Nirmatrelvir, ritonavir (Paxlovid▼): be alert to the risk of drug interactions with ritonavir

There is a risk of harmful drug interactions with the ritonavir component of the COVID-19 treatment Paxlovid▼ due to its inhibition of the enzyme CYP3A, which metabolises many commonly used drugs. Prescribers should obtain a detailed patient history of current medications before prescribing Paxlovid, checking the Paxlovid product information for known and potential drug interactions.

From:
Medicines and Healthcare products Regulatory Agency
Published
23 November 2023
Therapeutic area:
Immunology and vaccination, Infectious disease, Respiratory disease and allergy

Advice for healthcare professionals:

  • there is a risk of potentially serious drug interactions with the ritonavir component of Paxlovid leading to increased toxicity from, or reduced effectiveness of concomitant medications
  • ritonavir is a potent CYP3A4 inhibitor that acts to boost the plasma levels of the nirmatrelvir component of Paxlovid by preventing its degradation; as many commonly used drugs are metabolised by CYP3A4, the risk of harmful drug interactions with Paxlovid is significant
  • drug interactions may also reduce the effectiveness of Paxlovid, in the treatment of COVID-19
  • obtain a thorough history of patients’ current medications, including over the counter (OTC) medications, herbal remedies and illicit or recreational drug use
  • refer to the Paxlovid Summary of Product Characteristics (SmPC) (especially sections 4.3, 4.4 and 4.5) before prescribing Paxlovid to check for contraindications and potential interactions – links to other resources to assist with this are available below
  • remind patients to read the Patient Information Leaflet (PIL) and to be vigilant for any adverse reactions, seeking medical advice when required
  • report suspected adverse drug reactions associated with Paxlovid on a Yellow Card

Advice for healthcare professionals to provide to patiens:

  • Paxlovid is used to treat COVID-19 infection in patients at risk of developing severe disease
  • Paxlovid is an antiviral medicine composed of 2 drugs called ritonavir and nirmatrelvir
  • ritonavir can affect how other medicines work, potentially leading to harmful effects
  • because of this risk, your doctor or healthcare provider should ask you detailed questions about which medicines you are currently taking before prescribing Paxlovid and it is important that you mention all medicines that you use, including over the counter (without prescription) medicines, herbal remedies and any recreational drug use
  • it is important not to change or stop taking any medications before discussing this with a healthcare professional
  • please read the leaflet that accompanies your medicine and be vigilant for any side effects
  • if you are concerned about a potential side effect after taking Paxlovid or any other medication, seek advice from a healthcare professional and submit a Yellow Card

Risk of adverse drug interactions with Paxlovid

Nirmatrelvir and ritonavir (Paxlovid 150mg/100mg film-coated tablets) is an anti-viral treatment that is indicated for the treatment of COVID-19 in adults who do not require supplemental oxygen and who are at increased risk of progression to severe COVID-19.

Paxlovid should be given as soon as possible after positive results of SARS-CoV-2 viral testing and within 5 days of onset of symptoms. The approved dose is 300mg nirmatrelvir (two 150mg tablets) with 100mg ritonavir (one 100mg tablet) all taken together, orally twice daily, for 5 days.

Prescribing of Paxlovid to eligible patients in England has recently transferred from Covid Medicines Delivery Units (CMDUs) to primary care providers. The MHRA sought advice from members of the COVID-19 Therapeutics Expert Working Group (EWG) and Commission on Human Medicines (CHM) in February 2022 about communicating the risks of drug interactions with Paxlovid via a DSU article. The publication of a DSU was supported by members of the CHM and the EWG in the event of Paxlovid deployment becoming more widespread.

The ritonavir component of Paxlovid is not active against SARS-CoV-2 but inhibits the CYP3A-mediated metabolism of nirmatrelvir (the active antiviral), thereby increasing plasma concentrations of nirmatrelvir. It is this CYP3A inhibitory activity of ritonavir that poses a risk of harmful drug interactions with Paxlovid.

Harmful interactions can occur with many medicines. Section 4.3 of the (SmPC) lists all the drugs with which Paxlovid is contraindicated and must not be co-administered, including commonly-used medicines such as analgesics, antibiotics and antihistamines, and more specialized treatments such as antianginal drugs, anticancer drugs and anticonvulsants. Use of Paxlovid with these medicines may lead to serious or life-threatening side effects.

Section 4.5 of the (SmPC) lists medicines which may lead to potentially significant interactions with Paxlovid, and where Paxlovid should be considered only if the benefits outweigh the risks.

Healthcare professionals must review these sections of the (SmPC) in detail before prescribing Paxlovid.

The risks of potential drug interactions when taking Paxlovid, and what actions to take if an adverse event occurs, should be explained to patients by the prescriber. Paxlovid is also contraindicated in patients with hypersensitivities to nirmatrelvir, ritonavir or any of the listed excipients, and in patients with severe renal and / or hepatic impairment.

Patients should be reminded to read the Patient Information Leaflet (PIL) and speak to a healthcare professional if they have questions.

Resources to assist prescribers of Paxlovid

There are several online resources available to aid in the safe prescribing of Paxlovid1[footnote 1]:

Specialist Pharmacy Service (SPS): Using nirmatrelvir and ritonavir (Paxlovid) in practice sets out comprehensive information on checking interacting medicines as well as other safety-related issues. This guidance also includes links to specific patient information, including:

The SPS clinical enquiry answering service supports primary care healthcare professionals in England with questions about Paxlovid. Contact details can be found via Medicines Advice contact details – SPS - Specialist Pharmacy Service – The first stop for professional medicines advice.

In addition, the University of Liverpool hosts several online resources which provide information about the safe prescribing of Paxlovid, such as the Liverpool COVID-19 Interaction Checker. The University has also created a flowchart to aid prescribers in the identification of potential unsafe prescribing regarding patient concomitant medications. You can access the flowchart by selecting the first link under the heading ‘Resources for nirmatrelvir/ritonavir (Paxlovid; 5 day administration)’ available on this page: Liverpool COVID-19 Interactions (covid19-druginteractions.org).

Report any suspected adverse drug reactions

Please continue to report suspected adverse drug reactions to Paxlovid via the Yellow Card scheme. Your report will help us safeguard public health. Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting, please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Article citation: Drug Safety Update volume 17, issue 4: November 2023: 2.

  1. Resources accessed on 6 November 2023. The MHRA is not responsible for the content of external websites. ↩

Published 23 November 2023