Oral Medicines Receive FDA Authorization for COVID Treatment for the First Time: Paxlovid and Covinavir (Molnupiravir)

On 22 December 2021, the FDA (US Food and Drug Administration) granted Emergency Use Authorization for adults and pediatric patients who tested positive for SARS-CoV-2 and were at high risk of severe COVID-19, including hospitalization or death (over age 12 and weighing 40 kilograms or more), for Pfizer's Paxlovid. This made it the first oral medicine to receive FDA authorization for COVID-19 treatment. A day later, on 23 December, the FDA granted Emergency Use Authorization for the treatment of adult patients who tested positive for SARS-CoV-2, were at risk of progression to severe disease, and could not access alternative COVID-19 treatments or for whom those alternatives were not clinically appropriate, for Merck's Molnupiravir (brand name Covinavir).

Both medicines are available by prescription only, and starting them as soon as possible after a COVID-19 diagnosis and within five days of symptom onset is considered appropriate. Patrizia Cavazzoni, director of the FDA's Center for Drug Evaluation and Research, says these authorizations represent the first oral treatments for COVID-19 and a major step forward in the fight against the global pandemic.

Cavazzoni said of Paxlovid, "This authorization provides a new tool to combat COVID-19 at a critical time in the pandemic as new variants emerge, and promises to make antiviral treatment more accessible to patients at high risk of progressing to severe COVID-19", and of Covinavir, "Molnupiravir will be a useful treatment option for certain COVID-19 patients at high risk of hospitalization or death when other FDA-approved COVID-19 treatments are not accessible or are not clinically appropriate for the patient" (see molnupiravir's Trojan horse-like mechanism of action).

"As new coronavirus variants continue to emerge, expanding the United States' COVID-19 treatment options through emergency use authorization and continuing to generate additional data about their safety and effectiveness is essential."

Paxlovid

Paxlovid is recommended only early in the course of illness in people diagnosed with COVID who are not hospitalized. It is not authorized for prophylaxis/prevention, meaning prevention of COVID-19 before or after exposure to the virus, or for initiation of treatment in people who need hospitalization for severe COVID-19. It also does not replace a COVID-19 vaccine.

Mechanism of action

Paxlovid contains a medicine that inhibits a SARS-CoV-2 protein to stop viral replication, nirmatrelvir, and a medicine that slows nirmatrelvir's breakdown to help it remain in the body longer at higher concentrations, ritronavir. In other words, it is a combination of two pills.

Paxlovid dosage

The 30-tablet treatment consists of 3 tablets (two nirmatrelvir tablets and one ritonavir tablet) taken twice daily for five days. Paxlovid is not authorized for use for more than five days.

Paxlovid Efficacy Study

Initial data for Emergency Use Authorization came from EPIC-HR, a randomized, double-blind, placebo-controlled clinical trial investigating Paxlovid for treating symptomatic, nonhospitalized adults with laboratory-confirmed SARS-CoV-2 infection. The patient group included adults over age 18, older people with a prespecified risk factor for developing severe disease, or people age 60 and over regardless of a chronic medical condition. None had previously had COVID-19 or received a COVID-19 vaccine.

The study outcome was assessed by the proportion of people hospitalized for COVID-19 or who died from any cause during 28 days of follow-up. Among patients treated within five days of symptom onset who did not receive COVID-19 therapeutic monoclonal antibodies, Paxlovid, compared with placebo, reduced the proportion hospitalized for COVID-19 or who died from any cause by up to 88%. In this analysis, 1039 patients received Paxlovid and 1046 received placebo. Of these patients, 0.8% receiving Paxlovid were hospitalized or died during 28 days of follow-up, compared with 6% receiving placebo. This difference is substantial. Paxlovid's safety and effectiveness for treating COVID-19 continue to be evaluated.

Paxlovid Side Effects

Possible side effects of Paxlovid include an impaired sense of taste, diarrhea, high blood pressure and muscle aches. Taking it alongside certain other medicines may cause potentially significant drug interactions.

Ritonavir may cause liver damage. Caution is therefore necessary when using Paxlovid in patients with preexisting liver disease, liver enzyme abnormalities or liver inflammation. Because Paxlovid works partly by inhibiting a group of enzymes that break down certain drugs, it is contraindicated with certain medicines that are highly dependent on these enzymes for metabolism and for which high concentrations are associated with serious and/or life-threatening reactions.

Taking Paxlovid with medicines that strongly induce the same enzymes and cause nirmatrelvir or ritonavir to break down faster is also contraindicated, because this may lower their concentrations and potentially result in loss of virologic response and development of viral resistance. Paxlovid is not started immediately after stopping these medicines, since their effects persist after discontinuation.

For a complete list of medicines that should not be taken with Paxlovid, consulting the FDA fact sheet is recommended.

Paxlovid is also not recommended for patients with severe kidney or liver impairment. A reduced dose is recommended for moderate kidney impairment. Patients with kidney or liver problems should consult specialists about whether Paxlovid is appropriate for them.

What is the price of Paxlovid?

The reported price per box of Paxlovid was approximately 530 dollars. Pfizer had also promised to provide the prescription medicine to US citizens without an additional charge during the pandemic.

Paxlovid is currently unavailable in Türkiye.

Covinavir

Covinavir is not authorized for patients under age 18 because it may affect bone and cartilage growth. Like Paxlovid, it is not authorized for use before or after exposure to the virus. Nor is it authorized for initiation of treatment after hospitalization for COVID-19, since no benefit was seen in people whose treatment began after admission.

Mechanism of action

Covinavir works by introducing errors into the SARS-CoV-2 virus's genetic code, preventing further replication. The 40-tablet treatment consists of 200mg tablets taken four times daily at 12-hour intervals for five days, and is not authorized for use for more than five days.

Covinavir Efficacy Study

Initial data for Emergency Use Authorization came from MOVe-OUT, a randomized, double-blind, placebo-controlled clinical trial investigating Molnupiravir in nonhospitalized patients with mild to moderate COVID-19 at high risk of developing severe COVID-19 and/or hospitalization. Participants were adults age 18 and over who had not received a COVID-19 vaccine and had a chronic medical condition or were otherwise at high risk of SARS-CoV-2 infection.

The study outcome was measured by the proportion of people hospitalized or who died from any cause during 29 days of follow-up. Of 709 people receiving Molnupiravir, 6.8% were hospitalized or died, compared with 9.7% of 699 people receiving placebo. One person receiving Molnupiravir died during follow-up, compared with 9 receiving placebo. Molnupiravir's safety and effectiveness for treating COVID-19 continue to be evaluated.

Covinavir Side Effects

Side effects observed during the trial included diarrhea, nausea and dizziness.

Findings from animal reproduction studies suggest Molnupiravir may cause fetal harm when used during pregnancy. It is therefore not recommended during pregnancy. It may be prescribed only after determining that the benefits outweigh the risks for that patient and after a specialist has explained the potential benefits and risks to the pregnant individual. Women considering pregnancy are advised to use a reliable contraceptive method correctly and consistently during Molnupiravir treatment and for four days afterward. Men taking Molnupiravir are also advised to use reliable contraception correctly and consistently during treatment and for at least three months afterward.

What is Emergency Use Authorization?

When deciding whether to issue an Emergency Use Authorization (EUA), which involves regulations different from FDA approval, the FDA evaluates all available scientific evidence and carefully balances known or potential risks against known or potential benefits.

Based on its review of all available scientific evidence, the FDA determined that Paxlovid may be effective for treating mild to moderate COVID-19 in authorized patients, and that Molnupiravir may be effective in certain adults with mild to moderate COVID-19 who cannot access other COVID-19 treatments or for whom those treatments are not clinically appropriate. The FDA also stated that, when used under the specified conditions, the known and potential benefits of both medicines outweigh their risks. Neither Paxlovid nor Molnupiravir has an equivalent, approved and available alternative.

Under Emergency Use Authorization, fact sheets giving important information on the authorized use of Paxlovid and Covinavir for COVID-19 treatment are provided to healthcare personnel. They include dosage instructions, potential side effects and information on who may be prescribed the medicines.