Paxlovid 150 mg/100 mg film-coated tablets

Paxlovid is indicated for the treatment of COVID‑19 in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID‑19 (see section 5.1).

Paxlovid is nirmatrelvir tablets co-packaged with ritonavir tablets.

Nirmatrelvir must be coadministered with ritonavir. Failure to correctly coadminister nirmatrelvir with ritonavir will result in plasma concentrations of nirmatrelvir that will be insufficient to achieve the desired therapeutic effect.

Posology

The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) all taken together orally twice daily every 12 hours for 5 days. Paxlovid should be given as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 5 days of onset of symptoms even if baseline COVID-19 symptoms are mild.

A missed dose should be taken as soon as possible and within 8 hours of the scheduled time, and the normal dosing schedule should be resumed. If more than 8 hours has elapsed, the missed dose should not be taken and the treatment should resume according to the normal dosing schedule.

If a patient requires hospitalisation due to severe or critical COVID-19 after starting treatment with Paxlovid, the patient should complete the full 5-day treatment course at the discretion of his/her healthcare provider.

Special populations

Paediatric population

The safety and efficacy of Paxlovid in paediatric patients younger than 18 years of age have not yet been established.

Elderly

No dosage adjustment is currently recommended for elderly patients.

Renal impairment

No dosage adjustment is needed in patients with mild renal impairment [estimated glomerular filtration rate (eGFR) ≥ 60 to < 90 mL/min].

In patients with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min) or with severe renal impairment (eGFR < 30 mL/min) including those requiring haemodialysis, the dosage of Paxlovid should be reduced as shown in Table 1. Paxlovid should be administered at approximately the same time each day for 5 days. On days patients with severe renal impairment undergo haemodialysis, the Paxlovid dose should be administered after haemodialysis (see section 5.2).

The remaining tablets should be disposed of in accordance with local requirements (see section 6.6).

Hepatic impairment

No dosage adjustment of Paxlovid is needed for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe (Child-Pugh Class C) hepatic impairment, therefore, Paxlovid is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).

Concomitant therapy with ritonavir- or cobicistat-containing regimen

No dosage adjustment is needed; the dose of Paxlovid is 300 mg/100 mg twice daily for 5 days.

Patients diagnosed with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) infection who are receiving ritonavir- or cobicistat-containing regimen should continue their treatment as indicated.

Method of administration

For oral use.

Paxlovid can be taken with or without food (see section 5.2). The tablets should be swallowed whole and not chewed, broken or crushed.

Paxlovid is contraindicated in patients:

- with a history of clinically significant hypersensitivity to the active substances (nirmatrelvir/ritonavir) or to any of the excipients listed in section 6.1.

- with severe hepatic impairment.

Paxlovid is also contraindicated with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life‑threatening reactions. Paxlovid is also contraindicated with medicinal products that are potent CYP3A inducers where significantly reduced plasma nirmatrelvir/ritonavir concentrations may be associated with the potential for loss of virologic response and possible resistance. Medicinal products listed in Table 2 and Table 3 (section 4.5) are a guide and not considered a comprehensive list of all possible medicinal products that may be contraindicated with Paxlovid.

a. See section 5.2, Interaction studies conducted with nirmatrelvir/ritonavir.

Risk of serious adverse reactions due to interactions with other medicinal products

Initiation of Paxlovid, a CYP3A inhibitor, in patients receiving medicinal products metabolised by CYP3A or initiation of medicinal products metabolised by CYP3A in patients already receiving Paxlovid, may increase plasma concentrations of medicinal products metabolised by CYP3A.

Initiation of medicinal products that inhibit or induce CYP3A may increase or decrease concentrations of Paxlovid, respectively.

These interactions may lead to:

• Clinically significant adverse reactions, potentially leading to severe, life-threatening or fatal events from greater exposures of concomitant medicinal products.

• Clinically significant adverse reactions from greater exposures of Paxlovid.

• Loss of therapeutic effect of Paxlovid and possible development of viral resistance.

Severe, life-threatening, and fatal adverse reactions due to drug interactions have been reported in patients treated with Paxlovid.

See Table 1 for medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir (see section 4.3) and Table 2 for potentially significant interactions with other medicinal products (see section 4.5). Potential for interactions should be considered with other medicinal products prior to and during Paxlovid therapy; concomitant medicinal products should be reviewed during Paxlovid therapy and the patient should be monitored for the adverse reactions associated with the concomitant medicinal products. The risk of interactions with concomitant medications during the 5-day treatment period for Paxlovid should be weighed against the risk of not receiving Paxlovid.

Coadministration of Paxlovid with calcineurin inhibitors and mTOR inhibitors

Consultation of a multidisciplinary group (e.g., involving physicians, specialists in immunosuppressive therapy, and/or specialists in clinical pharmacology) is required to handle the complexity of this coadministration by closely and regularly monitoring immunosuppressant blood concentrations and adjusting the dose of the immunosuppressant in accordance with the latest guidelines (see section 4.5).

Hypersensitivity reactions

Anaphylaxis, hypersensitivity reactions, and serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported with Paxlovid (see section 4.8). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue Paxlovid and initiate appropriate medications and/or supportive care.

Hepatotoxicity

Hepatic transaminase elevations, clinical hepatitis and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering Paxlovid to patients with pre-existing liver diseases, liver enzyme abnormalities or hepatitis.

HIV resistance

As nirmatrelvir is coadministered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

Excipients

Lactose

Nirmatrelvir tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

Nirmatrelvir and ritonavir tablets each contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium‑free'.

Paxlovid (nirmatrelvir/ritonavir) is a strong inhibitor of CYP3A and an inhibitor of CYP2D6, P-gp and OATP1B1. Coadministration of Paxlovid with medicinal products that are primarily metabolised by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of such medicinal products and increase the risk of adverse reactions.

Medicinal products that are extensively metabolised by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in exposure when coadministered with nirmatrelvir/ritonavir. Thus, coadministration of Paxlovid with medicinal products highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life‑threatening events is contraindicated (see Table 1, section 4.3).

In vitro study results showed nirmatrelvir may be inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9. The clinical relevance is unknown. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3 and OCT2. There is a potential for nirmatrelvir to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations.

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Ritonavir also has a high affinity for P‑glycoprotein (P-gp) and may inhibit this transporter. Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways and may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.

Coadministration of other CYP3A4 substrates that may lead to potentially significant interaction should be considered only if the benefits outweigh the risks (see Table 2).

Nirmatrelvir/ritonavir is a CYP3A substrate; therefore, medicinal products that induce CYP3A may decrease plasma concentrations of nirmatrelvir and ritonavir and reduce Paxlovid therapeutic effect.

Medicinal products listed in Table 2 (section 4.3) and Table 3 are a guide and not considered a comprehensive list of all possible medicinal products that may interact with nirmatrelvir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information.

Women of childbearing potential/Contraception in males and females

There are limited human data on the use of Paxlovid during pregnancy to inform the drug-associated risk of adverse developmental outcomes, women of childbearing potential should avoid becoming pregnant during treatment with Paxlovid.

Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment and until after one complete menstrual cycle after stopping Paxlovid (see section 4.5).

Pregnancy

There are limited data from the use of Paxlovid in pregnant women. Paxlovid should be used during pregnancy only if the potential benefits outweigh the potential risks for the mother and the foetus.

Animal data with nirmatrelvir have shown developmental toxicity in the rabbit (lower foetal body weights) but not in the rat. There was no nirmatrelvir-related effect on foetal morphology or embryo-foetal viability at any dose tested in rat or rabbit embryo-foetal developmental toxicity studies. There were no nirmatrelvir-related adverse effects in a pre- and postnatal developmental study in rats (see section 5.3).

A large number (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of these, 2800 live births were exposed during the first trimester. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other protease inhibitors, similar to the ritonavir dose used for nirmatrelvir/ritonavir. These data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data with ritonavir have shown reproductive toxicity (see section 5.3).

Breast-feeding

In a clinical pharmacokinetics study, 8 healthy lactating women who were at least 12 weeks postpartum were administered 3 doses (steady-state dosing) of 300 mg/100 mg nirmatrelvir/ritonavir. Nirmatrelvir and ritonavir were excreted in breastmilk in small amounts, with a milk to plasma AUC ratio of 0.26 and 0.07, respectively. The mean (range) estimated daily infant dose (assuming average milk consumption of 150 mL/kg/day), was 1.8% (1.3-2.5%) and 0.2% (0.1-0.3%) of the maternal dose.

There are no available data on the effects of nirmatrelvir or ritonavir on the breast‑fed newborn/infant or on milk production. A risk to the newborn/infant cannot be excluded. Breast‑feeding should be discontinued during treatment with Paxlovid and for 48 hours after the last dose of Paxlovid.

Fertility

There are no human data on the effect of Paxlovid on fertility. No human data on the effect of nirmatrelvir on fertility are available. Nirmatrelvir produced no effects on fertility in rats (see section 5.3).

There are no human data on the effect of ritonavir on fertility. Ritonavir produced no effects on fertility in rats.

There are no clinical studies that evaluated the effects of Paxlovid on ability to drive and use machines.

Summary of the safety profile

The safety of Paxlovid was based on data from three phase 2/3 randomised, placebo-controlled trials in non‑hospitalised adult participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection (see section 5.1).

• Study C4671005 (EPIC-HR) and Study C4671002 (EPIC-SR) investigated Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) every 12 hours for 5 days in symptomatic participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Participants were to present with mild-to-moderate COVID-19 at baseline.

• Study C4671006 (EPIC-PEP) investigated Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) every 12 hours for 5 or 10 days in asymptomatic household contact of individuals with a recent diagnosis of SARS-CoV-2 infection. Participants were to have a negative SARS-CoV-2 result at baseline.

Across the three studies, 3,515 participants received a dose of Paxlovid and 2,585 participants received a dose of placebo. The most common adverse reactions (≥1% incidence in the Paxlovid group and occurring at a greater frequency than in the placebo group) were dysgeusia (5.9% and 0.4%, respectively) and diarrhoea (2.9% and 1.9%, respectively).

The safety profile of Paxlovid in participants with severe renal impairment, including those requiring haemodialysis, was consistent with the safety profile observed in the placebo‑controlled trials.

Tabulated summary of adverse reactions

The adverse reactions in Table 4 are listed below by system organ class and frequency. Frequencies are defined as follows: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (frequency cannot be estimated from the available data).

Paediatric population

The safety and efficacy of Paxlovid in paediatric patients have not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Coronavirus Yellow Card Reporting site at https://coronavirus-yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

Treatment of overdose with Paxlovid should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with Paxlovid.

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors, ATC code: J05AE30.

Mechanism of action

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (M^pro), also referred to as 3C-like protease (3CL^pro) or nsp5 protease. Inhibition of the SARS-CoV-2 M^pro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication.

Ritonavir is not active against SARS-CoV-2 M^pro. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, thereby providing increased plasma concentrations of nirmatrelvir.

Antiviral activity

In vitro antiviral activity

Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 infection of differentiated normal human bronchial epithelial (dNHBE) cells, a primary human lung alveolar epithelial cell line (EC₅₀ value of 61.8 nM and EC₉₀ value of 181 nM) after 3 days of exposure.

The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7 (P252L+F294L), BF.7 (T243I), BQ.1.11, BQ.1, XBB.1.5, EG.5 and JN.1 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC₅₀ value of 88 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC₅₀ value fold‑changes ≤1.8 relative to the USA-WA1/2020 isolate.

In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvir had a median EC₅₀ value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptible variant tested, with an EC₅₀ value fold-change of 3.7 relative to USA‑WA1/2020. The other variants had EC₅₀ value fold-changes ≤1.1 relative to USA‑WA1/2020.

Antiviral resistance in cell culture and biochemical assays

SARS-CoV-2 M^pro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with M^pro substitutions, and biochemical assays with recombinant SARS-CoV-2 M^pro containing amino acid substitutions. Table 5 indicates M^pro substitutions and combinations of M^pro substitutions that have been observed in nirmatrelvir‑selected SARS-CoV-2 in cell culture. Individual M^pro substitutions are listed regardless of whether they occurred alone or in combination with other M^pro substitutions. Note that the M^pro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of M^pro. Substitutions at other M^pro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown.

In a biochemical assay using recombinant SARS-CoV-2 M^pro containing amino acid substitutions, the following SARS-CoV-2 M^pro substitutions led to ≥3-fold reduced activity (fold‑change based on Ki values) of nirmatrelvir: Y54A (25), F140A (21), F140L (7.6), F140S (230), G143S (3.6), S144A (46), S144E (480), S144T (170), H164N (6.7), E166A (35), E166G (6.2), E166V (7,700), P168del (9.3), H172Y (250), A173S (4.1), A173V (16), R188G (38), Q192L (29), Q192P (7.8), and V297A (3.0). In addition, the following combinations of M^pro substitutions led to ≥3-fold reduced nirmatrelvir activity: T21I+S144A (20), T21I+E166V (11,000), T21I+A173V (15), L50F+E166V (4,500), E55L+S144A (56), T135I+T304I (5.1), F140L+A173V (95), S144A+T304I (28), E166V+L232R (5,700), P168del+A173V (170), H172Y+P252L (180), A173V+T304I (28), T21I+S144A+T304I (51), T21I+A173V+T304I (55), L50F+E166A+L167F (180), T21I+L50F+A193P+S301P (7.3), L50F+F140L+L167F+T304I (190), and T21I+C160F+A173V+V186A+T304I (28). The following substitutions and substitution combinations emerged in cell culture but conferred <3‑fold reduced nirmatrelvir activity in biochemical assays: T21I (1.6), L50F (0.2), P108S (2.9), T135I (2.2), C160F (0.6), L167F (1.5), T169I (1.4), V186A (0.8), A191V (0.8), A193P (0.9), P252L (0.9), S301P (0.2), T304I (1.0), T21I+T304I (1.8), and L50F+T304I (1.3). The clinical significance of these substitutions is unknown.

Most single and some double M^pro amino acid substitutions identified which reduced the susceptibility of SARS-CoV-2 to nirmatrelvir resulted in an EC₅₀ shift of <5-fold compared to wild type SARS‑CoV-2 in an antiviral cell assay. Virus containing E166V shows the greatest reduction in susceptibility to nirmatrelvir and appears to have replication defect since it either could not be generated or had a very low virus titer.⁴² In general, triple and some double M^pro amino acid substitutions led to EC₅₀ changes of >5-fold to that of wild type. The clinical significance needs to be further understood, particularly in the context of nirmatrelvir high clinical exposure (≥5× EC₉₀). Thus far, these substitutions have not been identified as treatment‑emergent substitutions associated with hospitalisation or death from the EPIC-HR or EPIC-SR studies.

Treatment-emergent substitutions were evaluated among participants in clinical trials EPIC‑HR/SR with sequence data available at both baseline and a post-baseline visit (n=907 Paxlovid-treated participants, n=946 placebo-treated participants). SARS-CoV-2 M^pro amino acid changes were classified as Paxlovid treatment‑emergent substitutions if they were absent at baseline, occurred at the same amino acid position in 3 or more Paxlovid‑treated participants and were ≥2.5-fold more common in Paxlovid-treated participants than placebo‑treated participants post-dose. The following Paxlovid treatment-emergent M^pro substitutions were observed: T98I/R/del (n=4), E166V (n=3), and W207L/R/del (n=4). Within the M^pro cleavage sites, the following Paxlovid treatment‑emergent substitutions were observed: A5328S/V (n=7) and S6799A/P/Y (n=4). These cleavage site substitutions were not associated with the co-occurrence of any specific M^pro substitutions.

None of the treatment-emergent substitutions listed above in M^pro or M^pro cleavage sites occurred in Paxlovid‑treated participants who experienced hospitalisation. Thus, the clinical significance of these substitutions is unknown.

Because nirmatrelvir is coadministered with low dose ritonavir, there may be a risk of HIV‑1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV‑1 infection.

Viral load rebound

Post-treatment increases in SARS-CoV-2 nasal RNA levels (i.e., viral RNA rebound) were observed on Day 10 and/or Day 14 in a subset of Paxlovid and placebo recipients in EPIC-HR and EPIC-SR, irrespective of COVID-19 symptoms. The frequency of detection of post-treatment nasal viral RNA rebound varied according to analysis parameters but was generally similar among Paxlovid and placebo recipients. A similar or smaller percentage of placebo recipients compared to Paxlovid recipients had nasal viral RNA results < lower limit of quantitation (LLOQ) at all study timepoints in both the treatment and post-treatment periods.

Post-treatment viral RNA rebound was not associated with the primary clinical outcome of COVID‑19-related hospitalisation or death from any cause through Day 28 following the single 5-day course of Paxlovid treatment. The clinical relevance of post-treatment increases in viral RNA following Paxlovid or placebo treatment is unknown.

EPIC-HR and EPIC-SR were not designed to evaluate symptomatic viral RNA rebound, and most episodes of symptom rebound occurred after Day 14 (the last day SARS-CoV-2 RNA levels were routinely assessed). The frequency of symptom rebound through Day 28, irrespective of viral RNA results, was similar among Paxlovid and placebo recipients.

Cross-resistance

Cross-resistance is not expected between nirmatrelvir and remdesivir or any other anti-SARS-CoV-2 agents with different mechanisms of action (i.e., agents that are not M^pro inhibitors).

Pharmacodynamic effects

Cardiac electrophysiology

At 3 times the steady‑state peak plasma concentration (C_max) at the recommended dose, nirmatrelvir does not prolong the QTc interval to any clinically relevant extent.

Effects on viral RNA levels

Changes from baseline relative to placebo at Day 5 in viral RNA levels in nasopharyngeal samples are summarised by study in Table 6.

The degree of reduction in viral RNA levels relative to placebo following 5 days of Paxlovid treatment was similar across studies, including those enrolling unvaccinated participants (EPIC-HR) and those enrolling both unvaccinated and vaccinated participants (EPIC‑SR and EPIC-PEP).

Effect on lipids

The changes in lipids in nirmatrelvir/ritonavir treated group were not statistically different than placebo/ritonavir treated group in an exploratory analysis of lipids in multiple ascending dose cohorts in which healthy participants were randomised to receive either escalating doses (75, 250 and 500 mg) of nirmatrelvir (n=4 per cohort) or placebo (n=2 per cohort), enhanced with ritonavir 100 mg, twice a day for 10 days.

In participants receiving placebo/ritonavir twice a day, a modest increase in cholesterol (≤ 27.2 mg/dL), LDL cholesterol (≤ 23.2 mg/dL), triglycerides (≤ 64.3 mg/dL) and decrease in HDL cholesterol (≤ 4 mg/dL) was observed. The clinical significance of such changes with short‑term treatment is unknown.

Clinical efficacy

Efficacy in participants at high risk of progressing to severe COVID-19 illness (EPIC-HR)

The efficacy of Paxlovid is based on the final analysis of EPIC‑HR, a phase 2/3, randomised, double-blind, placebo-controlled study in non‑hospitalised symptomatic adult participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Participants with COVID-19 symptom onset of ≤ 5 days were included in the study. Participants were randomised (1:1) to receive Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) or placebo orally every 12 hours for 5 days. The study excluded individuals with a history of prior COVID-19 infection or vaccination. The primary efficacy endpoint was the proportion of participants with COVID-19 related hospitalisation or death from any cause through Day 28. Time to sustained alleviation and sustained resolution of all targeted symptoms through Day 28 were key secondary efficacy endpoints. These analyses were conducted in the modified intent-to-treat (mITT) analysis set [all treated participants with onset of symptoms ≤ 3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment], the mITT1 analysis set (all treated participants with onset of symptoms ≤ 5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment), and the mITT2 analysis set (all treated participants with onset of symptoms ≤ 5 days). Secondary efficacy endpoints included assessments of COVID‑19 hospitalisation or death from any cause through Day 28 in the mITT1 analysis set.

A total of 2,113 participants were randomised to receive either Paxlovid or placebo. At baseline, mean age was 45 years; 51% were male; 71% were White, 4% were Black or African American, 15% were Asian and 41% were Hispanic or Latino; 67% of participants had onset of symptoms ≤ 3 days before initiation of study treatment; 49% of participants were serological negative at baseline. The most frequently reported risk factors were BMI ≥ 25 kg/m² (1,692 [80.1%] participants), tobacco use (826 [39.1%] participants), hypertension (671 [31.8%] participants), age ≥ 60 years (438 [20.7%] participants), and diabetes mellitus (228 [10.8%] participants). Other risk factors were cardiovascular disorder (87 [4.1%] participants), chronic kidney disease (12 [0.6%] participants), chronic lung disease (100 [4.7%] participants), immunosuppression (13 [0.6%] participants), cancer (114 [0.5%] participants), neurodevelopmental disorders (3 [0.1%] participants), HIV infection (1 [<0.1%] participant) and device dependency (7 [0.3%] participants). The mean (SD) baseline viral load was 4.71 log₁₀ copies/mL (2.89); 27% of participants had a baseline viral load of ≥7 log₁₀ copies/mL; 6% of participants either received or were expected to receive COVID-19 therapeutic mAb treatment at the time of randomisation and were excluded from the mITT and mITT1 analyses.

The baseline demographic and disease characteristics were balanced between the Paxlovid and placebo groups.

Table 7 provides results of the primary endpoint in the mITT1 analysis population demonstrating superiority of Paxlovid compared to placebo for COVID‑19 related hospitalisation or death from any cause through Day 28. For the primary endpoint, the relative risk reduction in the mITT1 analysis population for Paxlovid compared to placebo was 86% (95% CI: 72%, 93%). The determination of primary efficacy was based on a planned interim analysis of 754 participants in mITT population. The estimated risk reduction was -6.5% with a 95% CI of (-9.3%, -3.7%) and 2-sided p value <0.0001.

Through Week 24, no deaths were reported in the Paxlovid group compared with 15 deaths in the placebo group. The proportions of participants who discontinued treatment due to an adverse event were 2.0% in the Paxlovid group and 4.3% in the placebo group.

Consistent results were observed in the final mITT and mITT2 analysis populations. A total of 1,318 subjects were included in the mITT analysis population. The event rates were 5/671 (0.75%) in the Paxlovid group, and 44/647 (6.80%) in the placebo group.

Similar trends have been observed across subgroups of participants. (see Figure 1).

Figure 1: Adults with COVID-19 dosed within 5 days of symptom onset with COVID‑19‑related hospitalisation or death from any cause through Day 28

Abbreviations: BMI=body mass index, COVID-19=Coronavirus Disease 2019; mAb=monoclonal antibody; mITT1=modified intent‑to‑treat 1 (all participants randomly assigned to study intervention, who took at least 1 dose of study intervention, with at least 1 post-baseline visit through Day 28, who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment and were treated ≤5 days after COVID-19 symptom onset); N=number of participants in the category of the analysis set; SARS-COV-2=severe acute respiratory syndrome coronavirus 2.

All categories are based on mITT1 population except for COVID-19 mAb treatment which is based on mITT2 population.

Seropositivity was defined if results were positive in either Elecsys anti SARS-CoV-2 S or Elecsys SARS‑CoV-2 (N) assay.

The difference of the proportions in the 2 treatment groups and its 95% confidence interval based on normal approximation of the data are presented.

Participants performed daily self-assessments of COVID-19 associated symptoms of cough, shortness of breath or difficulty breathing, feeling feverish, chills or shivering, muscle or body aches, diarrhoea, nausea, vomiting, headache, sore throat, stuffy or runny nose. The severity of each symptom was rated as absent, mild, moderate, or severe. Sustained symptom alleviation was defined as the first of 4 consecutive days when all of the above symptoms scored as moderate or severe at study entry were scored as mild or absent, and all of the above symptoms scored mild or absent at study entry were scored as absent. Sustained symptom resolution was defined as the time when all of the above symptoms were scored as absent for 4 consecutive days. Table 8 displays the results for time to sustained symptom alleviation and sustained symptom resolution in the mITT1 population. The Paxlovid group demonstrated superiority to the placebo group in both analyses.

The proportion of participants with any severe COVID‑19 associated symptom was 22% in the Paxlovid group and 19% in the placebo group at baseline (Day 1), 17% and 18%, respectively, during treatment (from Day 2 to Day 6), and 8% and 11%, respectively, after treatment (from Day 7 to Day 28).

Efficacy in vaccinated participants with at least 1 risk factor for progression to severe COVID‑19 illness (EPIC-SR)

EPIC-SR was a phase 2/3, randomised, double-blind, placebo-controlled study in non‑hospitalised symptomatic adult participants with a laboratory confirmed diagnosis of SARS‑CoV‑2 infection. Eligible participants were 18 years of age and older with COVID-19 symptom onset of ≤ 5 days who were at standard risk for progression to severe disease. The study included previously unvaccinated participants without risk factors or fully vaccinated participants with at least 1 of the risk factors for progression to severe disease (as defined in the EPIC-HR section above and by local regulations and practices). A total of 1,296 participants were randomised (1:1) to receive Paxlovid or placebo orally every 12 hours for 5 days; of these, 49% were vaccinated at baseline with at least 1 risk factor for progression to severe disease.

Analyses of efficacy presented below is based on vaccinated participants with at least 1 risk factor for progression to severe disease. In vaccinated participants, Table 9 provides results of the proportion of participants with COVID-19 related hospitalisation or death from any cause through Day 28 (secondary endpoint of EPIC-SR). The relative risk reduction in the mITT1 analysis population for Paxlovid compared to placebo was 58%. The result did not reach statistical significance.

Post-exposure prophylaxis (EPIC-PEP)

EPIC-PEP was a phase 2/3, randomised, double-blind, double-dummy, placebo-controlled study assessing the efficacy of Paxlovid (administered 5 days or 10 days) in post‑exposure prophylaxis of COVID-19 in household contacts of symptomatic individuals infected with SARS-CoV-2. Eligible participants were asymptomatic adults 18 years of age and older who were SARS-CoV-2 negative at screening and who lived in the same household with symptomatic individuals with a recent diagnosis of SARS-CoV-2. A total of 2,736 participants were randomised (1:1:1) to receive Paxlovid orally every 12 hours for 5 days, Paxlovid orally every 12 hours for 10 days, or placebo.

Compared with placebo, the Paxlovid 5‑day and 10‑day regimens led to a 30% and 36% relative risk reduction, respectively, in the risk of developing a symptomatic, reverse transcriptase–polymerase chain reaction (RT-PCR) or rapid antigen test (RAT) confirmed SARS-CoV-2 infection through household contact; these results did not reach statistical significance. In a post hoc analysis, the risk of developing a symptomatic or asymptomatic confirmed SARS-CoV-2 infection was reduced by 31% and 35% with the Paxlovid 5-day and 10‑day regimens, respectively, compared with placebo (Table 10).

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

Paediatric population

The Agency has deferred the obligation to submit the results of studies with Paxlovid in one or more subsets of the paediatric population in the treatment of coronavirus disease 2019 (COVID-19) (see section 4.2 for information on paediatric use).

The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy participants and in participants with mild‑to‑moderate COVID-19.

Ritonavir is administered with nirmatrelvir as a pharmacokinetic (PK) enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir. In healthy participants in the fasted state, the mean half-life (t_1/2) of a single dose of 150 mg nirmatrelvir administered alone was approximately 2 hours compared to 7 hours after administration of a single dose of 250 mg/100 mg nirmatrelvir/ritonavir thereby supporting a twice‑daily administration regimen.

Upon administration of single dose of nirmatrelvir/ritonavir 250 mg/100 mg to healthy participants in the fasted state, the geometric mean (CV%) maximum plasma concentration (C_max) and area under the plasma concentration-time curve from 0 to the time of last measurement (AUC_last) was 2.88 ug/mL (25%) and 27.6 ug*hr/mL (13%), respectively. Upon repeat-dose of nirmatrelvir/ritonavir 75 mg/100 mg, 250 mg/100 mg, and 500 mg/100 mg administered twice daily, the increase in systemic exposure at steady-state appears to be less than dose proportional. Multiple dosing over 10 days achieved steady-state on Day 2 with approximately 2-fold accumulation. Systemic exposures on Day 5 were similar to Day 10 across all doses. Simulated repeat-dose exposures of nirmatrelvir/ritonavir 300 mg/100 mg administered twice daily in adult participants from EPIC-HR, suggested the mean AUC_tau was 28.3 µg*hr/mL, mean C_max was 3.29 µg/mL, and mean C_min was 1.40 µg/mL.

Absorption

Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir (CV%) C_max and area under the plasma concentration‑time curve from 0 to infinity (AUC_inf) at steady-state was 2.21 µg/mL (33) and 23.01 µg*hr/mL (23), respectively. The median (range) time to C_max (T_max) was 3.00 hrs (1.02-6.00). The arithmetic mean (±SD) terminal elimination half-life was 6.1 (1.8) hours.

Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean ritonavir (CV%) C_max and AUC_inf was 0.36 µg/mL (46) and 3.60 µg*hr/mL (47), respectively. The median (range) time to C_max (T_max) was 3.98 hrs (1.48-4.20). The arithmetic mean (±SD) terminal elimination half-life was 6.1 (2.2) hours.

Effect of food on oral absorption

Dosing with a high fat meal increased the exposure of nirmatrelvir (approximately 61% increase in mean C_max and 20% increase in mean AUC_last) relative to fasting conditions following administration of 300 mg nirmatrelvir (2 x 150 mg)/100 mg ritonavir tablets.

Distribution

The protein binding of nirmatrelvir in human plasma is approximately 69%.

The protein binding of ritonavir in human plasma is approximately 98-99%.

Biotransformation

In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolised by CYP3A4. Nirmatrelvir does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8, or CYP1A2 in vitro at clinically relevant concentrations. In vitro study results showed nirmatrelvir may be inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9. The clinical relevance is unknown. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3 and OCT2. There is a potential for nirmatrelvir to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations. Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In plasma, the only drug-related entity observed was unchanged nirmatrelvir. Minor oxidative metabolites were observed in the faeces and urine.

In vitro studies utilising human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of oxidation metabolite M–2.

Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of ritonavir.

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Ritonavir also has a high affinity for P‑glycoprotein (P-gp) and may inhibit this transporter. Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways and may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.

Elimination

The primary route of elimination of nirmatrelvir when administered with ritonavir was renal excretion of intact drug. Approximately 49.6% and 35.3% of the administered dose of nirmatrelvir 300 mg was recovered in urine and faeces, respectively. Nirmatrelvir was the predominant drug‑related entity with small amounts of metabolites arising from hydrolysis reactions in excreta. In plasma, the only drug-related entity quantifiable was unchanged nirmatrelvir.

Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir.

Specific populations

Age and gender

In a population PK analysis, age and gender did not affect the pharmacokinetics of nirmatrelvir.

Racial or ethnic groups

Systemic exposure in Japanese participants was numerically lower but not clinically meaningfully different than those in Western participants. In a population PK analysis, race did not affect the pharmacokinetics of nirmatrelvir.

Patients with renal impairment

Compared to healthy controls with no renal impairment, the C_max and AUC_inf of nirmatrelvir in participants with mild renal impairment were 30% and 24% higher, in patients with moderate renal impairment were 38% and 87% higher, and in patients with severe renal impairment were 48% and 204% higher, respectively.

Patients with severe renal impairment including those requiring haemodialysis

The pharmacokinetics of nirmatrelvir in participants with mild-to-moderate COVID-19 and severe renal impairment (eGFR < 30 mL/min) either requiring haemodialysis (n=12) or not requiring haemodialysis (n=2) were evaluated after administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 for a total of 5 doses.

During a 4-hour haemodialysis session, approximately 6.9% of nirmatrelvir dose was cleared through dialysis. Haemodialysis clearance was 1.83 L/h.

Population pharmacokinetic model-based simulations showed that administration of 300 mg/100 mg nirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 in participants with severe renal impairment resulted in comparable exposures on Day 1 and at steady-state (AUC_0-24 and C_max) to those observed in participants with normal renal function receiving 300 mg/100 mg nirmatrelvir/ritonavir twice daily for 5 days.

Patients with hepatic impairment

Compared to healthy controls with no hepatic impairment, the pharmacokinetics of nirmatrelvir in participants with moderate hepatic impairment were not significantly different. Adjusted geometric mean ratio (90% CI) of AUC_inf and C_max of nirmatrelvir comparing moderate hepatic impairment (test) to normal hepatic function (reference) were 98.78% (70.65%, 138.12%) and 101.96% (74.20%, 140.11%), respectively.

Nirmatrelvir/ritonavir has not been studied in patients with severe hepatic impairment.

Interaction studies conducted with nirmatrelvir/ritonavir

CYP3A4 was the major contributor to the oxidative metabolism of nirmatrelvir, when nirmatrelvir was tested alone in human liver microsomes. Ritonavir is an inhibitor of CYP3A and increases plasma concentrations of nirmatrelvir and other medicinal products that are primarily metabolised by CYP3A. Despite being coadministered with ritonavir as a PK enhancer, there is potential for strong inhibitors and inducers to alter the pharmacokinetics of nirmatrelvir.

Interaction studies conducted with nirmatrelvir

In vitro data indicates that nirmatrelvir is a substrate for human MDR1 (P-gp) and CYP3A4, but not a substrate for human BCRP, MATE1, MATE2K, NTCP, OAT1, OAT2, OAT3, OCT1, OCT2, PEPT1, OATPs 1B1, 1B3, 2B1, or 4C1.

Nirmatrelvir does not reversibly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 in vitro at clinically relevant concentrations. Nirmatrelvir has the potential to reversibly and time dependently inhibit CYP3A4 and inhibit MDR1 (P-gp) and OATP1B1.

Nirmatrelvir does not induce any CYPs at clinically relevant concentrations.

Interaction studies conducted with ritonavir

In vitro studies indicate that ritonavir is mainly a substrate of CYP3A. Ritonavir also appears to be a substrate of CYP2D6 which contributes to the formation of isopropylthiazole oxidation metabolite M‑2.

Ritonavir is an inhibitor of CYP3A and to a lesser extent CYP2D6. Ritonavir appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

The effects of coadministration of Paxlovid with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and C_max are summarised in Table 11.

The effects of coadministration of Paxlovid with oral midazolam (CYP3A4 substrate), dabigatran (P‑gp substrate), or rosuvastatin (OATP1B1 substrate) on the midazolam, dabigatran, and rosuvastatin AUC_inf and C_max, respectively, are summarized in Table 12.

Toxicology

Repeat‑dose toxicity studies up to 1 month duration of nirmatrelvir in rats and monkeys resulted in no adverse findings.

Repeat-dose toxicity studies of ritonavir in animals identified major target organs as the liver, retina, thyroid gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests.

Renal changes including tubular degeneration, chronic inflammation and proteinuria were noted in rats and are considered to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.

Carcinogenesis

Paxlovid has not been evaluated for the potential to cause carcinogenicity.

Nirmatrelvir has not been evaluated for the potential to cause carcinogenicity.

Long-term carcinogenicity studies of ritonavir in mice and rats revealed tumorigenic potential specific for these species, but are regarded as of no relevance for humans.

Mutagenesis

Paxlovid has not been evaluated for the potential to cause mutagenicity.

Nirmatrelvir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human lymphoblastoid TK6 cells and in vivo rat micronucleus assays.

Ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Reproductive toxicity

Nirmatrelvir

In a fertility and early embryonic development study, nirmatrelvir was administered to male and female rats by oral gavage at doses of 60, 200, or 1,000 mg/kg/day once daily beginning 14 days prior to mating, throughout the mating phase, and continued through Gestation Day (GD) 6 for females and for a total of 32 doses for males. There were no effects on fertility, reproductive performance, or early embryonic development at doses up to 1,000 mg/kg/day representing 5× clinical exposures at the approved dose of Paxlovid.

Embryo-foetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1000 mg/kg/day during organogenesis [on Gestation Days (GD) 6 through 17 in rats and GD 7 through 19 in rabbits]. No biologically significant developmental effects were observed in the rat EFD study. At the highest dose of 1000 mg/kg/day, the systemic nirmatrelvir exposure (AUC₂₄) in rats was approximately 9× higher than clinical exposures at the approved human dose of Paxlovid. In the rabbit EFD study, lower foetal body weights (9% decrease) were observed at 1000 mg/kg/day in the absence of significant maternal toxicity findings. At 1000 mg/kg/day, the systemic exposure (AUC₂₄) in rabbits was approximately 11× higher than clinical exposures at the approved human dose of Paxlovid. No other significant developmental toxicities (malformations and embryo-foetal lethality) were observed at up to the highest dose tested, 1000 mg/kg/day. No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC₂₄) approximately 3× higher than clinical exposures at the approved human dose of Paxlovid.

In the pre- and postnatal developmental study, body weight decreases (up to 8%) were observed in the offspring of pregnant rats administered nirmatrelvir at maternal systemic exposure (AUC₂₄) approximately 9× higher than clinical exposures at the approved human dose of Paxlovid. No body weight changes in the offspring were noted at maternal systemic exposure (AUC₂₄) approximately 6× higher than clinical exposures at the approved human dose of Paxlovid.

Ritonavir

Ritonavir produced no effects on fertility in rats.

Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on GD 6 through 17 in rats and 6 through 19 in rabbits). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) 5× (rats) or 8× (rabbits) higher than exposure at the approved human dose of Paxlovid. Increased incidences of early resorptions, ossification delays and developmental variations, as well as decreased foetal body weights were observed in the rat in the presence of maternal toxicity, at systemic exposures approximately 10× higher than exposure at the approved human dose of Paxlovid. In rabbits, resorptions, decreased litter size and decreased foetal weights were observed at maternally toxic doses, at systemic exposures greater than 8× higher than exposure at the approved human dose of Paxlovid. In a pre- and post-natal development study in rats, administration 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through Postnatal Day 20 resulted in no developmental toxicity, at ritonavir systemic exposures greater than 10× the exposure at the approved human dose of Paxlovid.

Nirmatrelvir

Tablet core:

Microcrystalline cellulose

Lactose monohydrate

Croscarmellose sodium

Colloidal silicon dioxide

Sodium stearyl fumarate

Film-coat:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol (E1521)

Iron oxide red (E172)

Ritonavir

Tablet core:

Copovidone

Sorbitan laurate

Silica colloidal anhydrous (E551)

Calcium hydrogen phosphate

Sodium stearyl fumarate

Film-coat:

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol (E1521)

Hydroxypropyl cellulose (E463)

Talc (E553b)

Silica colloidal anhydrous (E551)

Polysorbate 80 (E433)

Not applicable.

2 years.

This medicinal product does not require any special storage conditions.

OPA/Al/PVC foil blister cards.

Twice daily dose blister card

Pack size of 5 blister cards each containing 4 nirmatrelvir tablets and 2 ritonavir tablets for morning and evening dose (total of 30 tablets).

Once daily dose blister card

Pack size of one blister card of 11 tablets. The blister card contains 6 nirmatrelvir tablets and 5 ritonavir tablets for once daily dose.

Not all pack sizes may be marketed.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.