Paxlovid

Nirmatrelvir, ritonavir.

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 to off white, capsule shaped tablets, with a dimension of approximately 17.1 mm in length and 9.1 mm in width, debossed with 'H' on one side and 'R9' on other side.
Each white to off white ritonavir film-coated tablet contains 100 mg of ritonavir.
Excipients with known effect: Each nirmatrelvir 150 mg film-coated tablet contains 176 mg of lactose.
Excipients/Inactive Ingredients: Nirmatrelvir: Tablet core: Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium, Colloidal silicon dioxide, Sodium stearyl fumarate.
Film-coat: Hypromellose (E464), Titanium dioxide (E171), Macrogol (E1521), Iron oxide red (E172).
Ritonavir: Tablet core: Copovidone, Sorbitan laurate, Colloidal anhydrous silica (E551), Anhydrous calcium hydrogen phosphate, Sodium stearyl fumarate.
Film-coat: Hypromellose (E464), Titanium dioxide (E171), Macrogol (E1521), Hydroxypropyl cellulose (E463), Talc (E553b), Colloidal anhydrous silica (E551), Polysorbate 80 (E433).

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals. ATC code: Not yet assigned.
Pharmacology: Pharmacodynamics: Mechanism of action: Nirmatrelvir is a peptidomimetic inhibitor of the coronavirus 3C-like (3CL) protease, including the SARS-CoV-2 3CL protease. Inhibition of the 3CL protease renders the protein incapable of processing polyprotein precursors which leads to the prevention of viral replication. Nirmatrelvir was shown to be a potent inhibitor of SARS-CoV-2 3CL protease (Ki=0.00311 μM or IC₅₀=0.0192 μM) in a biochemical enzymatic assay.
Ritonavir is not active against SARS-CoV-2 3CL protease. 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 dNHBE cells, a primary human lung alveolar epithelial cell line (EC90 value of 181 nM) after Day 3 post-infection.
In vivo antiviral activity: Nirmatrelvir showed antiviral activity in mouse models with mouse-adapted SAR-CoV-2 infection in BALB/c and 129 mouse strains. Oral administration of nirmatrelvir at 300 mg/kg or 1,000 mg/kg twice daily initiated 4 hours post-inoculation or 1,000 mg/kg twice daily initiated 12 hours post inoculation with SARS-CoV-2 MA10 resulted in reduction of lung viral titres and ameliorated indicators of disease (weight loss and lung pathology) compared to placebo-treated animals.
Antiviral resistance: Because nirmatrelvir is coadministered with low dose ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.
Pharmacodynamic effects: Cardiac electrophysiology: No clinically relevant effect of nirmatrelvir on QTcF interval was observed in a double-blind, randomised, placebo-controlled, cross-over study in 10 healthy adults. The model predicted upper bound of 90% confidence interval (CI) for baseline and ritonavir adjusted QTcF estimate was 1.96 ms at approximately 4-fold higher concentration than the mean steady-state peak concentration after a therapeutic dose of nirmatrelvir/ritonavir 300 mg/100 mg.
Clinical efficacy and safety: The efficacy of Paxlovid is based on the interim analysis and the supporting final analysis of EPIC-HR, a Phase 2/3, randomised, double-blind, placebo-controlled study in non-hospitalised, symptomatic adult participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection. 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. The study excluded individuals with a history of prior COVID-19 infection or vaccination.
Participants were randomised (1:1) to receive Paxlovid (nirmatrelvir 300 mg/ritonavir 100 mg) or placebo orally every 12 hours for 5 days. The primary efficacy endpoint was the proportion of participants with COVID-19 related hospitalisation or death from any cause through Day 28. The analysis was conducted in the modified intent-to-treat (mITT) analysis set [all treated subjects with onset of symptoms ≤3 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonal antibody (mAb) treatment], the mITT1 analysis set (all treated 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 2,246 participants were randomised to receive either Paxlovid or placebo. At baseline, mean age was 46 years with 13% of participants 65 years of age and older (3% were 75 years of age and older); 51% were male; 72% were White, 5% were Black, and 14% were Asian; 45% were Hispanic or Latino; 66% of participants had onset of symptoms ≤3 days from initiation of study treatment; 81% had a BMI ≥25 kg/m² (37% a BMI ≥30 kg/m²); 12% had diabetes mellitus; less than 1% of the study population had immune deficiency, 47% of participants were serological negative at baseline and 51% were serological positive. The mean (SD) baseline viral load was 4.63 log₁₀ copies/mL (2.87); 26% of participants had a baseline viral load of >10^7 (copies/mL); 6.2% 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 primary SARS-CoV-2 variant across both treatment arms was Delta (98%), mostly clade 21J (based on interim analysis).
The baseline demographic and disease characteristics were balanced between the Paxlovid and placebo groups.
The determination of primary efficacy was based on a planned interim analysis of 774 subjects in mITT population. The estimated risk reduction was -6.3% with unadjusted 95% CI of (-9.0%, -3.6%) and a 95% CI of (-10.61%, -2.02%) when adjusting for multiplicity. The 2-sided p-value was <0.0001 with 2-sided significance level of 0.002.
Table 1 provides results of the primary endpoint in the mITT1 analysis population for the full data set at final study completion. (See Table 1.)

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The estimated risk reduction was -5.8% with 95% CI of (-7.8%, -3.8%) in participants dosed within 3 days of symptom onset, and -5.2% with 95% CI of (-7.9%, -2.5%) in the mITT1 subset of participants dosed >3 days from symptom onset.
Consistent results were observed in the final mITT and mITT2 analysis populations. A total of 1,379 subjects were included in the mITT analysis population. The event rates were 5/697 (0.72%) in the Paxlovid group, and 44/682 (6.45) in the placebo group. (See Table 2.)

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Efficacy results for mITT1 were consistent across subgroups of participants including age (≥65 years) and BMI (BMI >25 and BMI >30) and diabetes.
These subgroup analyses are considered exploratory. (See figure.)

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Pharmacokinetics: The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy participants.
Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic concentrations of nirmatrelvir. In healthy participants in the fasted state, the mean half-life (t_½) 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 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.
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 modestly increased the exposure of nirmatrelvir (approximately 15% increase in mean C_max and 1.6% increase in mean AUC_last) relative to fasting conditions following administration of a suspension formulation of nirmatrelvir coadministered with ritonavir tablets.
Distribution: The protein binding of nirmatrelvir in human plasma is approximately 69%.
The protein binding of ritonavir in human plasma is approximately 98-99%.
Biotransformation: In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir is primarily metabolised by CYP3A4. Nirmatrelvir does not reversibly inhibit CYP2D6, CYP2C9, CYP2C19, CYP2C8, or CYP1A2 in vitro at clinically relevant concentrations. In vitro study results showed nirmatrelvir may be inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9. The clinical relevance is unknown. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3 and OCT2. There is a potential for nirmatrelvir to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations. Administration of nirmatrelvir with ritonavir inhibits the metabolism of nirmatrelvir. In plasma, the only drug-related entity observed was unchanged nirmatrelvir. Minor oxidative metabolites were observed in the faeces and urine.
In vitro studies utilising human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of oxidation metabolite M-2.
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of ritonavir.
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Ritonavir also has a high affinity for P-glycoprotein (P-gp) and may inhibit this transporter. Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways and may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Elimination: The primary route of elimination of nirmatrelvir when administered with ritonavir was renal excretion of intact drug. Approximately 49.6% and 35.3% of the administered dose of nirmatrelvir 300 mg was recovered in urine and faeces, respectively. Nirmatrelvir was the predominant drug-related entity with small amounts of metabolites arising from hydrolysis reactions in excreta. In plasma, the only drug-related entity quantifiable was unchanged nirmatrelvir.
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir.
Specific populations: 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: Compared to healthy controls with no renal impairment, the C_max 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 3.)

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Patients with hepatic impairment: Compared to healthy controls with no hepatic impairment, the pharmacokinetics of nirmatrelvir in subjects with moderate hepatic impairment was not significantly different. (See Table 4.)

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Nirmatrelvir/ritonavir has not been studied in patients with severe hepatic impairment.
Interaction studies conducted with nirmatrelvir/ritonavir: CYP3A4 was the major contributor to the oxidative metabolism of nirmatrelvir, when nirmatrelvir was tested alone in human liver microsomes. Ritonavir is an inhibitor of CYP3A and increases plasma concentrations of nirmatrelvir and other drugs that are primarily metabolised by CYP3A. Despite being coadministered with ritonavir as a pharmacokinetic enhancer, there is potential for strong inhibitors and inducers to alter the pharmacokinetics of nirmatrelvir.
The effects of coadministration of Paxlovid with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on the nirmatrelvir AUC and C_max are summarised in Table 5 (effect of other medicinal products on nirmatrelvir). (See Table 5.)

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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 medicinal product-induced ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significant alteration in thyroid function tests.
Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no clinically significant renal abnormalities were noted in clinical trials.
Carcinogenesis: Paxlovid has not been evaluated for the potential to cause carcinogenicity.
Nirmatrelvir has not been evaluated for the potential to cause carcinogenicity.
Long-term carcinogenicity studies of ritonavir in mice and rats revealed tumorigenic potential specific for these species, but are regarded as of no relevance for humans.
Mutagenesis: Paxlovid has not been evaluated for the potential to cause mutagenicity.
Nirmatrelvir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human lymphoblastoid TK6 cells and in vivo rat micronucleus assays.
Ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Reproductive toxicity: Nirmatrelvir: In a fertility and early embryonic development study, nirmatrelvir was administered to male and female rats by oral gavage at doses of 60, 200, or 1,000 mg/kg/day once daily beginning 14 days prior to mating, throughout the mating phase, and continued through Gestation Day (GD) 6 for females and for a total of 32 doses for males. There were no effects on fertility, reproductive performance, or early embryonic development at doses up to 1,000 mg/kg/day representing 12x/4.3x based on the predicted human C_max/AUC₂₄ at a twice-daily dose of 300 mg/100 mg nirmatrelvir/ritonavir.
The potential embryo-foetal toxicity of nirmatrelvir was evaluated in the definitive rat and rabbit studies at doses up to 1,000 mg/kg/day. There was no nirmatrelvir-related effect in any of the parameters in the rat embryo-foetal development (EFD) study up to the highest dose of 1,000 mg/kg/day (exposure margin of 16x/7.8x based on total C_max/AUC₂₄ over the predicted human exposures at a dose of 300 mg/100 mg nirmatrelvir/ritonavir twice daily). In the rabbit EFD study, there was no nirmatrelvir-related effect on foetal morphology or embryo-foetal viability up to the highest dose of 1,000 mg/kg/day (exposure margin of 24x/10x based on total C_max/AUC₂₄), however adverse nirmatrelvir-related lower foetal body weights (0.91x control) were observed at 1,000 mg/kg/day in the presence of nonadverse, low magnitude effects on maternal body weight change and food consumption at this dose. Growth delay is likely reversible following cessation of exposure in human, and it was not present at the intermediate dose (10x/2.8x C_max/AUC₂₄ over the predicted clinical exposure). There were no nirmatrelvir-related severe manifestations of developmental toxicity (malformations and embryo-foetal lethality) at the highest dose tested, 1,000 mg/kg/day.
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 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits. Increased incidences of early resorptions, ossification delays and developmental variations, as well as decreased foetal body weights were observed in the rat in the presence of maternal toxicity. A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose). In the rabbit, resorptions, decreased litter size and decreased foetal weights were observed in the presence of maternal toxicity. In pre- and post-natal development study in rats, administration 0, 15, 35, and 60 mg/kg/day ritonavir from GD 6 through Post-natal Day 20 resulted in no developmental toxicity.

Paxlovid is indicated for the treatment of COVID-19 in patients with 18 years of age and older who do not require supplemental oxygen and who are at high risk for progression to severe COVID-19 (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions).

Paxlovid is nirmatrelvir tablets co-packaged with ritonavir tablets.
Nirmatrelvir must be coadministered with ritonavir. Failure to correctly coadminister Nirmatrelvir with ritonavir will result in plasma concentrations of nirmatrelvir that will be insufficient to achieve the desired therapeutic effect.
Posology: The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) all taken together orally twice daily for 5 days. Paxlovid should be given as soon as possible after positive results of direct SARS-CoV-2 viral testing and within 5 days of onset of symptoms.
Paxlovid can be taken with or without food. The tablets should be swallowed whole and not chewed, broken or crushed.
Usage limitation: Do not take Paxlovid more than 5 consecutive days because there is no safety and efficacy study support.
Do not use Paxlovid before or after exposure for purpose of COVID-19 prevention.
Do not use Paxlovid in another indication that is not for COVID-19 treatment.
If forget to take medicine: A missed dose should be taken as soon as possible and within 8 hours of the scheduled time, and the normal dosing schedule should be resumed. If more than 8 hours has elapsed, the missed dose should not be taken and the treatment should resume according to the normal dosing schedule.
If a patient requires hospitalization due to severe or critical COVID-19 after starting treatment with Paxlovid, the patient should complete the full 5-day treatment course at the discretion of his/her healthcare provider.
Patient selection: The following medical conditions or other factors may place adult patients 18 years of age and older 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 the approved use of Paxlovid is not limited to the medical conditions or factors listed as previously mentioned. Healthcare providers should consider the benefit-risk for an individual patient.
Special populations: Paediatric population: The safety and efficacy of Paxlovid in paediatric patients younger than 18 years of age have not yet been established.
Elderly: No dose adjustment is currently recommended for elderly patients.
Renal impairment: No dose adjustment is needed in patients with mild renal impairment. In patients with moderate renal impairment, the dose of Paxlovid should be reduced to nirmatrelvir/ritonavir 150 mg/100 mg (1 tablet of each) twice daily for 5 days. The remaining tablet of nirmatrelvir should be disposed of in accordance with local requirements (see Special precautions for disposal under Cautions for Usage).
Paxlovid is not recommended in patients with severe renal impairment (eGFR <30 ml/minute) or with renal failure as the appropriate dose has not yet been determined (see Pharmacology: Pharmacokinetics under Actions).
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 contraindicated in patients with severe hepatic impairment.
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.

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 excipients listed Description; with severe hepatic impairment; with severe renal impairment.
Paxlovid is also contraindicated with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions. Paxlovid is also contraindicated with medicinal products that are potent CYP3A inducers where significantly reduced plasma nirmatrelvir/ritonavir concentrations may be associated with the potential for loss of virologic response and possible resistance. (See Table 6.)

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There is limit of clinical data of Paxlovid. Severe and no reported adverse effects may be occurred more than report.
Risk of serious adverse reactions due to interactions with other medicinal products: Initiation of Paxlovid, a CYP3A inhibitor, in patients receiving medicinal products metabolised by CYP3A or initiation of medicinal products metabolised by CYP3A in patients already receiving Paxlovid, may increase plasma concentrations of medicinal products metabolised by CYP3A.
Initiation of medicinal products that inhibit or induce CYP3A may increase or decrease concentrations of Paxlovid, respectively.
These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life-threatening or fatal events from greater exposures of concomitant medicinal products; Clinically significant adverse reactions from greater exposures of Paxlovid; Loss of therapeutic effect of Paxlovid and possible development of viral resistance.
See Table 6 for medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir (see Contraindications) and Table 8 for potentially significant interactions with other medicinal products (see Interactions). Potential for interactions should be considered with other medicinal products prior to and during Paxlovid therapy; concomitant medicinal products should be reviewed during Paxlovid therapy and the patient should be monitored for the adverse reactions associated with the concomitant medicinal products. The risk of interactions with concomitant medications during the 5-day treatment period for Paxlovid should be weighed against the risk of not receiving Paxlovid.
Hepatotoxicity: Hepatic transaminase elevations, clinical hepatitis and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering Paxlovid to patients with pre-existing liver diseases, liver enzyme abnormalities or hepatitis.
HIV resistance: As nirmatrelvir is coadministered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.
Excipients: Nirmatrelvir tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Nirmatrelvir and ritonavir tablets each contain less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.
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 no human data on the use of Paxlovid during pregnancy to inform the drug-associated risk of adverse developmental outcomes, women of childbearing potential should avoid becoming pregnant during treatment with Paxlovid.
Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment and until after one complete menstrual cycle after stopping Paxlovid (see Interactions).
Pregnancy: There are no data from the use of Paxlovid in pregnant women. Paxlovid is not recommended during pregnancy and in women of childbearing potential not using effective contraception.
There was no nirmatrelvir-related effect on foetal morphology or embryo-foetal viability at any dose tested in rat or rabbit embryo-foetal developmental toxicity studies (see Pharmacology: Toxicology: Preclinical safety data under Actions).
A large number of pregnant women were exposed to ritonavir during pregnancy. These data largely refer to exposures where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower doses as a pharmacokinetic enhancer for other protease inhibitors, similar to the ritonavir dose used for nirmatrelvir/ritonavir. These data indicate no increase in the rate of birth defects compared to rates observed in population-based birth defect surveillance systems. Animal data with ritonavir have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Breast-feeding: There are no human data on the use of Paxlovid in breast-feeding.
It is unknown whether nirmatrelvir is excreted in human or animal milk, and the effects of it on the breast-fed newborn/infant, or the effects on milk production. Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breast-fed newborn/infant or the effects of the medicinal product on milk production. A risk to the newborn/infant cannot be excluded. Breast-feeding should be discontinued during treatment with Paxlovid and for 7 days after the last dose of Paxlovid.
Fertility: There are no human data on the effect of Paxlovid on fertility. No human data on the effect of nirmatrelvir on fertility are available. Nirmatrelvir produced no effects on fertility in rats (see 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 is based on data from Study C4671005 (EPIC-HR), a Phase 2/3 randomised, placebo-controlled trial in non-hospitalised adult participants with a laboratory confirmed diagnosis of SARS-CoV-2 infection (see Pharmacology: Pharmacodynamics under Actions). A total of 1,349 symptomatic adult participants 18 years of age and older who are at high risk of developing severe COVID-19 illness received at least one dose of either Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) (n=672) or placebo (n=677). Study drugs were to be taken twice daily for up to 5 days.
Adverse reactions in the Paxlovid group (≥1%) that occurred at a greater frequency than in the placebo group were diarrhoea (3.9% and 1.9%, respectively), vomiting (1.3% and 0.3%) and dysgeusia (4.8% and 0.1%).
Tabulated summary of adverse reactions: The adverse reactions in Table 7 are listed as follows by system organ class and frequency. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (frequency cannot be estimated from the available data). (See Table 7.)

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Paediatric population: The safety and efficacy of Paxlovid in paediatric patients have not been established.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Paxlovid (nirmatrelvir/ritonavir) is an inhibitor of CYP3A and may increase plasma concentrations of medicinal products that are primarily metabolised by CYP3A. Medicinal products that are extensively metabolised by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in exposure when coadministered with nirmatrelvir/ritonavir. Thus, coadministration of nirmatrelvir/ritonavir with medicinal products highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (see Table 6 under Contraindications).
In vitro study results showed nirmatrelvir may be inducer of CYP3A4, CYP2B6, CYP2C8, and CYP2C9. The clinical relevance is unknown. Based on in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3 and OCT2. There is a potential for nirmatrelvir to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations.
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Ritonavir also has a high affinity for P-glycoprotein (P-gp) and may inhibit this transporter. Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways and may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Coadministration of other CYP3A4 substrates that may lead to potentially significant interaction should be considered only if the benefits outweigh the risks (see Table 8).
Nirmatrelvir/ritonavir is a CYP3A substrate; therefore, medicinal products that induce CYP3A may decrease plasma concentrations of nirmatrelvir and ritonavir and reduce Paxlovid therapeutic effect.
Medicinal products listed in Table 6 (see Contraindications) and Table 8 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. (See Tables 8A, 8B, 8C, 8D, 8E.)

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

Store below 25°C.
Do not refrigerate or freeze.
Shelf life: 2 years.

Antivirals

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

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