during therapy.

Some medicines could be continued with a small risk of increased adverse effects due to increased concentrations. An example is warfarin, which for many people with stable INR, a modest change in concentration, and therefore INR, would not be harmful. Advising patients to be vigilant to monitor for signs of bruising or bleeding and call if it occurs could be appropriate, as is monitoring INR if clinically indicated.

An alternative COVID-19 treatment may be the best option if there are RED interactions or unmanageable ORANGE interactions. See HealthPathways for currently available alternatives and how to access these for eligible patients.


Other contraindications

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.


Side effects

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).


5 key management points for prescribers

1. Assess patient eligibility for nirmatrelvir/ritonavir (Paxlovid)

2. Assess drug–drug interactions and contraindications

3. Develop and document a medication management plan with the patient

4. Communicate the medication management plan to the dispensing pharmacist

5. Prescribe appropriate dose for renal function


5 key management points for dispensing pharmacists

1. Check patient meets access criteria for nirmatrelvir/ritonavir (Paxlovid)

2. Assess drug–drug interactions

3. Check prescriber has modified co-medicines appropriately

4. Check dosing for renal function

5. Counsel patient to ensure understanding of the dosing regimen and changes to co-medicines

  • Notify patient’s usual pharmacist (if not dispensing pharmacist) of the medication management plan


Self-audit reflection activity

This activity allows primary care prescribers to self-assess their use of oral antiviral medicines for the treatment of patients with COVID-19. Endorsed by the RNZCGP for up to two CME credits for Continuing Professional Development purposes, the self-audit reflection activity may also be adapted to suit the learning needs of dispensing pharmacists and primary care nurses.

The activity is formatted as an editable PDF, please note that this will not automatically save to your device. You must download the document, save it to your device, and then fill it in.

Click here to complete the self-audit reflection activity.

Acknowledgements

Written by:

Eamon Duffy BPharm - Lead Antimicrobial Stewardship Pharmacist, Pharmacy and Infectious Disease, ADHB

Reviewed by:

Dr Justine Lancaster MBChB, DCH, DipObs, FRNZCGP - Clinical Lead, COVID Care in Community, Health System Preparedness Programme

Bronwen Shepherd BPharm, MPS - Community Pharmacist Advisor, COVID Care in Community, Health System Preparedness Programme

Professional college endorsements

This activity has been endorsed by The Royal New Zealand College of General Practitioners (RNZCGP) and has been approved for 0.25 CME credits for Continuing Professional Development (CPD) purposes. To claim your credits, log in to your RNZCGP dashboard to record this activity in the CME component of your CPD programme.

This activity has been endorsed by the Pharmaceutical Society of NZ Inc (PSNZ) as suitable for inclusion in a pharmacist’s CE records for Continuing Professional Development (CPD) purposes.

RNZCGP logoPSNZ logo

References

1. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of Antibodies and Antiviral Drugs against Covid-19 Omicron Variant. New England Journal of Medicine 2022;386:10 (26 January 2022). DOI: 10.1056/NEJMc2119407.

2. New Zealand Ministry Health. Medsafe data sheet (Paxlovid). https://medsafe.govt.nz/profs/Datasheet/p/paxlovidtab.pdf Accessed March 2022.

3. US National Institutes of Health. COVID-19 Treatment Guidelines: Ritonavir-boosted nirmatrelvir (Paxlovid). www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir--paxlovid-/ Accessed March 2022.

4. Roberts JA, Duncan A, Cairns KA. Pandora’s box: Paxlovid, prescribing, pharmacists and pandemic. Journal of Pharmacy Practice and Research 2022;52(1):1-4. https://doi.org/10.1002/jppr.1799

5. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19. New England Journal of Medicine (16 February 2022). DOI: 10.1056/NEJMoa2118542.

6. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA. 2. New England Journal of Medicine (9 March 2022). DOI: 10.1056/NEJMc2201933.

7. New Zealand Ministry of Health. COVID-19: Case demographics. https://www.health.govt.nz/covid-19-novel-coronavirus/covid-19-data-and-statistics/covid-19-case-demographics.

8. New Zealand Ministry of Health. COVID-19: Higher risk people. www.health.govt.nz/covid-19-novel-coronavirus/covid-19-information-specific-audiences/covid-19-higher-risk-people Accessed March 2022.

Other resources

Marzolini C, Kuritzkes DR, Marra F, et al. Prescribing Nirmatrelvir–Ritonavir: How to Recognize and Manage Drug–Drug Interactions. Annals of Internal Medicine (1 March 2022). https://doi.org/10.7326/M22-0281

Roberts JA, Duncan A, Cairns KA. Pandora’s box: Paxlovid, prescribing, pharmacists and pandemic. Journal of Pharmacy Practice and Research 2022;52(1):1-4. https://doi.org/10.1002/jppr.1799

Pharmac. Proposal on access criteria for two oral COVID-19 treatments. 16 February 2022. https://pharmac.govt.nz/news-and-resources/consultations-and-decisions/2022-02-16-proposal-on-access-criteria-for-two-oral-covid-19-treatments

Pharmac. New Zealand’s COVID-19 treatments portfolio. https://pharmac.govt.nz/news-and-resources/covid19/treatcovid Accessed March 2022.

Content updates

  • 9 June 2022: The Ontario Science Brief link was updated from version 2.0 to version 3.0 (Published by the Ontario COVID-19 Science Advisory Table on 6 June 2022).
  • 9 June 2022: The statistic relating to reduction in hospitalisation/death (Evidence Base section) was updated from 88 per cent to 89 per cent.
  • 12 July 2022: Pfizer Medical Information contact details added to "Other useful links".