Paxlovid

Nirmatrelvir: Pink, oval, with a dimension of approximately 17.6 mm in length and 8.6 mm in width debossed with 'PFE' on one side and '3CL' on the other side.
Each pink nirmatrelvir film-coated tablet contains 150 mg of nirmatrelvir.
Ritonavir: White film-coated ovaloid tablets debossed with [Abbott logo] and the code 'NK' on one side; or White film-coated ovaloid tablets debossed with 'NK' on one side.
Each white ritonavir film-coated tablet contains 100 mg of ritonavir.
Excipients/Inactive Ingredients: Nirmatrelvir: Tablet core: Colloidal silicon dioxide, Croscarmellose sodium, Lactose monohydrate, Microcrystalline cellulose, Sodium stearyl fumarate.
Film coating: Hydroxy propyl methylcellulose, Iron oxide red, Polyethylene glycol, Titanium dioxide.
Ritonavir: AbbVie Ritonavir (Brand name: Norvir) contains the following inactive ingredients: copovidone, dibasic calcium phosphate anhydrous/calcium hydrogen phosphate anhydrous, sorbitan monolaurate, colloidal silicon dioxide/colloidal anhydrous silica and sodium stearyl fumarate. The following are the ingredients in the film coating: hypromellose, titanium dioxide E171, polyethylene glycol 400/macrogol type 400, hydroxylpropyl cellulose, talc, polyethylene glycol 3350/macrogol type 3350, colloidal silicon dioxide/colloidal silica anhydrous and polysorbate 80.
Refer to prescribing information of AbbVie Ritonavir (Brand name: Norvir) for the latest information.

Pharmacology: Pharmacodynamics: 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 drug 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 1 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. (See Table 1.)

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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. 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 hospitalization 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 previously in M^pro or M^pro cleavage sites occurred in PAXLOVID-treated participants who experienced hospitalization. Thus, the clinical significance of these substitutions is unknown.
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 after initiating study treatment 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 hospitalization 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 summarized by study in Table 2. (See Table 2.)

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The degree of reduction in viral RNA levels relative to placebo following 5 days of PAXLOVID treatment was similar between unvaccinated high-risk subjects in EPIC-HR and vaccinated high-risk subjects in EPIC-SR.
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 randomized 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, randomized, double-blind, placebo-controlled study in non-hospitalized symptomatic adult participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible participants were 18 years of age and older with at least 1 of the following risk factors for progression to severe disease: diabetes, overweight (BMI >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. Participants with COVID-19 symptom onset of ≤5 days were included in the study.
Participants 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 was the proportion of participants with COVID-19 related hospitalization 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 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).
A total of 2,113 participants were randomized 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, and 15% were Asian; 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 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 randomization and were excluded from the mITT and mITT1 analyses.
The baseline demographic and disease characteristics were balanced between the PAXLOVID and placebo groups.
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.
Table 3 provides results of the primary endpoint in the mITT1 analysis population demonstrating superiority of PAXLOVID compared to placebo for COVID-19 related hospitalization 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%). (See Table 3.)

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Through Week 24, no deaths were reported in the PAXLOVID group compared with 15 deaths in the placebo group.
Consistent results were observed in the mITT and mITT2 analysis populations. A total of 1,318 participants were included in the mITT analysis population. The event rates of COVID-19 related hospitalization or death from any cause through Day 28 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).

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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, diarrhea, 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 previously mentioned symptoms scored as moderate or severe at study entry were scored as mild or absent, and all of the previously mentioned symptoms scored mild or absent at study entry were scored as absent. Sustained symptom resolution was defined as the time when all of the previously mentioned symptoms were scored as absent for 4 consecutive days. Table 4 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. (See Table 4.)

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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): PAXLOVID is not indicated for the treatment of COVID-19 in patients without a risk factor for progression to severe COVID-19.
EPIC-SR was a Phase 2/3, randomized, double-blind, placebo-controlled study in non-hospitalized 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 previously defined in the EPIC-HR section and by local regulations and practices). A total of 1,296 participants were randomized (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.
The primary endpoint in this study, the difference in time to sustained alleviation of all targeted COVID-19 signs and symptoms through Day 28 among PAXLOVID versus placebo recipients, was not met.
Analyses of efficacy presented as follows is based on an exploratory analysis of the subgroup of vaccinated participants with at least 1 risk factor for progression to severe disease. In vaccinated participants, Table 5 provides results of the proportion of participants with COVID-19 related hospitalization 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. (See Table 5.)

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Post-exposure prophylaxis (EPIC-PEP): PAXLOVID is not indicated for the post-exposure prophylaxis of COVID-19.
EPIC-PEP was a Phase 2/3, randomized, 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 randomized (1:1:1) to receive PAXLOVID orally every 12 hours for 5 days, PAXLOVID orally every 12 hours for 10 days, or placebo.
The primary endpoint in this study, the risk reduction between the PAXLOVID 5-day and 10-day PAXLOVID regimens versus placebo in the proportion of participants who developed symptomatic reverse transcriptase-polymerase chain reaction (RT-PCR) or rapid antigen test (RAT)-confirmed SARS-CoV-2 infection through Day 14 among participants who had a negative SARS-CoV-2 RT-PCR result at baseline, was not met.
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, RT-PCR or RAT confirmed SARS-CoV-2 infection through household contact; these results did not reach statistical significance.
Pharmacokinetics: 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 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 × 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 metabolized by CYP3A4. Nirmatrelvir is not a substrate of other CYP enzymes. Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In human plasma, the only drug-related entity quantifiable was unchanged nirmatrelvir.
In vitro studies utilizing 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 metabolized by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of ritonavir.
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 feces, respectively. Nirmatrelvir was the predominant drug-related entity with small amounts of metabolites arising from hydrolysis reactions in excreta.
Human studies with radiolabeled 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, there were no clinically significant differences in the pharmacokinetics of nirmatrelvir based on age and gender.
Pediatric patients: The pharmacokinetics of nirmatrelvir/ritonavir in pediatric patients have not been evaluated.
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 participants with severe renal impairment were 48% and 204% higher, respectively.
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.
Drug 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.
Drug interaction studies conducted with nirmatrelvir/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 co-administration of PAXLOVID with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and C_max are summarized in Table 6. (See Table 6.)

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The effects of co-administration of PAXLOVID with 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 7. (See Table 7.)

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Toxicology: Preclinical safety data: 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 drug-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: 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.
Genotoxicity: 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, there were no nirmatrelvir effects on fertility and reproductive performance at doses up to 1,000 mg/kg/day representing 5x clinical exposures at the approved dose of PAXLOVID.
Embryo-fetal developmental (EFD) toxicity studies were conducted in pregnant rats and rabbits administered oral nirmatrelvir doses of up to 1,000 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 1,000 mg/kg/day, the systemic nirmatrelvir exposure (AUC₂₄) in rats was approximately 9x higher than clinical exposures at the approved human dose of PAXLOVID. In the rabbit EFD study, lower fetal body weights (9% decrease) were observed at 1,000 mg/kg/day in the absence of significant maternal toxicity findings. At 1,000 mg/kg/day, the systemic exposure (AUC₂₄) in rabbits was approximately 11x higher than clinical exposures at the approved human dose of PAXLOVID. No other significant developmental toxicities (malformations and embryo-fetal lethality) were observed at up to the highest dose tested, 1,000 mg/kg/day. No developmental effects were observed in rabbits at 300 mg/kg/day resulting in systemic exposure (AUC₂₄) approximately 3x 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 9x 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 6x 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 GD 6 through 19 in rabbits). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at systemic exposures (AUC) 5x (rats) or 8x (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 fetal body weights were observed in rats in the presence of maternal toxicity, at systemic exposures approximately 10x higher than exposure at the approved human dose of PAXLOVID. In rabbits, resorptions, decreased litter size, and decreased fetal weights were observed at maternally toxic doses, at systemic exposures greater than 8x higher than exposure at the approved human dose of PAXLOVID. In a pre- and postnatal development study in rats, administration of 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 10x the exposure at the approved human dose of PAXLOVID.

PAXLOVID is indicated for the treatment of mild-to-moderate Coronavirus Disease 2019 (COVID-19) in adults who are at high risk for progression to severe COVID-19, including hospitalization or death.

PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets.
Nirmatrelvir must be co-administered with ritonavir. Failure to correctly co-administer nirmatrelvir with ritonavir may result in plasma levels of nirmatrelvir that are 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 for 5 days. PAXLOVID should be given as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptom onset even if baseline COVID-19 symptoms are mild. If a patient requires hospitalization due to severe or critical COVID-19 after starting treatment with PAXLOVID, it is recommended that the patient should complete the full 5-day treatment course per the healthcare provider's discretion.
If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.
Patient selection: The following medical conditions or other factors place adult patients at high risk for progression to severe COVID-19: Older age (e.g., 60 years of age and older); Obesity or being overweight [e.g., body mass index (BMI) >25 kg/m²]; Current smoker; Chronic kidney disease; Diabetes; Immunosuppressive disease or immunosuppressive treatment; Cardiovascular disease (including congenital heart disease) or hypertension; Chronic lung disease [e.g., chronic obstructive pulmonary disease, asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, and pulmonary hypertension]; Sickle cell disease; Neurodevelopmental disorders (e.g., cerebral palsy, Down's syndrome) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes and severe congenital anomalies); Active cancer; Medical-related technological dependence not related to COVID-19 (e.g., tracheostomy, gastrostomy, or positive pressure ventilation).
Other medical conditions or factors (e.g., race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and are not limited to the medical conditions or factors listed previously. Healthcare providers should consider the benefit-risk for an individual patient.
Special populations: Pediatric population: The safety and efficacy of PAXLOVID have not been studied in patients younger than 18 years of age.
Renal impairment: No dosage adjustment is needed in patients with mild renal impairment (eGFR ≥60 to <90 mL/min).
In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), the dose of PAXLOVID should be reduced to nirmatrelvir/ritonavir 150 mg/100 mg twice daily for 5 days.
Note: The daily blister contains two separated parts each containing two tablets of nirmatrelvir and one tablet of ritonavir corresponding to the daily administration at the standard dose. Therefore, patients with moderate renal impairment should be alerted on the fact that only one tablet of nirmatrelvir with the tablet of ritonavir should be taken every 12 hours.
PAXLOVID is not recommended in patients with severe renal impairment (eGFR <30 mL/min) until more data are available; the appropriate dosage for patients with severe renal impairment has not been determined (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dosage adjustment is needed in patients with 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 participants with severe (Child-Pugh Class C) hepatic impairment; therefore, PAXLOVID is not recommended for use in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Concomitant therapy with ritonavir- or cobicistat-containing regimen: No dose 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 Pharmacology: Pharmacokinetics under Actions). The tablets should be swallowed whole and not chewed, broken, or crushed.

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.

PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity to the active substances (nirmatrelvir/ritonavir) or to any of the product excipients.
PAXLOVID is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions (see Interactions). Drugs listed in this section and Interactions are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated with PAXLOVID.
Alpha 1-adrenoreceptor antagonist: alfuzosin.
Antianginal: ranolazine.
Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine.
Anti-gout: colchicine.
Antipsychotics: lurasidone, pimozide.
Benign prostatic hyperplasia agents: silodosin.
Cardiovascular agents: eplerenone, ivabradine.
Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine.
HMG-CoA reductase inhibitors: lovastatin, simvastatin.
Immunosuppressants: voclosporin.
Microsomal triglyceride transfer protein inhibitor: lomitapide.
Migraine medications: eletriptan, ubrogepant.
Mineralocorticoid receptor antagonists: finerenone.
Non-opioid analgesic (selective blocker of Na_v1.8 sodium channels): suzetrigine.
Opioid antagonists: naloxegol.
PDE5 inhibitor: sildenafil when used for pulmonary arterial hypertension (PAH).
Sedative/hypnotics: triazolam, oral midazolam.
Serotonin receptor 1A agonist/serotonin receptor 2A antagonist: flibanserin.
Vasopressin receptor antagonists: tolvaptan.
PAXLOVID is contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer (see Interactions).
Anticancer drugs: apalutamide, enzalutamide.
Anticonvulsant: carbamazepine, phenobarbital, primidone, phenytoin.
Antimycobacterials: rifampin, rifapentine.
Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor.
Herbal products: St. John's Wort (Hypericum perforatum).

Risk of serious adverse reactions due to drug interactions: Initiation of PAXLOVID, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of medications metabolized by CYP3A.
Initiation of medications 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 medications.
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 9 for drugs that are contraindicated for concomitant use with nirmatrelvir/ritonavir and for potentially significant interactions with other drugs (see Interactions; also see Contraindications for drugs that are contraindicated for concomitant use). Potential for drug interactions should be considered prior to and during PAXLOVID therapy; concomitant medications should be reviewed during PAXLOVID therapy and the patient should be monitored for the adverse reactions associated with the concomitant medications.
Co-administration 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 co-administration by closely and regularly monitoring immunosuppressant blood concentrations and adjusting the dose of the immunosuppressant in accordance with the latest guidelines (see Interactions).
Hypersensitivity reactions: Anaphylaxis, hypersensitivity reactions, and serious skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported with PAXLOVID (see Adverse Reactions). 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.
Risk of HIV-1 resistance development: Because nirmatrelvir is co-administered 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.
Effects on ability to drive and use machines: There are no clinical studies that evaluated the effects of PAXLOVID on ability to drive and use machines.

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 and for 7 days after completing PAXLOVID treatment.
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 with PAXLOVID, and until one menstrual cycle after stopping PAXLOVID (see Interactions).
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 fetus.
Animal data with nirmatrelvir have shown developmental toxicity in the rabbit (lower fetal body weights) but not in the rat. There was no nirmatrelvir-related effect on fetal morphology or embryo-fetal viability at any dose tested in rat or rabbit embryo-fetal developmental toxicity studies. There were no nirmatrelvir-related adverse effects in a pre- and postnatal developmental study in rats (see Pharmacology: Toxicology: Preclinical safety data under Actions).
A large number (6,100 live births) of pregnant women were exposed to ritonavir during pregnancy; of these, 2,800 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 PK 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 Pharmacology: Toxicology: Preclinical safety data under Actions).
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 breast milk in small amounts, with a milk to plasma AUC ratio of 0.26 and 0.07, respectively. The estimated daily infant dose (assuming average milk consumption of 150 mL/kg/day), was 1.8% and 0.2% 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 completing PAXLOVID treatment.
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 Pharmacology: Toxicology: Preclinical safety data under Actions).
There are no human data on the effect of ritonavir on fertility. Ritonavir produced no effects on fertility in rats.

Summary of the safety profile: The safety of PAXLOVID was based on data from three Phase 2/3 randomized, placebo-controlled trials in adult participants 18 years of age and older (see Pharmacology: Pharmacodynamics under Actions): 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 diarrhea (2.9% and 1.9%, respectively).
Tabulated summary of adverse drug reactions (ADRs): The adverse drug reactions in Table 8 are listed as follows by system organ class. (See Table 8.)

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PAXLOVID (nirmatrelvir/ritonavir) is a strong inhibitor of CYP3A and an inhibitor of CYP2D6, P-gp and OATP1B1. Co-administration of PAXLOVID with drugs that are primarily metabolized by CYP3A and CYP2D6 or are transported by P-gp or OATP1B1 may result in increased plasma concentrations of such drugs and increase the risk of adverse reactions.
Drugs that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in exposure when co-administered with nirmatrelvir/ritonavir. Thus, 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 (see Contraindications).
Co-administration of other CYP3A4 substrates that may lead to potentially significant interaction should be considered only if the benefits outweigh the risks (see Table 9).
Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce PAXLOVID therapeutic effect.
Drugs listed in Table 9 are a guide and not considered a comprehensive list of all possible drugs that may interact with nirmatrelvir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information. (See Tables 9a, 9b and 9c.)

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Incompatibilities: Not applicable.
Special precautions for disposal and other handling: No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Special precautions for storage: Store at or below 30°C.

Antivirals

J05AE30 - nirmatrelvir and ritonavir ; Belongs to the class of protease inhibitors. Used in the systemic treatment of viral infections.

POM