1 Name of Medicine
Paxlovid contains nirmatrelvir tablets co-packaged with ritonavir tablets.
2 Qualitative and Quantitative Composition
Each nirmatrelvir film-coated tablet contains 150 mg of nirmatrelvir.
Each ritonavir film-coated tablet contains 100 mg ritonavir.
Excipient(s) with known effect.
Each nirmatrelvir tablet contains 176 mg lactose.
For the full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
Nirmatrelvir.
Nirmatrelvir tablets are oval, pink immediate-release, film-coated tablets debossed with "PFE" on one side and "3CL" on the other side.
Ritonavir.
Ritonavir tablets are white to off-white coated, oval tablets debossed with the "a" logo and "NK"; or white to off-white film coated oval tablets debossed with "NK" on one side.4.1 Therapeutic Indications
Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults 18 years of age and older, who do not require initiation of supplemental oxygen due to COVID-19 and are at increased risk of progression to hospitalisation or death (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
4.2 Dose and Method of Administration
Nirmatrelvir must be taken together with ritonavir. Failure to correctly take nirmatrelvir with ritonavir will result in plasma levels of nirmatrelvir that will be insufficient to achieve the desired therapeutic effect.
Dosage.
The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) taken together orally every 12 hours for 5 days.
Paxlovid should be taken as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptoms onset even if baseline COVID-19 symptoms are mild. Paxlovid treatment should not be initiated in patients requiring hospitalisation due to severe or critical COVID-19. 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 their healthcare provider.
Paxlovid (both nirmatrelvir and ritonavir tablets) can be taken with or without food (see Section 5.2 Pharmacokinetic Properties). The tablets should be swallowed whole and not chewed, broken, or crushed.
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.
Dose adjustment.
Renal impairment. Mild (eGFR ≥ 60 to < 90 mL/min/1.73 m2).
No dose adjustment is needed in patients with mild renal impairment.
Moderate (eGFR ≥ 30 to < 60 mL/min/1.73 m2).
In patients with moderate renal impairment, the dose of Paxlovid should be reduced to nirmatrelvir/ritonavir 150 mg/100 mg every 12 hours for 5 days to avoid increased toxicity due to over-exposure (this dose adjustment has not been clinically tested).
Note.
The daily blister contains two separated parts each containing 2 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.
Severe (eGFR < 30 mL/min/1.73 m2).
Appropriate dose for patients with severe renal impairment has not yet been determined. Paxlovid is contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) until more data are available; the appropriate dosage for patients with severe renal impairment has not been determined (see Section 4.3 Contraindications).
Hepatic impairment. Mild and moderate.
No dosage adjustment of Paxlovid is needed for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.
Severe.
No pharmacokinetic or safety data are available regarding the use of nirmatrelvir or ritonavir in subjects with (Child-Pugh Class C) severe hepatic impairment, therefore, Paxlovid is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).
Paediatric use. The safety and efficacy of Paxlovid in paediatric patients younger than 18 years of age have not yet been established. No data are available.4.3 Contraindications
Paxlovid is contraindicated in patients with a history of clinically significant hypersensitivity reactions to its active ingredients (nirmatrelvir/ritonavir) or any other components of the product listed in Section 6.1 List of Excipients.
Paxlovid is contraindicated in patients with severe renal impairment.
Paxlovid is contraindicated in patients with severe hepatic impairment.
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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Drugs listed in this section and Section 4.5 are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated with Paxlovid.
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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
4.4 Special Warnings and Precautions for Use
Risk of serious adverse reactions due to interactions with other medicines.
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 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 Tables 1 and 2 for medicinal products that are contraindicated for concomitant use with Paxlovid (see Section 4.3 Contraindications) and Table 3 for potentially significant interactions with other medicinal products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Consider the potential for interactions with other medicinal products prior to and during Paxlovid therapy; review concomitant medications during Paxlovid therapy and monitor 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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 Adverse Effects (Undesirable Effects)). 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 (see Section 4.2 Dose and Method of Administration, Hepatic impairment).
Risk of HIV-1 resistance development.
As nirmatrelvir is co-administered 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.
Excipients.
Paxlovid contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. The level of lactose within this preparation should not routinely preclude the use of this medication in those with galactosaemia.
Nirmatrelvir and ritonavir each contain less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.
Use in 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 hepatic impairment (Child-Pugh Class C), therefore, Paxlovid is not recommended for use in patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration, Hepatic impairment; Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Patients with hepatic impairment).
Use in renal impairment.
Systemic exposure of nirmatrelvir increases in renally impaired patients with increase in the severity of renal impairment (see Section 5.2 Pharmacokinetic Properties).
No dose adjustment is needed in patients with mild renal impairment. In patients with moderate renal impairment the dose of Paxlovid should be reduced. (See Section 4.2 Dose and Method of Administration, Renal impairment.) Paxlovid is contraindicated in patients with severe renal impairment (see Section 4.3 Contraindications).
Use in the elderly.
Clinical studies of Paxlovid include participants 65 years of age and older and their data contributes to the overall assessment of safety and efficacy (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials). Of the total number of participants in EPIC-HR randomised to receive Paxlovid (N = 1,120), 13% were 65 years of age and older and 3% were 75 years of age and older.
Paediatric use.
The safety and efficacy of Paxlovid in paediatric patients younger than 18 years of age have not yet been established. No data available.
Effects on laboratory tests.
Ritonavir has been associated with alterations in cholesterol, triglycerides, AST, ALT, GGT, CPK and uric acid (also see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment). For comprehensive information concerning laboratory test alterations associated with nucleoside analogues, physicians should refer to the complete product information for each of these drugs.4.5 Interactions with Other Medicines and Other Forms of Interactions
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 metabolised 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.
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 co-administered with nirmatrelvir/ritonavir. Thus, co-administration 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 Section 4.3 Contraindications, Table 1).
Nirmatrelvir does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8 and CYP1A2 or UGT1A1, UGT1A4, UGTA6, UGT1A9, UGT2B7 and UGTB15 in vitro at clinically relevant concentrations. Nirmatrelvir is unlikely to be an inducer of CYP1A2, CYP2C19, CYP2B6, CYP2C8 and CYP2C9 enzymes. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE1, MATE2K, OAT1, OAT3, OATP1B3, OCT1 and OCT2.
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6 > CYP2C9, CYP2C19 >> CYP2A6, CYP1A2, CYP2E1. 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.
Co-administration of other CYP3A4 substrates that may lead to potentially significant drug interactions should be considered only if the benefits outweigh the risks (see Table 3).
Nirmatrelvir and ritonavir are CYP3A substrates; therefore, medicinal products that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce Paxlovid therapeutic effect.
The drug-drug interactions listed in Tables 1 and 2 (see Section 4.3 Contraindications) and Table 3 correspond to drug-drug interactions related to ritonavir. As a conservative approach, they should also apply for Paxlovid.
Medicinal products listed in Tables 1 and 2 (see Section 4.3 Contraindications) 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.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
There are no human data on the effect of Paxlovid on fertility.
Nirmatrelvir.
No human data on the effect of nirmatrelvir on fertility are available.
There were no nirmatrelvir-related effects on fertility and reproductive performance in male and female rats treated orally at doses up to 1,000 mg/kg/day for 14 days before mating, resulting in systemic exposure approximately 5 times the human exposure based on total AUC at the recommended clinical dose.
Ritonavir.
There are no human data on the effect of ritonavir on fertility. Ritonavir produced no effects on fertility in rats.
(Category B3)
Paxlovid is not recommended during pregnancy and in women of childbearing potential not using contraception.
There are limited human data on the use of Paxlovid during pregnancy to evaluate the drug-associated risk of adverse developmental outcomes; women of childbearing potential should avoid becoming pregnant during treatment and until after 7 days after stopping Paxlovid.
Nirmatrelvir.
The potential embryo-fetal toxicity of nirmatrelvir was evaluated in rats and rabbits. Animal data with nirmatrelvir have shown developmental toxicity in rabbits (lower fetal body weights) but not in rats. There was no nirmatrelvir-related effect on rat embryo-fetal development up to the highest dose of 1,000 mg/kg/day (10 times the human exposure based on total AUC at the recommended clinical dose). In the rabbit embryo-fetal development study, adverse nirmatrelvir-related lower fetal body weights (9% decrease) were observed at the highest dose of 1,000 mg/kg/day (13 times the human exposure based on total AUC at the recommended clinical dose) in the presence of low magnitude effects on maternal body weight change and food consumption. These findings were not present at the intermediate dose of 300 mg/kg/day (14 x/3.6 x Cmax/AUC24 over the predicted clinical exposure).
There were no nirmatrelvir-related adverse effects in a pre- and postnatal developmental study in rats. In a pre- and postnatal developmental study in rats dosed with nirmatrelvir from gestation day 6 to lactation day 20, lower body weights (up to < 8% lower than that of the control group on postnatal day 17) were observed in the offspring of pregnant rats at 1000 mg/kg/day (10 times the human exposure based on total AUC at the recommended clinical dose). No significant differences in offspring body weight were observed from PND 28 to PND 56. No body weight changes in the offspring were noted at 300 mg/kg/day (6 times the human exposure based on total AUC at the recommended clinical human dose).
Ritonavir.
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 during a menstrual cycle after stopping Paxlovid (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
A large number of pregnant women exposed to ritonavir during pregnancy indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems.
Based on the review of data from the US Antiretroviral (ART) Pregnancy Registry through 31 July 2016, among women exposed to ritonavir-containing antiretroviral therapy (ART) during first trimester the prevalence rate of birth defects per 100 live births (65 cases in 2,983 enrolled) was 2.2% (95% CI 1.7, 2.8%). The prevalence rate of birth defects for exposure to ritonavir-containing ART during second/third trimester (97 cases in 3,330 enrolled) was 2.9% (95% CI 2.4%, 3.5%). In a reference population in the US CDC's birth defects surveillance system (MACDP) the reported background rate of birth defects is 2.7%. 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 PK enhancer for other protease inhibitors, similar to the ritonavir dose used for nirmatrelvir/ritonavir.
No treatment-related malformations were observed when ritonavir was administered orally to pregnant rats or rabbits. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage of 75 mg/kg/day. A slight increase in the incidence of cryptorchidism was also noted in rats given 35 mg/kg/day. Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage of 110 mg/kg/day. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
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 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 breastfed 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.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
4.8 Adverse Effects (Undesirable Effects)
The safety of Paxlovid is based on data from three phase 2/3 randomised, placebo controlled trials in adult participants 18 years of age and older (see Section 5.1 Pharmacodynamic Properties):
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 had mild to moderate COVID-19 disease 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).
In Study C4671005 (EPIC-HR), the proportions of subjects who discontinued treatment due to an adverse event were 21 (2.0%) in the Paxlovid group and 45 (4.3%) in the placebo group. The proportion of subjects with serious adverse events were 18 (1.7%) and 71 (6.7%) in the Paxlovid group and in the placebo group, respectively. See Table 4.
The adverse drug reactions in Table 5 are listed by system organ class and frequency. Frequencies are defined as follows: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); not known (frequency cannot be estimated from the available data).
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication. Nirmatrelvir was shown to be an inhibitor of SARS-CoV-2 Mpro (Ki=3.1 nanoM, or IC50=19.2 nanoM) in a biochemical enzymatic assay. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography.
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 nanoM and EC90 value of 181 nanoM) after 3 days of drug exposure.
Nirmatrelvir had similar cell culture antiviral activity (EC50 values in the low nanomolar range ≤ 1.1-fold relative to USA-WA1/2020) against SARS-CoV-2 isolates belonging to the Alpha (B.1.1.7), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621.1) and Omicron (B.1.1.529/BA.1) variants assessed in Vero E6 P-gp knockout cells. The Beta (B.1.351) variant was the least susceptible tested variant with approximately 3.7-fold reduced susceptibility relative to the USA-WA1/2020 isolate.
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, and XBB.1.5 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC50 value of 72 nanoM (range: 39-146 nanoM) against the Omicron sub-variants, reflecting EC50 value fold-changes ≤ 1.5 relative to the USA-WA1/2020 isolate.
Nirmatrelvir showed antiviral activity in different assays than those used for the other variants of concern against the Omicron variant with IC50 values of 70 nanoM and 23 nanoM in the HeLa-ACE2 and Vero-TMPRSS cells compared to the SARS-CoV-2 USA-WA1/2020 strain which had IC50 values of 207 nanoM and 38 nanoM in the same cell lines, respectively, using an immunostaining-based method.
Antiviral resistance in cell culture and biochemical assays.
SARS-CoV-2 Mpro 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 Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2 Mpro containing amino acid substitutions. Table 6 indicates Mpro substitutions and combinations of Mpro substitutions that have been observed in nirmatrelvir-selected SARS-CoV-2 in cell culture. Individual Mpro substitutions are listed regardless of whether they occurred alone or in combination with other Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro 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 Mpro containing amino acid substitutions, the following SARS-CoV-2 Mpro 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 Mpro 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 (0.9), 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 Mpro 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. Virus containing E166V, which confers high resistance, appears to have replication defect since it either could not be generated or had a very low virus titre although double mutants E166V + T21I or L50F replicated well with growth kinetics similar to WT. Both T21I and L50F rescued the replication defect conferred by E166V and double mutants T21I + E166V and L50F + E166V, as well as E166V, are highly resistant to nirmatrelvir. In general, triple and some double Mpro 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 (≥ 5x EC90). Thus far, these substitutions have not been identified as treatment-emergent substitutions associated hospitalisation from the EPIC-HR or the 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 Mpro 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 Mpro substitutions were observed: T98I/R/del (n=4), E166V (n=3), and W207L/R/del (n=4). Within the Mpro 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 Mpro substitutions.
None of the treatment-emergent substitutions listed above in Mpro or Mpro cleavage sites occurred in Paxlovid treated participants who experienced hospitalisation. Thus, the clinical significance of these substitutions is unknown.
Viral load rebound.
Post-treatment increases in SARS-CoV-2 RNA shedding levels (i.e. viral RNA rebound) in nasopharyngeal samples were observed on Day 10 and/or Day 14 in both nirmatrelvir-ritonavir and placebo recipients in the EPIC-HR and EPIC-SR studies. Viral RNA rebound was detected in 4.2% (36 of 852) of placebo participants and 6.3% (54 of 862) of nirmatrelvir-ritonavir participants in the EPIC-HR study. In the EPIC-SR study, viral RNA rebound was detected in 4.6% (27 of 584) of placebo participants and 5.5% (33 of 599) of nirmatrelvir-ritonavir participants. The results of EPIC-HR and EPIC-SR do not suggest an association between viral RNA rebound and COVID-19 related hospitalisation or death from any cause. The clinical relevance of viral RNA rebound following Paxlovid or placebo remains unclear.
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 Mpro inhibitors).
Pharmacodynamic effects.
Cardiac electrophysiology.
At 3 times the steady state peak plasma concentration (Cmax) at the recommended dose, nirmatrelvir does not prolong the QTc interval to any clinically relevant extent.
Effects on viral RNA levels.
Changes in viral RNA levels in nasopharyngeal samples from baseline to Day 5 were evaluated in 1,359 participants who had a detectable nasal viral load by RT-PCR at baseline in EPIC-HR, and 971 participants in EPIC-SR. In EPIC-HR and EPIC-SR the mean viral load reduction in Paxlovid recipients relative to placebo was -0.777 log10 copies/mL (95% CI: -0.937, -0.617) and -0.868 log10 copies/mL (95% CI: -1.073, -0.663), respectively.
Clinical trials.
Efficacy in participants at high risk of progressing to severe COVID-19 illness (EPIC-HR).
The efficacy of Paxlovid is based on the analysis of EPIC-HR, a Phase 2/3, randomised, double-blind, placebo-controlled study in non-hospitalised symptomatic adult participants with a 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, diabetes, sickle cell disease, neurodevelopmental disorders, active cancer or medically-related technological dependence, or were 60 years of age and older regardless of comorbidities. The study excluded individuals with a known history of prior COVID-19 infection or vaccination. 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 primary efficacy endpoint is 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 at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment), the mITT1 analysis set (all treated subjects 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 subjects with onset of symptoms ≤ 5 days).
A total of 2,213 participants were randomised to receive either Paxlovid or placebo. At baseline, mean age was 45 years with 51% were male; 71% were White, 4% were Black or African American, and 15% were Asian; 41% were Hispanic or Latino; 67% of subjects had onset of symptoms ≤ 3 days before initiation of study treatment; 49% of subjects were serological negative at baseline; the mean (SD) baseline viral load was 4.71 log10 copies/mL (2.89); 27% of subjects 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.
At the primary completion date (PCD) analysis, 697 (62.2%) participants in the Paxlovid group and 682 (60.6%) participants in the placebo group were included in the mITT analysis set. The event rate of a COVID-19-related hospitalisation or death from any cause through Day 28 in the mITT analysis set in participants who received treatment within 3 days of symptom onset was 44/682 (6.45%) in the placebo group, and 5/697 (0.72%) in the Paxlovid group. The Paxlovid group showed a 5.81% (95% CI: -7.78% to -3.84; p < 0.0001) absolute reduction, or 88.9% relative reduction in primary endpoint events compared to placebo. No deaths were reported in the Paxlovid group compared with 9 deaths in the placebo group.
Table 7 provides results of the primary endpoint in 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: 73%, 93%).
Consistent results were observed in the mITT and mITT2 analysis populations. A total of 1318 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). These subgroup analyses are considered exploratory.
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 trial in non-hospitalised symptomatic adult subjects with a laboratory confirmed diagnosis of SARS-CoV-2 infection. Eligible subjects were 18 years of age or older with COVID-19 symptom onset of ≤ 5 days who were at standard risk for progression to severe disease. The trial included previously unvaccinated subjects with no risk factors for progression to severe disease or subjects fully vaccinated against COVID-19 (i.e. completed a primary vaccination series) with at least 1 of the risk factors for progression to severe disease as defined in EPIC-HR. A total of 1,296 subjects were randomised (1:1) to receive Paxlovid or placebo orally every 12 hours for 5 days; of these, 49% were fully vaccinated with at least 1 risk factor for progression to severe disease.
The primary endpoint in this trial, 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.
In an exploratory analysis of the subgroup of fully vaccinated subjects with at least 1 risk factor for progression to severe disease, a non-statistically significant numerical reduction (3/317 (0.9%) Paxlovid recipients versus 7/314 (2.2%) placebo recipients) relative to placebo for the secondary endpoint of COVID-19 related hospitalisation or death from any cause through Day 28 was observed.
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.
The results of the primary endpoint for EPIC-PEP are presented in Table 9.
5.2 Pharmacokinetic Properties
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 (t1/2) 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 as oral suspension formulation to healthy participants in the fasted state, the geometric mean (CV%) maximum concentration (Cmax) and area under the plasma concentration-time curve from 0 to the time of last measurement (AUClast) was 2.88 microgram/mL (25%) and 27.6 microgram.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.
Absorption.
Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir (CV%) Cmax and area under the plasma concentration time curve from 0 to infinity (AUCinf) was 2.21 microgram/mL (33) and 23.01 microgram.hr/mL (23), respectively. The median (range) time to Cmax (Tmax) 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%) Cmax and (AUCinf) was 0.36 microgram/mL (46) and 3.60 microgram.hr/mL (47), respectively. The median (range) time to Cmax (Tmax) 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 Cmax and 20% increase in mean AUClast) relative to fasting conditions following administration of a 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%.
Metabolism.
Nirmatrelvir.
In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolised by CYP3A4. 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.
Ritonavir.
Nearly all of the plasma radiolabel after a single oral 600 mg dose of radiolabelled ritonavir was attributed to unchanged ritonavir. Four ritonavir metabolites have been identified in man. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite. The AUC of the M-2 metabolite was approximately 3% of the AUC of parent drug. Studies utilising human liver microsomes have demonstrated that CYP3A4 is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formulation of M-2. The metabolites are principally eliminated in the faeces.
Excretion.
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.
Special populations.
The pharmacokinetics of nirmatrelvir/ritonavir based on age and gender 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.
Patients with renal impairment.
An open-label study compared nirmatrelvir/ritonavir pharmacokinetics in healthy adult subjects and subjects with mild (eGFR ≥ 60 to < 90 mL/min/1.73 m2), moderate (eGFR ≥ 30 to < 60 mL/min/1.73 m2), and severe (eGFR < 30 mL/min/1.73 m2) 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. Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in patients with mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was 38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher, respectively. See Table 10.
Patients with hepatic impairment.
A single oral dose of 100 mg nirmatrelvir enhanced with 100 mg ritonavir at -12 hours, 0 hours, 12 hours and 24 hours in subjects with moderate hepatic impairment resulted in similar exposures compared to subjects with normal hepatic function (see Table 11).
The pharmacokinetics of nirmatrelvir/ritonavir have not been evaluated in patients with severe hepatic impairment.
Drug 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 drugs that are primarily metabolised by CYP3A. Despite being co-administered with ritonavir as a pharmacokinetic enhancer, there is potential for strong inhibitors and inducers to alter the pharmacokinetics of nirmatrelvir.
The effects of co-administration of Paxlovid with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and Cmax are summarised in Table 12 (effect of other medicinal products on nirmatrelvir).
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 AUCinf and Cmax, respectively, are summarised in Table 13.
5.3 Preclinical Safety Data
No nonclinical safety studies have been conducted with nirmatrelvir in combination with ritonavir. Complete nonclinical development program was conducted on the individual entities (nirmatrelvir and ritonavir) and no nonclinical combination toxicity studies were performed.
Genotoxicity.
Paxlovid has not been evaluated for the potential to cause genotoxicity.
Nirmatrelvir.
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.
Ritonavir showed no mutagenic potential in a series of assays for gene mutations (S. typhimurium, E. coli and mouse lymphoma cells) and chromosomal damage (mouse micronucleus assay in-vivo and human lymphocytes in-vitro).
Carcinogenicity.
Paxlovid has not been evaluated for the potential to cause carcinogenicity.
Nirmatrelvir.
Nirmatrelvir has not been evaluated for the potential to cause carcinogenicity.
Ritonavir.
Two-year carcinogenicity studies have been conducted in rodents, at ritonavir dietary levels of 50, 100 and 200 mg/kg/day in mice, and 7, 15 and 30 mg/kg/day in rats. In male mice there was a dose dependent increase in the incidence of hepatocellular adenomas, and adenomas and carcinomas combined, both reaching statistical significance only at the high-dose. In female mice there were small, statistically significant increases in these tumour incidences only at the high-dose. In rats, there were no tumorigenic effects.6 Pharmaceutical Particulars
6.1 List of Excipients
Nirmatrelvir.
Tablet core.
Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal anhydrous silica, sodium stearylfumarate.
Film coat.
Opadry Complete Film Coating System 05B140011 Pink.
Ritonavir.
Tablet core.
Copovidone, calcium hydrogen phosphate, sorbitan monolaurate, colloidal anhydrous silica, sodium stearylfumarate.
Film coating.
Hypromellose, titanium dioxide, macrogol 400, hyprolose, purified talc, macrogol 3350, colloidal anhydrous silica, polysorbate 80.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C.
6.5 Nature and Contents of Container
Paxlovid is supplied in a carton containing five PA/Al/PVC/Al blister cards marked as "Morning Dose" and "Evening Dose" for tablets to be taken each morning and each evening. Paxlovid is available in the following pack sizes (see Table 14):
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Chemical structure.
Nirmatrelvir.
Chemical name: (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl) ethyl)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide.
The molecular formula is C23H32F3N5O4 and the molecular weight is 499.54.
CAS number.
2628280-40-8.
Chemical structure.
Ritonavir.
Chemical name: 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)].
The molecular formula is C37H48N6O5S2 and the molecular weight is 720.95.
CAS number.
155213-67-5.7 Medicine Schedule (Poisons Standard)
Schedule 4 - Prescription Only Medicine.
Summary Table of Changes
