Summary Basis of Decision for Paxlovid

The New Drug Submission for Paxlovid (nirmatrelvir and ritonavir) was submitted and reviewed in accordance with the Food and Drug Regulations, which permitted a rolling submission and review process. Following review of the provided information, a Notice of Compliance was issued in relation to Paxlovid, with accompanying terms and conditions to manage any uncertainties or mitigate risks related to the drug.

Clinical Pharmacology

Paxlovid contains 150 mg nirmatrelvir tablets co-packaged with 100 mg ritonavir tablets.

Nirmatrelvir (also known as PF-07321332) is a new active substance. It is a peptidomimetic inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro; also referred to as 3-chymotrypsin-like protease [3CLpro] or nonstructural protein 5 [NSP5] protease). Inhibition of the SARS-CoV-2 3CLpro renders the enzyme incapable of processing polyprotein precursors, preventing viral replication.

Nirmatrelvir must be co-administered with ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, which is not active against the SARS-CoV-2 3CLpro. Ritonavir acts as a pharmacokinetic enhancer, as it inhibits the cytochrome P450 (CYP) 3A-mediated metabolism of nirmatrelvir, thereby increasing the plasma concentrations of nirmatrelvir. Ritonavir was first authorized in Canada as a single agent in 1996 and as a component of a fixed-dose combination antiretroviral product in 2001.

The pharmacokinetic properties of nirmatrelvir/ritonavir have been studied in healthy subjects.

Following oral administration of single ascending doses of nirmatrelvir (ranging from 250 mg to 750 mg; as an oral suspension formulation) enhanced with 100 mg of ritonavir, the increase in systemic exposure of nirmatrelvir appeared to be less than dose proportional up to 750 mg of nirmatrelvir. Following multiple oral doses of nirmatrelvir (ranging from 75 mg to 500 mg; as an oral suspension formulation) enhanced with 100 mg ritonavir, the increase in systemic exposure of nirmatrelvir appeared to be less than dose proportional up to 500 mg of nirmatrelvir. Twice-daily dosing over 10 days achieved steady-state plasma concentrations of nirmatrelvir on Day 2 with approximately 2-fold accumulation.

The pharmacokinetic properties of nirmatrelvir/ritonavir based on age and gender have not been evaluated. Systemic exposure of nirmatrelvir in Japanese subjects was found to be numerically lower than that in Caucasian subjects, but the data were limited and the difference observed was not clinically meaningful. A preliminary population pharmacokinetic model was developed based on limited pharmacokinetic data from healthy volunteers. As per the terms and conditions associated with the Notice of Compliance for Paxlovid, the sponsor is required to submit an updated population pharmacokinetic analysis to provide a complete evaluation and description of nirmatrelvir pharmacokinetics in patients, and provide information about potential covariate effects including, but not limited to, the impact of age, sex, body mass index, weight, race, ethnicity, hepatic impairment, and renal impairment.

Current non-clinical and clinical data do not suggest that Paxlovid is associated with a risk of QT prolongation. However, the impact of Paxlovid on QT prolongation has not been fully evaluated in humans.

An open-label study examined the pharmacokinetics of nirmatrelvir/ritonavir in healthy adult subjects and subjects with mild (estimated glomerular filtration rate [eGFR] 60 to <90 mL/min), moderate (eGFR ≥30 to <60 mL/min), and severe (eGFR <30 mL/min) renal impairment following administration of a single oral dose of nirmatrelvir 100 mg enhanced with ritonavir 100 mg administered at -12, 0, 12, and 24 hours relative to nirmatrelvir dosing. Compared to healthy controls with no renal impairment, the maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) of nirmatrelvir were found to be 30% and 24% higher in patients with mild renal impairment, 38% and 87% higher in patients with moderate renal impairment, and 48% and 204% higher in patients with severe renal impairment. Based on these data, the use of Paxlovid is not recommended in patients with severe renal impairment. Furthermore, dose reduction of Paxlovid is required in patients with moderate renal impairment (150 mg nirmatrelvir [one 150 mg tablet] and 100 mg ritonavir [one 100 mg tablet], taken together twice daily for 5 days). No dose adjustment is needed in patients with mild renal impairment.

No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C). Therefore, the use of Paxlovid is not recommended in these patients. Based on current preliminary pharmacokinetic and safety data, no dosage adjustment of Paxlovid is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The sponsor is required to submit the final results of a Phase I, non-randomized, open-label study assessing the pharmacokinetics, safety, and tolerability of nirmatrelvir boosted with ritonavir in adult participants with moderate hepatic impairment and healthy participants with normal hepatic function.

The main contributor to the metabolism of nirmatrelvir is the CYP3A4 enzyme. Ritonavir is also a CYP3A substrate. A Phase I study investigated the effect of a strong CYP3A4 inducer, carbamazepine, on the pharmacokinetics of nirmatrelvir and ritonavir in healthy participants. Results of the study showed that the exposures of both nirmatrelvir and ritonavir were significantly decreased. Reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible development of SARS-CoV-2 resistance to Paxlovid. For that reason, Paxlovid is contraindicated for use with drugs that are potent CYP3A inducers.

Importantly, ritonavir is a known strong inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Therefore, co-administration of Paxlovid with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring. Ritonavir also inhibits, to a lesser extent, CYP2D6. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase. The risk of drug-drug interactions leading to potentially serious and/or life-threatening reactions due to the effects of ritonavir on the hepatic metabolism of certain drugs is highlighted in a Serious Warnings and Precautions Box in the Paxlovid Product Monograph. The Paxlovid Product Monograph recommends that prescribers consider the potential for drug interactions prior to and during Paxlovid therapy, review concomitant medications during Paxlovid therapy, and monitor for the adverse reactions associated with the concomitant medications.

Established and potentially significant drug interactions have been listed in the Paxlovid Product Monograph. At present, the list is considered a guide and does not represent a comprehensive source of information on all possible drugs that may interact with Paxlovid. As per the terms and conditions, the sponsor is required to submit the final reports of two ongoing Phase I drug-drug interaction studies investigating the effects of nirmatrelvir/ritonavir on the pharmacokinetics of midazolam (a benzodiazepine) and dabigtran (an anticoagulant), respectively.

The submitted clinical pharmacology data support the use of Paxlovid for the specified indication. Further evaluation will take place upon provision of the final study reports requested in the terms and conditions imposed in respect of Paxlovid.

For further details, please refer to the Paxlovid Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.  

Clinical Efficacy

The efficacy of Paxlovid in the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adult patients with positive results of direct SARS-CoV-2 viral testing and at high risk for progression to severe COVID-19 was supported by results from the Phase II/III, randomized, double-blind, placebo-controlled EPIC-HR (C4671005) study.

This clinical study involved non-hospitalized symptomatic adults (18 years of age and older) with a laboratory-confirmed diagnosis of SARS-CoV-2 infection and at least one of the following risk factors for progression to severe disease: diabetes, overweight (body mass index >25), chronic lung disease (including asthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressive treatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders, active cancer, medically related technological dependence, or were 60 years of age and older, regardless of comorbidities. Patients with COVID-19 symptom onset of ≤5 days were included in the study and were randomized (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 of the study was the proportion of patients with COVID-19-related hospitalization or death from any cause through Day 28. The analysis was conducted in:

• the modified intention-to-treat (mITT) analysis set (all treated patients with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody treatment);

• the mITT1 analysis set (all treated patients with onset of symptoms ≤5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody treatment); and

• the mITT2 analysis set (all treated patients with onset of symptoms ≤5 days).

There were 1,361 patients randomized to receive either Paxlovid or placebo. The baseline demographic and disease characteristics were balanced between the Paxlovid and placebo groups. At the time of the interim analysis, the mITT analysis set included 389 patients in the Paxlovid group and 385 patients in the placebo group. Paxlovid was shown to reduce the proportion of patients with COVID-19-related hospitalization or death through Day 28 by 89.1%, compared with placebo. In the Paxlovid group, 0.8% (3/389) of patients were hospitalized or died compared to 7% (27/385) of patients in the placebo group (representing an absolute risk reduction of -6.32%, 95% confidence interval: -9.04, -3.59). This reduction was statistically significant (p<0.0001). Furthermore, no deaths occurred in the Paxlovid group compared with 7 reported deaths in the placebo group.

Efficacy results obtained in the mITT1 and mITT2 analysis sets were consistent with those of the mITT analysis set. In addition, the provided primary efficacy data from the topline final analysis were consistent with the efficacy results of the interim analysis. Similar trends were observed across subgroups of patients. These subgroup analyses were considered exploratory.

Viral genome sequencing data were available for 2 of the 5 patients in the Paxlovid treatment group who experienced treatment failure (hospitalization or death). No treatment-emergent SARS-CoV-2 mutations were associated with treatment failure. However, due to the limited data, no conclusions on the effect of treatment-emergent SARS-CoV-2 mutations on treatment failure could be drawn at this time. The sponsor is required to provide final viral genome sequencing results from participants enrolled in the EPIC-HR study with complete data on the mutational pressure of nirmatrelvir on the SARS-CoV-2 3CL protease gene regions of interest.

The available evidence supports the efficacy of Paxlovid in the treatment of non-hospitalized adults with mild-to-moderate COVID-19 who are at risk of progressing to severe disease. To confirm the efficacy of Paxlovid in the target patient population, the sponsor is required to provide the final study report of the EPIC-HR study to Health Canada.

Indication

The New Drug Submission for Paxlovid was filed by the sponsor with the following indication:

Paxlovid (nirmatrelvir tablets; ritonavir tablets) is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adult and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Limitations of authorized use:

• Paxlovid is not authorized for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19.
• Paxlovid is not authorized for pre-exposure or post-exposure prophylaxis for prevention of COVID-19.
• Paxlovid is not authorized for use for longer than 5 consecutive days.

As no safety and efficacy data were submitted for pediatric patients, Health Canada revised the initially proposed indication to exclude “patients 12 years of age and older weighing at least 40 kg” from the target patient population. Accordingly, Health Canada approved the following indication:

Paxlovid (nirmatrelvir tablets; ritonavir tablets) is indicated for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Paxlovid is not authorized for:

• initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19;
• pre-exposure or post-exposure prophylaxis for prevention of COVID-19;
• use for longer than 5 consecutive days.

For more information, refer to the Paxlovid Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.

 

Clinical Safety

The safety evaluation of Paxlovid is based on the provided summary of key safety data from the EPIC-HR study (described in the Clinical Efficacy section).

At the time of the approval of Paxlovid, a topline analysis of the final study results was available for 2,224 patients (1,109 in the Paxlovid group and 1,115 in the placebo group). Adverse events presented in the submitted information were those reported while patients were on study medication and through Day 34 after initiating study treatment. The incidence of adverse events was 22.6% in the Paxlovid group and 23.9% in the placebo group. Adverse events of all grades, regardless of causality, in the Paxlovid group (at a frequency of ≥1%) that occurred at a greater frequency (a difference of ≥5 subjects) than in the placebo group were dysgeusia (6% versus <1%), diarrhea (3% versus 2%), hypertension (1% versus <1%), and myalgia (1% versus <1%). Serious adverse events were reported in a lower proportion of patients in the Paxlovid group (1.6%) compared to those in the placebo group (6.6%). The proportions of patients who discontinued treatment due to an adverse event were 2.1% in the Paxlovid group and 4.2% in the placebo group.

In the interim analysis of data from 1,361 patients assigned to treatment (678 patients in the Paxlovid group and 683 patients in the placebo group), the most frequently reported (≥1%) treatment-emergent adverse events in the Paxlovid group were dysgeusia (5.6%), diarrhea (3.1%), increased D-dimer (1.9%), increased alanine aminotransferase (1.5%), nausea (1.4%), decreased creatinine renal clearance (1.4%), headache (1.4%), and vomiting (1.1%). Dysgeusia, diarrhea, and vomiting were reported at higher frequencies in the Paxlovid group in comparison to the placebo group.

The interim analysis of data from 672 patients who received Paxlovid compared to 677 patients who received placebo demonstrated a higher proportion of patients reporting treatment-related adverse events in the Paxlovid group compared to patients in the placebo group (7.3% versus 4.3%). In the Paxlovid group, the most frequently reported treatment-related adverse events (≥1%) were dysgeusia and diarrhea. One patient in the Paxlovid group reported a serious adverse event (considered related to the ritonavir component) versus none in the placebo group. More patients in the Paxlovid group (n = 7) discontinued study drug due to a treatment-related adverse event compared to the placebo group (n = 3).

The main risk associated with Paxlovid is the potential for drug-drug interactions that may result in clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events, or loss of therapeutic effect of Paxlovid and possible development of viral resistance. The risk of drug-drug interactions is highlighted in the Paxlovid Product Monograph, which lists drugs that are contraindicated for concomitant use with Paxlovid and outlines potentially significant drug-drug interactions. The information included is considered a guide and does not represent a comprehensive source of all possible drugs that may interact with Paxlovid. The Paxlovid Product Monograph recommends that prescribers consider the potential for drug-drug interactions prior to and during Paxlovid therapy, review concomitant medications during Paxlovid therapy, and monitor for the adverse reactions associated with the concomitant medications.

Additionally, because nirmatrelvir is co-administered with ritonavir, which is an HIV protease inhibitor, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection. No dosage adjustment of Paxlovid is required when co-administered with other products containing ritonavir or cobicistat. Patients on ritonavir- or cobicistat-containing HIV or hepatitis C therapeutic regimens should continue their treatment as indicated. This information has been included in the Paxlovid Product Monograph.

Based on the submitted data, the safety profile of Paxlovid is considered acceptable for the target patient population. Additional safety data from ongoing studies (including data from the final study report of the EPIC-HR study and its 24-week patient follow-up) and post-market safety monitoring data will be submitted to Health Canada, as specified in the terms and conditions imposed in respect of Paxlovid to address the uncertainties in relation to the clinical safety evidence available at the time of the review.

For more information, refer to the Paxlovid Product Monograph, approved by Health Canada and available through the Drug Product Database and on the Health Canada COVID-19 vaccines and treatments portal.