US FDA authorises first oral antiviral to treat COVID

The US Food and Drug Administration (FDA) yesterday issued an Emergency Use Authorisation (EUA) for Pfizer’s Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults and paediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalisation or death. Paxlovid is available by prescription only and should be initiated as soon as possible after diagnosis of COVID-19 and within five days of symptom onset.

The authorisation introduces the first treatment for COVID-19 that is in the form of a pill that is taken orally, said Patrizia Cavazzoni, MD, Director, Center for Drug Evaluation and Research, FDA.

Cavazzoni, added, “This authorisation provides a new tool to combat COVID-19 at a crucial time in the pandemic as new variants emerge, and promises to make anti-viral treatment more accessible to patients who are at high risk for progression to severe COVID-19.”

Paxlovid is not authorised for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalisation due to severe or critical COVID-19. It is not a substitute for vaccination in individuals for whom COVID-19 vaccination and a booster dose are recommended. The FDA has approved one vaccine and authorised others to prevent COVID-19 and serious clinical outcomes associated with a COVID-19 infection, including hospitalisation and death. The FDA urges the public to get vaccinated and receive a booster, if eligible.

Paxlovid consists of nirmatrelvir, which inhibits a SARS-CoV-2 protein to stop the virus from replicating, and ritonavir, which slows down nirmatrelvir’s breakdown to help it remain in the body for a longer period at higher concentrations. Paxlovid is administered as three tablets (two tablets of nirmatrelvir and one tablet of ritonavir) taken together orally twice daily for five days, for a total of 30 tablets. Paxlovid is not authorised for use for longer than five consecutive days.

The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of scientific evidence available and carefully balances any known or potential risks with any known or potential benefits of the product. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that Paxlovid may be effective for the treatment of mild-to-moderate COVID-19 in authorised patients. The agency has also determined that the known and potential benefits of Paxlovid, when used consistent with the terms and conditions of the authorisation, outweigh the known and potential risks of the product. There are no adequate, approved and available alternatives to Paxlovid for the treatment of COVID-19.

The primary data supporting this EUA for Paxlovid are from EPIC-HR, a randomised, double-blind, placebo-controlled clinical trial studying Paxlovid for the treatment of non-hospitalised symptomatic adults with a laboratory-confirmed diagnosis of SARS-CoV-2 infection. Patients were 18 years of age and older with a pre-specified risk factor for progression to severe disease, or were 60 years and older regardless of pre-specified chronic medical conditions. All patients had not received a COVID-19 vaccine and had not been previously infected with COVID-19. The main outcome measured in the trial was the proportion of people who were hospitalised due to COVID-19 or died due to any cause during 28 days of follow-up. Paxlovid significantly reduced the proportion of people with COVID-19 related hospitalisation or death from any cause by 88 per cent compared to placebo among patients treated within five days of symptom onset and who did not receive COVID-19 therapeutic monoclonal anti-body treatment. In this analysis, 1,039 patients had received Paxlovid, and 1,046 patients had received placebo and among these patients, 0.8 per cent who received Paxlovid were hospitalised or died during 28 days of follow-up compared to six per cent of the patients who received placebo. The safety and effectiveness of Paxlovid for the treatment of COVID-19 continue to be evaluated.

Possible side effects of Paxlovid include impaired sense of taste, diarrhoea, high blood pressure and muscle aches. Using Paxlovid at the same time as certain other drugs may result in potentially significant drug interactions. Using Paxlovid in people with uncontrolled or undiagnosed HIV-1 infection may lead to HIV-1 drug resistance. Ritonavir may cause liver damage, so caution should be exercised when giving Paxlovid to patients with pre-existing liver diseases, liver enzyme abnormalities or liver inflammation.

Since Paxlovid works, in part, by inhibiting a group of enzymes that break down certain drugs, it is contraindicated with certain drugs that are highly dependent on those enzymes for metabolism and for which elevated concentrations of certain drugs are associated with serious and/or life-threatening reactions. Paxlovid is also contraindicated with drugs that, conversely, strongly induce those same enzymes, leading to the faster breakdown of nirmatrelvir or ritonavir, as reduced concentrations of nirmatrelvir or ritonavir may be associated with potentially losing virologic response and developing viral resistance. Paxlovid cannot be started immediately after discontinuing such medications because the effects of those medications remain after discontinuation.