Summary of Paxlovid product features

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Summary of product features

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1. Drug name

Paxlovid 150 mg/100 mg film-coated tablets

2. Qualitative and quantitative composition

Each pink PF 07321332 film-coated tablet contains 150 mg of PF 07321332.

Each white ritonavir film-coated tablet contains 100 mg of ritonavir.

Excipients with known effects

Each PF-07321332 150 mg film-coated tablet contains 176 mg of lactose. For a complete list of excipients, see Section 6.1.

3. Pharmaceutical form

PF 07321332

Film-coated tablets (tablets).

Pink, oval shape, about 17.6 mm long and 8.6 mm wide, with "PFE" engraved on one side and "3CL" engraved on the other side.

ritonavir

Film-coated tablets (tablets).

White to off-white capsule-shaped tablets, approximately 17.1 mm long and 9.1 mm wide, with a debossed "H" on one side and a debossed "R9" on the other side.

4.Clinical data

4.1 Treatment indications

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

4.2 Dosage and Administration

Paxlovid is PF-07321332 tablets co-packaged with ritonavir tablets.

PF-07321332 must be coadministered with ritonavir. Failure to properly coadminister PF 07321332 with ritonavir will result in plasma concentrations of PF-07321332 that are insufficient to achieve the desired therapeutic effect.

Lyrics

The recommended dose is 300 mg of PF 07321332 (two 150 mg tablets) and 100 mg of ritonavir (one 100 mg tablet) taken orally twice daily for 5 days. Paxlovid should be administered as soon as possible after a positive direct SARS-CoV-2 viral test result and within 5 days of the onset of symptoms.

Paxlovid can be taken with or without food. Tablets should be swallowed whole and not chewed, broken or crushed.

Missed doses should be taken as soon as possible within 8 hours of the scheduled time and the normal dosing schedule should be resumed. If more than 8 hours have passed, the missed dose should not be taken and treatment should be resumed according to the normal dosing schedule.

If a patient requires hospitalization for severe or critical COVID-19 after starting treatment with Paxlovid, the patient should complete the entire 5-day treatment course at the discretion of their healthcare provider.

Special groups

pediatric population

The safety and effectiveness of Paxlovid in pediatric patients under 18 years of age have not been established.

elderly

No dose adjustments are currently recommended for elderly patients.

renal insufficiency

No dose adjustment is required in patients with mild renal impairment.

In patients with moderate renal insufficiency, the dose of Paxlovid should be reduced to PF 07321332/ritonavir 150 mg/100 mg (1 tablet each) twice daily for 5 days. Remaining PF 07321332 tablets should be disposed of in accordance with local requirements (see Section 6.6).

Paxlovid is not recommended for use in patients with severe renal impairment or renal failure (see Section 5.2) as the appropriate dose has not yet been established.

liver damage

No dose adjustment of Paxlovid is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. There are no pharmacokinetic or safety data on the use of PF-07321332 or ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, Paxlovid is contraindicated in patients with severe hepatic impairment.

No dose adjustment is required for co-treatment with regimens containing ritonavir or cobicistat; Paxlovid dose 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 a regimen containing ritonavir or cobicistat should continue treatment as directed.

4.3 Contraindications

Paxlovid is contraindicated in patients with: * History of clinically significant hypersensitivity to the active substance (PF 07321332/ritonavir) or any of the excipients listed in Section 6.1. *Severe liver damage. *Severe renal insufficiency.

Paxlovid is also contraindicated in drugs that are highly dependent on CYP3A clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions. Paxlovid is also contraindicated for use with drugs that are potent CYP3A inducers, in which significantly reduced plasma PF-07321332/ritonavir concentrations may be associated with loss of virological response and possible drug resistance.

Table 1: Drugs prohibited for use with PF 07321332/ritonavir

Pharmaceutical products	Drugs within the category	clinical review
Interactions result in concomitant increases in drug concentrations because Paxlovid inhibits its CYP3A4 metabolic pathway
Alpha 1 adrenergic receptor antagonist	alfuzosin	Elevated plasma concentrations of alfuzosin may result in severe hypotension.
analgesics	pethidine, piroxicam, propoxyphene	Elevated plasma concentrations of norpiperidine, piroxicam, and propoxyphene may result in severe respiratory depression or hematologic abnormalities.
anti-angina pectoris	Ranolazine	Ranolazine plasma concentrations may be elevated potentially resulting in serious and/or life-threatening reactions.
Anti-cancer	Neratinib	The plasma concentrations of neratinib are increased, which may increase the potential for serious and/or life-threatening reactions, including hepatotoxicity.
Anti-cancer	Venetok	Plasma concentrations of venetoclax are increased, which may increase the risk of tumor lysis syndrome during dose initiation and dose titration phases.
antiarrhythmic drugs	Amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine	Plasma concentrations of amiodarone, beniprindil, dronedarone, encainide, flecainide, propafenone, and quinidine may be elevated, possibly resulting in cardiac arrhythmias or other serious adverse reactions.
antibiotic	fusidic acid	Plasma concentrations of fusidic acid and ritonavir are increased.
Anti-gout	colchicine	Elevated plasma concentrations of colchicine may cause serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.
antihistamines	Astemizole, terfenadine	Increased plasma concentrations of astemizole and terfenadine may result in severe cardiac arrhythmias associated with these drugs.
Antipsychotics/Antipsychotics	Lurasidone, pimozide, clozapine	Increased plasma concentrations of lurasidone, pimozide, and clozapine may result in serious and/or life-threatening reactions. Elevated plasma concentrations of quetiapine may result in coma.
Antipsychotics/Antipsychotics	Quetiapine	Elevated plasma concentrations of quetiapine may result in coma.
Ergot derivatives	Dihydroergotamine, ergometrine, ergotamine, methylergometrine	Elevated plasma concentrations of ergot derivatives result in acute ergot toxicity, including vasospasm and ischemia.
gastrointestinal motility agent	cisapride	Increases plasma concentrations of cisapride, thereby increasing the risk of serious cardiac arrhythmias caused by this drug.
Lipid Modulator: HMG-CoA Reductase Inhibitor	lovastatin, simvastatin	Increased plasma concentrations of lovastatin and simvastatin result in an increased risk of myopathies, including rhabdomyolysis.
Lipid Modulators: Microsomal Triglyceride Transfer Protein (MTTP) Inhibitors	Lomitian	Increases lomitapide plasma concentrations.
PDE5 inhibitors	vardenafil, vardenafil	Increases plasma concentrations of avanafil and vardenafil.
PDE5 inhibitors	Sildenafil (Revatio®) for the treatment of pulmonary arterial hypertension (PAH)	Elevated plasma concentrations of sildenafil may result in abnormal vision, hypotension, prolonged erections, and syncope.
sedatives/hypnotics	Clonazepam, diazepam, estazolam, flurazepam, triazolam, oral midazolam	Increased plasma concentrations of clonazepam, diazepam, estazolam, flurazepam, triazolam, and oral midazolam may increase the risk of profound sedation and respiratory depression.
Interaction leading to decreased PF-07321332/ritonavir concentrations as a concomitant drug induces the CYP3A4 metabolic pathway of Paxlovid
anticonvulsants	carbamazepine ^a , phenobarbital, phenytoin	Decreased plasma concentrations of PF 07321332/ritonavir may result in loss of virological response and possible drug resistance.
Antimycobacterial	rifampicin	Potential decreases in plasma concentrations of PF 07321332/ritonavir may result in loss of virological response and possible drug resistance.
herbal products	St. John's Wort (Hypericum perforatum)	Potential decreases in plasma concentrations of PF 07321332/ritonavir may result in loss of virological response and possible drug resistance.

^aSee Section 5.2, Interaction Studies with PF-07321332/ritonavir.

4.4 Special warnings and precautions for use

Risk of serious adverse reactions due to interactions with other medicines

Initiating Paxlovid (a CYP3A inhibitor) in patients receiving drugs metabolized by CYP3A or initiating drugs metabolized by CYP3A in patients already receiving Paxlovid may increase plasma concentrations of drugs metabolized by CYP3A.

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

These interactions may result in:

Clinically significant adverse reactions that may result in serious, life-threatening, or fatal events due to greater exposure to the concomitant drug.
Greater Paxlovid exposure resulted in clinically significant adverse reactions.
Loss of therapeutic efficacy of Paxlovid and possible development of viral resistance.

Medicinal products that are prohibited from being used concurrently with PF 07321332/ritonavir are listed in Table 1 (see Section 4.3), and potential significant interactions with other medicinal products are listed in Table 2 (see Section 4.5). Potential interactions with other drugs should be considered before and during treatment with Paxlovid; concomitant drug products should be reviewed during treatment with Paxlovid, and patients should be monitored for adverse reactions related to the concomitant drug products. The risk of interaction with concomitant medications during 5 days of treatment with Paxlovid should be weighed against the risk of not receiving Paxlovid.

Hepatotoxicity

Patients receiving ritonavir developed elevated hepatic transaminases, clinical hepatitis, and jaundice. Therefore, caution should be used when administering Paxlovid to patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis.

HIV drug resistance

Because PF-07321332 is coadministered with ritonavir, there may be a risk for HIV-1 resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

Excipients

PF-07321332 tablets contain lactose. Patients with the rare genetic problem of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

PF-07321332 and ritonavir tablets contain less than 1 mmol sodium (23 mg) per dose, which means they are essentially "sodium-free."

4.5 Interactions with other medicinal products and other forms of interactions

Paxlovid (PF-07321332/ritonavir) is a CYP3A inhibitor and may increase plasma concentrations of drugs primarily metabolized by CYP3A. Drugs that are extensively metabolized by CYP3A and have high first-pass metabolism appear to be most susceptible to substantially increased exposure when coadministered with PF 07321332/ritonavir. Therefore, coadministration of PF-07321332/ritonavir with medicinal products that are highly dependent on CYP3A clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is prohibited (see Table 1, section 4.3).

In vitro study results indicate that PF-07321332 may be an inducer of CYP3A4, CYP2B6, CYP2C8 and CYP2C9. Clinical relevance is unknown. Based on in vitro data, PF-07321332 has low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3, and OCT2. PF 07321332 has the potential to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations.

Ritonavir has high affinity for several cytochrome P450 (CYP) isomers and can inhibit oxidation in the following order: CYP3A4 > CYP2D6. Ritonavir also has high affinity for P-glycoprotein (P-gp) and may inhibit this transporter. Ritonavir may induce glucuronidation and oxidation via CYP1A2, CYP2C8, CYP2C9, and CYP2C19, thereby increasing the biotransformation of certain drugs metabolized through these pathways and may result in decreased systemic exposure to these drugs, which may decrease or shorten its therapeutic effect.

Coadministration with other CYP3A4 substrates that may result in potentially significant interactions should be considered only if the benefits outweigh the risks (see Table 2).

PF 07321332/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease plasma concentrations of PF 07321332 and ritonavir and reduce the therapeutic efficacy of Paxlovid.

The medicinal products listed in Table 1 (Section 4.3) and Table 2 are for reference only and are not a complete list of all medicinal products that may interact with PF-07321332/ritonavir. Healthcare providers should consult appropriate reference materials for comprehensive information.

Table 2: Potentially significant interactions with other medicinal products

Pharmaceutical products	Drugs within the class (change in AUC, change in Cmax)	clinical review
α1-adrenergic receptor antagonist	↑Alfuzosin	Elevated plasma concentrations of alfuzosin may cause severe hypotension and are therefore contraindicated (see section 4.3).
Amphetamine derivatives	↑Methylphenidate, ↑Dexaphetamine	Ritonavir administered as an antiretroviral drug may inhibit CYP2D6 and therefore is expected to increase concentrations of amphetamines and their derivatives. Careful monitoring for adverse reactions is recommended when these drugs are used concomitantly with Paxlovid.
analgesics	↑Buprenorphine (57%, 77%), ↑Norbuprenorphine (33%, 108%)	Increased plasma levels of buprenorphine and its active metabolite do not result in clinically significant pharmacodynamic changes in a population of opioid-tolerant patients. Therefore, buprenorphine dose adjustment may not be necessary when the two are administered together.
analgesics	↑Meperidine, ↑Piroxicam, ↑Propoxyphene	Elevated plasma concentrations of norpiperidine, piroxicam and propoxyphene may result in severe respiratory depression or hematological abnormalities (see Section 4.3).
analgesics	↑Fentanyl	Ritonavir administered as a pharmacokinetic enhancer inhibits CYP3A4 and therefore is expected to increase fentanyl plasma concentrations. Careful monitoring of treatment and adverse effects (including respiratory depression) is recommended when fentanyl is administered concurrently with ritonavir.
analgesics	↓Methadone(36%, 38%)	Due to induction of glucuronidation, increased methadone doses may be necessary when coadministered with ritonavir administered as a pharmacokinetic enhancer. Dosage adjustments should be considered based on the patient's clinical response to methadone treatment.
analgesics	↓Morphine	Morphine levels may be decreased due to coadministration of ritonavir, which acts as a pharmacokinetic enhancer and induces glucuronidation.
anti-angina pectoris	↑ Ranolazine	Ranolazine concentrations are expected to be increased due to the inhibitory effect of ritonavir on CYP3A. Concomitant administration with ranolazine is contraindicated (see Section 4.3).
antiarrhythmic drugs	↑Amiodarone, ↑ Dronedarone, ↑ Flecainide, ↑ Propafenone, ↑ Quinidine	Concomitant use of ritonavir may result in increased plasma concentrations of amiodarone, dronedarone, flecainide, propafenone and quinidine and is therefore contraindicated (see section 4.3).
antiarrhythmic drugs	↑digoxin	This interaction may be due to alteration of P-gp-mediated digoxin efflux by ritonavir administered as a pharmacokinetic enhancer.
antiasthmatic medicine	↓Theophylline (43%, 32%)	Due to induction of CYP1A2, an increased dose of theophylline may be necessary when coadministered with ritonavir.
anticancer agent	↑Afatinib	Serum concentrations may increase due to acute inhibition of P-gp by breast cancer resistance protein (BCRP) and ritonavir. The degree of increase in AUC and Cmax depends on the timing of ritonavir administration. Afatinib should be used with caution while using Paxlovid (see Afatinib SmPC). Monitor for afatinib-related ADRs.
anticancer agent	↑Abemaciclib	Serum concentrations may be increased due to ritonavir's inhibitory effect on CYP3A4. Coadministration of abemaciclib and Paxlovid should be avoided. If such coadministration is judged to be unavoidable, see abemaciclib SmPC for dosage adjustment recommendations. Monitoring ADRs related to abemaciclib.
anticancer agent	↑Apalutamide	Apalutamide is a moderate to strong inducer of CYP3A4, which may result in reduced exposure to PF-07321332/ritonavir and potential loss of virological response. Additionally, serum concentrations of apalutamide may be increased when coadministered with ritonavir, potentially resulting in serious adverse events including seizures. Concomitant use of Paxlovid with apalutamide is not recommended.
anticancer agent	↑Ceritinib	Seritinib serum concentrations may be increased due to the inhibitory effects of ritonavir on CYP3A and P-gp. Caution should be used when using ceritinib with Paxlovid. For dose adjustment recommendations, see Ceritinib SmPC. Monitor for ceritinib-related adverse reactions.
anticancer agent	↑Dasatinib, ↑Nilotinib, ↑Vincristine, ↑Vincristine	Serum concentrations may be increased when coadministered with ritonavir, potentially increasing the incidence of adverse events.
anticancer agent	↑Encorafenib	Encorafenib serum concentrations may be increased when coadministered with ritonavir, which may increase the risk of toxicity, including the risk of serious adverse events such as QT prolongation. Coadministration of encorafenib and ritonavir should be avoided. If the benefits are considered to outweigh the risks and ritonavir must be used, the patient should be carefully monitored for safety.
anticancer agent	↑Fosmatinib	Coadministration of fostamatinib with ritonavir may increase exposure to the fostamatinib metabolite R406, resulting in dose-related adverse events such as hepatotoxicity, neutropenia, hypertension, or diarrhea. If such events occur, see fostamatinib SmPC for dose reduction recommendations.
anticancer agent	↑Ibrutinib	Due to the inhibitory effect of ritonavir on CYP3A, ibrutinib serum concentrations may be increased resulting in an increased risk of toxicity, including the risk of tumor lysis syndrome. Coadministration of ibrutinib and ritonavir should be avoided. If the benefits are deemed to outweigh the risks and ritonavir is necessary, reduce the ibrutinib dose to 140 mg and monitor the patient closely for toxicity.
anticancer agent	↑Neratinib	Serum concentrations may be increased due to ritonavir's inhibitory effect on CYP3A4. Concomitant use of neratinib and Paxlovid is contraindicated due to potential for serious and/or life-threatening reactions, including hepatotoxicity (see Section 4.3).
anticancer agent	↑Venetoc	Due to the inhibitory effect of ritonavir on CYP3A, serum concentrations may increase, resulting in an increased risk of tumor lysis syndrome during dose initiation and acceleration phases (see Section 4.3 and refer to venetoclax SmPC). For patients who have completed the ramp-up phase and are taking a stable daily dose of venetoclax, reduce the venetoclax dose by at least 75% when used with a strong CYP3A inhibitor (see venetoclax SmPC for dosing instructions).
anticoagulant	↑Apixaban, ↑Dabigatran	Apixaban and dabigatran concentrations may be increased, which may result in an increased risk of bleeding. For more information, see Apixaban and Dabigatran SmPC.
anticoagulant	↑Rivaroxaban (153%, 53%)	Inhibition of CYP3A and P-gp results in increased plasma levels and pharmacodynamic effects of rivaroxaban, which may result in an increased risk of bleeding. Therefore, the use of ritonavir is not recommended in patients receiving rivaroxaban.
anticoagulant	↑Wora Pasha	Serum concentrations may be increased due to ritonavir's inhibitory effect on CYP3A. Coadministration of vorapaxar with Paxlovid is not recommended (see vorapaxar SmPC).
anticoagulant	Warfarin, ↑↓S-warfarin (9%, 9%), ↓↔R-warfarin (33%)	Induction of CYP1A2 and CYP2C9 results in reduced R-warfarin levels, whereas S-warfarin has little pharmacokinetic effect when coadministered with ritonavir. Reduced R-warfarin levels may result in reduced anticoagulant effect, therefore monitoring of anticoagulant parameters is recommended when warfarin is coadministered with ritonavir.
anticonvulsants	carbamazepine ^a	Carbamazepine is a strong CYP3A4 inducer, which may result in reduced exposure to PF-07321332 and ritonavir and potential loss of virological response. Concomitant use of carbamazepine and Paxlovid is contraindicated (see Section 4.3).
anticonvulsants	↓divalproex sodium, ↓lamotrigine, ↓phenytoin sodium	Ritonavir administered as a pharmacokinetic enhancer induces CYP2C9 oxidation and glucuronidation and is therefore expected to decrease anticonvulsant plasma concentrations. Careful monitoring of serum levels or treatment effect is recommended when these drugs are used concomitantly with ritonavir. Phenytoin may decrease the serum levels of ritonavir.
Antidepressants	↑amitriptyline, ↑fluoxetine, ↑imipramine, ↑nortriptyline, ↑paroxetine, ↑sertraline	Ritonavir administered as an antiretroviral agent may inhibit CYP2D6 and therefore increased concentrations of imipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine, or sertraline are expected. Careful monitoring of treatment and adverse effects is recommended when these drugs are administered concurrently with antiretroviral doses of ritonavir.
Antidepressants	↑Desipramine(145%, 22%)	The AUC and Cmax of the 2-hydroxy metabolite were reduced by 15% and 67%, respectively. A reduced dose of desipramine is recommended when coadministered with ritonavir.
Anti-gout	↑Colchicine	Colchicine concentrations are expected to be increased when coadministered with ritonavir. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and ritonavir (CYP3A4 and P-gp inhibition). Concomitant use of colchicine and Paxlovid is prohibited (see Section 4.3).
antihistamines	↑Fexofenadine	When administered as a pharmacokinetic enhancer, ritonavir may alter P-gp-mediated efflux of fexofenadine, resulting in increased fexofenadine concentrations.
antihistamines	↑loratadine	Ritonavir administered as a pharmacokinetic enhancer inhibits CYP3A and therefore is expected to increase loratadine plasma concentrations. Careful monitoring of treatment and adverse effects is recommended when loratadine is coadministered with ritonavir.
anti-infective drugs	↑Fusidic acid	Coadministration of ritonavir may result in increased plasma concentrations of fusidic acid and ritonavir and is therefore contraindicated (see Section 4.3).
anti-infective drugs	↑Rifabutin (4 times, 2.5 times), ↑25-O-desacetyl rifabutin metabolite (38 times, 16 times)	Due to the large increase in rifabutin AUC, the rifabutin dose may need to be reduced to 150 mg three times weekly when coadministered with ritonavir, which is a pharmacokinetic enhancer.
anti-infective drugs	rifampicin	Rifampicin is a strong CYP3A4 inducer, which may result in reduced exposure to PF-07321332/ritonavir and potential loss of virological response. Concomitant use of rifampicin and Paxlovid is prohibited (see Section 4.3).
anti-infective drugs	↓Voriconazole (39%, 24%)	Coadministration of voriconazole and ritonavir as a pharmacokinetic enhancer should be avoided unless a benefit/risk assessment for the patient justifies the use of voriconazole.
anti-infective drugs	↑Ketoconazole (3.4 times, 55%)	Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole. Due to an increased incidence of gastrointestinal and hepatic adverse reactions, a dose reduction of ketoconazole should be considered when coadministered with ritonavir.
anti-infective drugs	↑Itraconazole ^A , ↑Erythromycin	Ritonavir administered as a pharmacokinetic enhancer inhibits CYP3A4 and is therefore expected to increase plasma concentrations of itraconazole and erythromycin. Careful monitoring of treatment and adverse effects is recommended when erythromycin or itraconazole is coadministered with ritonavir.
anti-infective drugs	↓Atovaquone	Ritonavir administered as a pharmacokinetic enhancer induces glucuronidation and therefore is expected to decrease atovaquone plasma concentrations. Careful monitoring of serum levels or treatment effect is recommended when atovaquone is coadministered with ritonavir.
anti-infective drugs	↑Bedaquiline	There are no interaction studies related only to ritonavir. Coadministration should be avoided due to the risk of bedaquiline-related adverse events. If the benefits outweigh the risks, coadministration of bedaquiline with ritonavir must be done with caution. More frequent ECG monitoring and transaminase monitoring are recommended (see Bedaquiline SmPC)
anti-infective drugs	Dramanid	There are no interaction studies related only to ritonavir. In a healthy volunteer drug interaction study, delamanid 100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 14 days increased exposure to the delamanid metabolite DM-6705 30%. Due to the risk of QTc prolongation associated with DM-6705, if coadministration of delamanid with ritonavir is deemed necessary, very frequent ECG monitoring is recommended throughout delamanid treatment (see Section 4.4 and refer to delamanid SmPC).
anti-infective drugs	↑Clindamycin (77%, 31%), ↓14-OH clarithromycin metabolite (100%, 99%)	Because of the large therapeutic window of clarithromycin, dose reduction is not necessary in patients with normal renal function. Doses of clarithromycin greater than 1 g per day should not be coadministered with ritonavir administered as a pharmacokinetic enhancer. In patients with renal insufficiency, a dose reduction of clarithromycin should be considered: for patients with creatinine clearance 30 to 60 ml/min, the dose should be reduced by 50%, for patients with creatinine clearance less than 30 ml/min, the dose should be reduced by 75%.
anti-infective drugs	Sulfamethoxazole/Trimethoprim	Dosage changes of sulfamethoxazole/trimethoprim should be unnecessary during concomitant ritonavir therapy.
Anti-HIV Protease Inhibitors	↑Amprenavir (64%, 5x)	Ritonavir may increase amprenavir serum levels due to CYP3A4 inhibition. For more information, physicians should refer to the SmPC for amprenavir.
Anti-HIV Protease Inhibitors	↑Atazanavir (86%, 11 times)	Ritonavir may increase the serum levels of atazanavir due to CYP3A4 inhibition. For more information, physicians should refer to the SmPC for atazanavir.
Anti-HIV Protease Inhibitors	↑Darunavir (14 times)	Ritonavir may increase serum levels of darunavir due to CYP3A inhibition. Darunavir must be taken with ritonavir to ensure its therapeutic effectiveness. For more information, see SmPC for darunavir.
Anti-HIV Protease Inhibitors	↑Fosamprenavir (2.4-fold, 11-fold) based on amprenavir)	Ritonavir may increase serum levels of amprenavir (from fosamprenavir) due to CYP3A4 inhibition. Fosamprenavir must be taken with ritonavir to ensure its therapeutic effectiveness. For more information, physicians should refer to the SmPC for fosamprenavir.
anti HIV	↑Efavirenz (21%)	Adverse reactions (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes) were observed more frequently when efavirenz was coadministered with ritonavir.
anti HIV	↑Marawi Rock(161%, 28%)	Ritonavir may increase maraviroc serum levels due to CYP3A inhibition. Maraviroc may be administered with ritonavir to increase maraviroc exposure. For more information, see maraviroc-SmPC.
anti HIV	↓Raltegravir (16%, 1%)	Coadministration of ritonavir and raltegravir resulted in a slight decrease in raltegravir levels
anti HIV	↓Zidovudine (25%, undetectable)	Ritonavir may induce glucuronidation of zidovudine, resulting in a slight decrease in zidovudine levels. No dosage changes are required.
antipsychotics	↑Clozapine, ↑Pimozide	Coadministration with ritonavir may result in increased plasma concentrations of clozapine or pimozide and is therefore contraindicated (see section 4.3).
antipsychotics	↑Haloperidol, ↑Risperidone, ↑Thioridazine	Ritonavir may inhibit CYP2D6 and therefore would be expected to increase concentrations of haloperidol, risperidone, and thioridazine. Careful monitoring of treatment and adverse effects is recommended when these drugs are administered concurrently with antiretroviral doses of ritonavir.
antipsychotics	↑lurasidone	Increased concentrations of lurasidone are expected due to the inhibitory effect of ritonavir on CYP3A. Concomitant administration with lurasidone is contraindicated (see Section 4.3).
antipsychotics	↑Quetiapine	Increased quetiapine concentrations are expected due to the inhibitory effect of ritonavir on CYP3A. Concomitant use of Paxlovid and quetiapine is contraindicated as it may increase quetiapine-related toxicity (see Section 4.3).
β2-agonist (long-acting)	↑Salmeterol	Ritonavir inhibits CYP3A4, therefore salmeterol plasma concentrations are expected to be significantly increased. Therefore, simultaneous use is not recommended.
calcium channel antagonist	↑Amlodipine, ↑Diltiazem, ↑Nifedipine	Ritonavir administered as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A4 and therefore is expected to increase plasma concentrations of calcium channel antagonists. Careful monitoring of treatment and adverse effects is recommended when these drugs are administered concurrently with ritonavir.
endothelin antagonist	↑Bosentan	Coadministration of bosentan and ritonavir may increase steady-state bosentan Cmax and AUC.
endothelin antagonist	↑Leo Watermelon	Serum concentrations may be increased due to ritonavir's inhibitory effect on CYP3A and P-gp. Concomitant use of riociguat with Paxlovid is not recommended (see riociguat SmPC).
Ergot derivatives	↑Dihydroergotamine, ↑ergometrine, ↑ergotamine, ↑methylergometrine	Coadministration with ritonavir may result in increased plasma concentrations of ergot derivatives and is therefore contraindicated (see Section 4.3)
HCV direct acting antivirals	↑ Glecaprevir / pibrentasvir	Serum concentrations may be increased due to the inhibitory effect of ritonavir on P-gp, BCRP, and OATP1B. Concomitant administration of glecaprevir/pibrentasvir and Paxlovid is not recommended due to the risk of ALT elevation associated with increased glecaprevir exposure.
HMG Co-A reductase	↑Lovastatin, ↑Simvastatin	HMG-CoA reductase inhibitors that are highly dependent on CYP3A metabolism, such as lovastatin and simvastatin, are expected to have significant effects when coadministered with ritonavir as an antiretroviral agent or pharmacokinetic enhancer Increase plasma concentration. Since increased concentrations of lovastatin and simvastatin may predispose patients to myopathies, including rhabdomyolysis, the combination of these drugs with ritonavir is contraindicated (see Section 4.3).
HMG Co-A reductase	↑atorvastatin, ↑fluvastatin, ↑pravastatin, ↑rosuvastatin	Atorvastatin is less dependent on CYP3A metabolism. Although the elimination of rosuvastatin is independent of CYP3A, coadministration with ritonavir has been reported to increase rosuvastatin exposure. The mechanism of this interaction is unclear but may be the result of transporter inhibition. When used with ritonavir administered as a pharmacokinetic enhancer or antiretroviral agent, the lowest possible dose of atorvastatin or rosuvastatin should be administered. Pravastatin and fluvastatin are metabolized independently of CYP3A and are not expected to interact with ritonavir. If treatment with an HMG-CoA reductase inhibitor is required, pravastatin or fluvastatin is recommended.
hormonal contraceptives	↓Ethinyl estradiol (40%, 32%)	Due to reduced ethinyl estradiol concentrations, barrier or other non-hormonal contraceptive methods should be considered for concurrent use with ritonavir when administered as an antiretroviral agent or as a pharmacokinetic enhancer. Ritonavir may alter uterine bleeding and reduce the effectiveness of estradiol-containing contraceptives.
immunosuppressant	↑cyclosporine, ↑tacrolimus, ↑everolimus	Ritonavir administered as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A4 and therefore is expected to increase plasma concentrations of cyclosporine, tacrolimus, or everolimus. Careful monitoring of treatment and adverse effects is recommended when these drugs are administered concurrently with ritonavir.
Lipid regulator	↑Lomita Pie	CYP3A4 inhibitors increase lomitapide exposure, with strong inhibitors increasing exposure approximately 27-fold. Increased concentrations of lomitapide are expected due to the inhibitory effect of ritonavir on CYP3A. The simultaneous use of Paxlovid and Lomitate (Lomitate see SmPC) is prohibited (see Section 4.3).
Phosphodiesterase (PDE5) inhibitors	↑Avanafil (13 times, 2.4 times)	Simultaneous use of avanafil with Paxlovid is prohibited (see Section 4.3).
Phosphodiesterase (PDE5) inhibitors	↑Sildenafil (11 times, 4 times)	Caution should be used with the concomitant use of sildenafil for the treatment of erectile dysfunction and ritonavir as an antiretroviral agent or pharmacokinetic enhancer, and under no circumstances should the dose of sildenafil be exceeded within 48 hours 25 mg. Concomitant use of sildenafil and Paxlovid is contraindicated in patients with pulmonary hypertension (see Section 4.3).
Phosphodiesterase (PDE5) inhibitors	↑Tadalafil (124%, ↔)	Caution should be exercised when tadalafil is used concomitantly with ritonavir as an antiretroviral agent or pharmacokinetic enhancer for the treatment of erectile dysfunction by reducing the dose by no more than 10 mg of tadalafil every 72 hours, and Increase monitoring of adverse reactions.
Phosphodiesterase (PDE5) inhibitors	↑vardenafil (49 times, 13 times)	Concomitant use of vardenafil and Paxlovid is prohibited (see Section 4.3).
Sedatives/hypnotics	↑Clonazepam, ↑Diazepam, ↑Estazolam, ↑Flazepam, ↑Oral and parenteral midazolam	Coadministration with ritonavir may result in increased plasma concentrations of clonazepam, diazepam, estazolam and flurazepam and is therefore contraindicated (see section 4.3). Midazolam is extensively metabolized by CYP3A4. Coadministration with Paxlovid may result in substantial increases in midazolam concentrations. Plasma concentrations of midazolam are expected to be significantly elevated when midazolam is administered orally. Therefore, Paxlovid should not be coadministered with oral midazolam (see Section 4.3), whereas coadministration of Paxlovid with parenteral midazolam should be done with caution. Data from concurrent use of parenteral midazolam with other protease inhibitors indicate that midazolam plasma levels may be increased 3- to 4-fold. If Paxlovid is co-administered with parenteral midazolam, it should be administered in an intensive care unit (ICU) or similar setting to ensure close clinical monitoring and appropriate Medical management. A dose adjustment of midazolam should be considered, especially if midazolam is used more than once.
Sedatives/hypnotics	↑Triazolam (>20 times, 87%)	Coadministration with ritonavir may increase triazolam plasma concentrations and is therefore contraindicated (see Section 4.3)
Sedatives/hypnotics	↓Meperidine (62%, 59%), ↑Normepetidine metabolite (47%, 87%)	The use of pethidine and ritonavir is contraindicated due to increased concentrations of the metabolite norpethidine, which has analgesic and CNS stimulant activity. Elevated norpiperidine concentrations may increase the risk of CNS effects (e.g. seizures) (see Section 4.3).
Sedatives/hypnotics	↑Alprazolam (2.5x, ↔)	Alprazolam metabolism is inhibited after the introduction of ritonavir. Caution is warranted when alprazolam is coadministered with ritonavir administered as an antiretroviral agent or as a pharmacokinetic enhancer in the days before alprazolam metabolism occurs.
Sedatives/hypnotics	↑Buspirone	Ritonavir administered as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A and therefore is expected to increase buspirone plasma concentrations. Careful monitoring of treatment and adverse effects is recommended when buspirone is administered concurrently with ritonavir.
sleep aid	↑Zolpidem(28%, 22%)	Zolpidem and ritonavir may be used concurrently with careful monitoring for excessive sedation.
quit smoking	↓Bupropion (22%, 21%)	Bupropion is primarily metabolized by CYP2B6. Coadministration of bupropion with repeated doses of ritonavir is expected to decrease bupropion levels. These effects are thought to represent induction of bupropion metabolism. However, because ritonavir has also been shown to inhibit CYP2B6 in vitro, the recommended bupropion dose should not be exceeded. There was no significant interaction with bupropion after short-term administration of low-dose ritonavir (200 mg twice daily for 2 days) compared with long-term administration of ritonavir, suggesting that bupropion concentrations may It begins to decrease within a few days of starting the medication. Ritonavir combination therapy.
Steroid	Inhalation, injection or intranasal injection of fluticasone propionate, budesonide, triamcinolone	Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (86% decrease in plasma cortisol levels), have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate; other corticosteroids metabolized by CYP3A may also Similar effects occur with drugs such as budesonide and triamcinolone acetonide. Therefore, concomitant administration of ritonavir as an antiretroviral agent or as a pharmacokinetic enhancer with these corticosteroids is not recommended unless the potential benefits of treatment outweigh the risks of systemic corticosteroid effects. Consideration should be given to reducing the corticosteroid dose with close monitoring of local and systemic effects or switching to a corticosteroid that is not a CYP3A4 substrate (e.g., beclomethasone). and,
Steroid	↑Dexamethasone	Ritonavir administered as a pharmacokinetic enhancer or antiretroviral agent inhibits CYP3A and therefore is expected to increase dexamethasone plasma concentrations. Careful monitoring of treatment and adverse effects is recommended when dexamethasone is administered concurrently with ritonavir.
Steroid	↑Prednisolone (28%, 9%)	Careful monitoring of treatment and adverse effects is recommended when prednisolone is administered concurrently with ritonavir. The AUC of the metabolite prednisolone increased by 37% and 28% after 4 and 14 days of ritonavir, respectively.
Thyroid hormone replacement therapy	Levothyroxine	Postmarketing cases have been reported indicating a potential interaction between ritonavir-containing products and levothyroxine. Patients receiving levothyroxine should have thyroid-stimulating hormone (TSH) monitored for at least the first month after initiation and/or discontinuation of ritonavir therapy.

Abbreviations: ATL=alanine aminotransferase, AUC=area under the curve, Cmax=maximum concentration. one. See Section 5.2, Interaction Studies with PF-07321332/ritonavir.

4.6 Fertility, pregnancy and lactation

Contraceptive methods for women/men and women of childbearing potential

There are no human data on the use of Paxlovid during pregnancy to inform the risk of drug-related adverse developmental outcomes, and women of childbearing potential should avoid becoming pregnant during treatment with Paxlovid.

Use of ritonavir may decrease the effectiveness of combined hormonal contraceptives. Patients receiving combined hormonal contraceptives should be advised to use an effective alternative or additional barrier method of contraception during treatment and for one full menstrual cycle after stopping Paxlovid (see section 4.5).

Pregnant

There are no data on the use of Paxlovid in pregnant women. Paxlovid is not recommended for use during pregnancy and in women of childbearing potential who are not using effective contraception.

PF-07321332 had no relevant effects on fetal morphology or embryo-fetal viability at any dose tested in rat or rabbit embryo-fetal developmental toxicity studies (see Section 5.3).

A large number of pregnant women are exposed to ritonavir during pregnancy. These data primarily refer to ritonavir exposure when used in combination therapy, not at therapeutic ritonavir doses, but at lower doses as a pharmacokinetic enhancer of other protease inhibitors, similar to Ritonavir dosage for PF 07321332/ritonavir. These data indicate that birth defect rates are not increased compared with rates observed in population-based birth defects surveillance systems. Animal data for ritonavir demonstrate reproductive toxicity (see Section 5.3).

breast-feeding

There are no human data on the use of Paxlovid during breastfeeding.

It is unknown whether PF-07321332 is excreted in human or animal milk, its effects on breastfed neonates/infants, or its effects on milk production. Limited published data report the presence of ritonavir in human milk. There is no information regarding the effects of ritonavir on the breastfed neonate/infant or on the effects of the medicinal product on milk production. Risk to neonates/infants cannot be excluded. Breastfeeding 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 effects of Paxlovid on fertility. There are no human data on the effects of PF 07321332 on fertility. PF 07321332 has no effect on fertility in rats (see Section 5.3).

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

4.7 Effects on ability to drive and use machines

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

4.8 Adverse effects

Security Profile Summary

The safety of Paxlovid is based on data from Study C4671005 (EPIC-HR), a Phase 2/3 randomized, placebo-controlled trial in non-hospitalized adult participants with laboratory-confirmed SARS-CoV-2 infection ( See Section 5.1). A total of 1,349 symptomatic adult participants 18 years and older at high risk for severe COVID-19 disease received at least one dose of Paxlovid (PF-07321332/ritonavir 300 mg/100 mg) (n =672) or placebo (n = 677). Study medication was taken twice daily for up to 5 days.

Adverse reactions that occurred more frequently (≥1%) in the Paxlovid group compared with the placebo group were diarrhea (3.9% vs. 1.9%, respectively), vomiting (1.3% vs. 0.3%), and dysgeusia (4.8% vs. 0.1%) )).

Summary of adverse reactions list

Adverse reactions in Table 3 are listed below by system organ category and frequency. Frequency is 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); unknown (frequency cannot be estimated from available data).

Table 3: Adverse reactions of Paxlovid

system organ class	frequency category	Adverse reactions
Nervous system disease	Common	dysgeusia
Gastrointestinal diseases	Common	Diarrhea, vomiting

pediatric population

The safety and effectiveness of Paxlovid in pediatric patients have not been established.

Suspected adverse reaction reports

It is important to report suspected adverse reactions after drug approval. It allows continuous monitoring of the benefit/risk balance of pharmaceutical products. Healthcare professionals are asked to report any suspected adverse reactions via the Coronavirus Yellow Card reporting website or search for MHRA Yellow Card in Google Play or the Apple App Store.

4.9 Overdose

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

5. Pharmacological properties

5.1 Pharmacodynamic properties

Drug Therapeutic Group: Systemically Used Antiviral Agents, Direct-Acting Antiviral Agents, ATC Code: Not yet assigned.

Mechanism

PF-07321332 is a peptidomimetic inhibitor of coronavirus 3C-like (3CL) proteases, including the SARS CoV 2 3CL protease. Inhibition of the 3CL protease renders the protein unable to process polyprotein precursors, thereby preventing viral replication. PF-07321332 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 enzyme assay.

Ritonavir has no activity against the SARS-CoV-2 3CL protease. Ritonavir inhibits CYP3A-mediated metabolism of PF-07321332, thereby increasing plasma concentrations of PF-07321332.

Antiviral activity

In vitro antiviral activity

PF-07321332 exhibited antiviral activity against SARS-CoV-2 infection of dNHBE cells, a primary human alveolar epithelial cell line (EC90 value of 181 nM), at day 3 postinfection.

In vivo antiviral activity

PF-07321332 showed antiviral activity in a mouse-adapted mouse model of SAR-CoV-2 infection in BALB/c and 129 mouse strains. 300 mg/kg or 1,000 mg/kg orally twice daily or 1,000 mg/kg orally twice daily starting 4 hours after vaccination with SARS-CoV-2 MA10 PF-07321332 starting 12 hours after vaccination with SARS-CoV-2 MA10, Resulting in reduced lung viral titers and improved disease markers (weight loss and lung pathology) compared to placebo-treated animals.

antiviral resistance

Because PF-07321332 is coadministered with low-dose ritonavir, there may be a risk for HIV 1 resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV 1 infection.

Pharmacodynamic effects

cardiac electrophysiology

In a double-blind, randomized, placebo-controlled, crossover study in 10 healthy adults, no clinically relevant effects of PF-07321332 on the QTcF interval were observed. The model predicted a 90% confidence interval (CI) upper limit of 1.96 ms for baseline and ritonavir-adjusted QTcF estimates at a concentration approximately 4 times the mean steady-state peak concentration following the therapeutic dose of PF 07321332/ritonavir 300 mg/ times. 100 mg.

Clinical efficacy and safety

The efficacy of Paxlovid was based on an interim analysis of EPIC HR, a Phase 2/3, randomized, double-blind, placebo-controlled study of non-hospitalized symptomatic adult participants with laboratory-confirmed SARS-CoV-2 infection. Participants with ≤5 days of COVID-19 symptom onset were included in the study. Participants were randomized (1:1) to receive Paxlovid (PF-07321332 300 mg/ritonavir 100 mg) or placebo orally every 12 hours for 5 days. The study excluded individuals with a history of COVID-19 infection or vaccination. The primary efficacy endpoint was a modified intention-to-treat (mITT) analysis group (all symptom onset ≤3 days and at least one postbaseline visit).

A total of 1,361 participants were randomly assigned to receive Paxlovid or placebo. At baseline, mean age was 45 years; 52% were male; 63% were white, 5% were black, 48% were Hispanic or Latino, and 20% were Asian; 63% of participants were ≤ 3 days after symptom onset; 44% of participants were seronegative at baseline. The most commonly reported risk factors were BMI ≥ 25 kg/m2 (1080 [79.4%] participants), tobacco use (501 [36.8%] participants), hypertension (441 [32.4%] participants), age ≥ 60 years (255 [18.7%] participants) and diabetes (175 [12.9%] participants). Other risk factors included cardiovascular disease (50 [3.7%] participants), chronic kidney disease (8 [0.6%] participants), chronic lung disease (67 [4.9%] participants), immunosuppression (12 [0.9%] participants patients), cancer (4 [0.3%] participants), neurodevelopmental disorders (2 [0.1%] participants), HIV infection (1 [<0.1%] participants), and device dependence (5 [0.4%] participants). Mean (SD) baseline viral load was 4.71 log10 copies/mL (2.78); 27% of participants had baseline viral load > 10^7 (units); 8.2% of participants were receiving or expected to receive COVID-19 at randomization 19 therapeutic monoclonal antibody treatment and were excluded from mITT and mITT1 analyses.

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

At the time of the interim analysis, 389 participants in the Paxlovid group and 385 participants in the placebo group were included in the mITT analysis set. Paxlovid significantly reduced (p<0.0001) the proportion of participants with COVID-19-related hospitalization or death by day 28 compared with placebo, ≤3 days from symptom onset and progression to severe disease, compared with placebo Among adult participants at increased risk. No deaths were reported in the Paxlovid group compared with 7 deaths in the placebo group. The proportion of participants who discontinued treatment due to adverse events was 2.4% in the Paxlovid group and 4.3% in the placebo group.

Similar trends were observed in the main efficacy analyzes across participant subgroups. Table 4 presents the results for the primary endpoint in mITT analysis populations and subgroups by baseline viral load, serostatus, or age.

Table 4: COVID-19 progression (hospitalization or death) to day 28 among symptomatic adults at increased risk of progression to severe disease; mITT analysis set

Paclovir 300mg/100mg	placebo
Number of patients (%)	Number of people=389	Number of people=385
Hospitalized or deceased ^patientsa (%)	3 (0.8%)	27 (7.0%)
Estimated proportion within 28 days [95% CI], %	0.78 (0.25, 2.39)	7.09 (4.92, 10.17)
Reduction relative to placebo [95% CI]	-6.32 (-9.04, -3.59)
p-value	p<0.0001
Viral load < 10^7 copies/mL	n=242	n=244
Hospitalized or deceased ^patientsa (%)	2 (0.8%)	12 (4.9%)
Estimated proportion within 28 days [95% CI], %	0.83 (0.21, 3.26)	4.96 (2.85, 8.57)
Reduction relative to placebo [95% CI]	-4.14 (-7.10, -1.17)
p-value	p=0.0063
Viral load ≥ 10^7 copies/mL	n=122	n=117
Hospitalized or deceased ^patientsa (%)	1 (0.8%)	13 (11.1%)
Estimated proportion within 28 days [95% CI], %	0.84 (0.12, 5.82)	11.28 (6.71, 18.63)
Reduction relative to placebo [95% CI]	-10.44 (-16.44, -4.43)
p-value	p=0.0007
Viral load < 10^4 copies/mL	n=124	n=119
Hospitalized or deceased ^patientsa (%)	0	1 (0.8%)
Estimated proportion within 28 days [95% CI], %	0	0.840 (0.12, 5.82)
Reduction relative to placebo [95% CI]	-0.84 (-2.48, 0.80)
p-value	p=0.3153
Viral load ≥ 10^4 copies/mL	n=240	n=242
Hospitalized or deceased ^patientsa (%)	3 (1.3%)	31 (12.8%)
Estimated proportion within 28 days [95% CI], %	1.26 (0.41, 3.85)	10.07 (6.87, 14.65)
Reduction relative to placebo [95% CI]	-8.81 (-12.89, -4.74)
p-value	p<0.0001
Negative serology	n=168	n=175
Hospitalized or deceased ^patientsa (%)	3 (1.8%)	24 (13.7%)
Estimated proportion within 28 days [95% CI], %	1.80 (0.58, 5.47)	13.97 (9.59, 20.12)
Reduction relative to placebo [95% CI]	-12.17 (-17.74, -6.61)
p-value	p<0.0001
Serology positive	n=217	n=204
Hospitalized or deceased ^patientsa (%)	0	3 (1.5%)
Estimated proportion within 28 days [95% CI], %	0	1.48 (0.48, 4.51)
Reduction relative to placebo [95% CI]	0.00 (0.00, 0.00)
p-value	p=0.0810
Age < 65 years	n=345	n=334
Hospitalized or deceased ^patientsa (%)	2 (0.6)	18 (5.4)
Estimated proportion within 28 days [95% CI], %	0.59 (0.15, 2.32)	5.47 (3.48, 8.54)
Reduction relative to placebo [95% CI]	-4.88 (-7.47, -2.30)
p-value	p=0.0002
Age ≥ 65 years old	n=44	n=51
Hospitalized or deceased ^patientsa (%)	1 (2.3%)	9 (17.6%)
Estimated proportion within 28 days [95% CI], %	2.27 (0.32, 15.06)	17.65 (9.60, 31.17)
Reduction relative to placebo [95% CI]	-15.37 (-26.73, -4.02)
p-value	p=0.0079

Abbreviations: CI=confidence interval; mITT=modified intention-to-treat. All participants were randomly assigned to the study intervention, who received at least 1 dose of the study intervention, had at least 1 post-baseline visit before Day 28, and who did not receive or expected to receive a COVID-19 therapeutic at baseline. Monoclonal antibody therapy, and treatment ≤ 3 days after the onset of COVID-19 symptoms. Hospitalization or death ^from any cause related to Covid-19.

Paxlovid treatment also significantly reduced the incidence of hospitalization or death by 85.2% on day 28 when initiated within 5 days of symptom onset (Table 5). No deaths were reported in the Paxlovid group, compared with 10 deaths in the placebo group. The results of subgroup analysis of mITT1 were consistent with those of mITT.

Table 5: COVID-19 progression (hospitalization or death) to day 28 among symptomatic adults at increased risk of progression to severe disease; mITT1 analysis set

Paclovir 300mg/100mg	placebo
Number of patients	N=607	N=612
Hospitalized or deceased ^patientsa (%)	6 (1.0%)	41 (6.7%)
Estimated proportion within 28 days [95% CI], %	1.00 (0.45, 2.21)	6.76 (5.03, 9.04)
Reduction relative to placebo [95% CI]	-5.77 (-7.92, -3.61)
p-value	p<0.0001

Abbreviations: CI = confidence interval; mITT1 = modified intention-to-treat analysis set including all participants randomized to study intervention who received at least 1 dose of study intervention and had at least 1 postbaseline visit before Day 28 , who were not receiving or expected to receive COVID-19 therapeutic monoclonal antibody treatment at baseline and received treatment ≤ 5 days after COVID-19 symptom onset.

Hospitalization or death ^from any cause related to Covid-19.

An interim evaluation was conducted of the effect of Paxlovid on viral load (copies/mL) relative to placebo. A total of 572 participants with detectable baseline viral loads were included in the interim assessment and changes from baseline to day 5 (end of treatment) were assessed. On day 5, the adjusted mean change in viral load (log10 copies/mL) showed an additional 0.93 log10 reduction compared with baseline, after accounting for baseline viral load levels, geographic region, serostatus, and symptom onset (copies/mL). Paxlovid group versus placebo. Among participants who were seronegative or had higher viral load levels at baseline, the additional viral load reduction was more pronounced with Paxlovid treatment compared with placebo. Likewise, among participants with ≤3 days of symptom onset, there was a decrease of 1 day.

Table 6: Analysis of log10 change from baseline to day 5 (viral load, copies/mL) at increased risk of progression to severe disease in adults with symptomatic COVID-19; mITT1 analysis set

Paclovir 300mg/100mg	placebo
Number of patients	N=269	N=303
Baseline, mean (SD)	5.41 (2.24)	5.11 (2.23)
Day 5, mean (SD)	2.50 (1.82)	3.22 (2.20)
Adjusted change from baseline, mean (SE)	-2.69 (0.10)	-1.75 (0.09)
Reduction relative to placebo, mean (SE)	-0.93 (0.13)
Negative serology	n=128	n=135
Baseline, mean (SD)	6.47 (1.57)	6.42 (1.66)
Day 5, mean (SD)	3.51 (1.54)	4.60 (1.91)
Adjusted change from baseline, mean (SE)	-3.26 (0.21)	-2.12 (0.20)
Reduction relative to placebo, mean (SE)	-1.15 (0.20)
Serology positive	n=137	n=160
Baseline, mean (SD)	4.42 (2.34)	4.01 (2.07)
Day 5, mean (SD)	1.54 (1.54)	2.15 (1.80)
Adjusted change from baseline, mean (SE)	-2.28 (0.14)	-1.51 (0.13)
Reduction relative to placebo, mean (SE)	-0.77 (0.17)
Viral load < 10^7 copies/mL	n=183	n=228
Baseline, mean (SD)	4.26 (1.76)	4.20 (1.78)
Day 5, mean (SD)	1.82 (1.56)	2.51 (1.94)
Adjusted change from baseline, mean (SE)	-2.04 (0.12)	-1.25 (0.11)
Reduction relative to placebo, mean (SE)	-0.79 (0.15)
Viral load ≥ 10^7 copies/mL	n=86	n=75
Baseline, mean (SD)	7.85 (0.52)	7.86 (0.57)
Day 5, mean (SD)	3.98 (1.43)	5.30 (1.50)
Adjusted change from baseline, mean (SE)	-4.41 (0.27)	-3.01 (0.27)
Reduction relative to placebo, mean (SE)	-1.40 (0.24)
Time from symptom onset to randomization ≤ 3 days (mITT)	n=179	n=201
Baseline, mean (SD)	5.73 (2.25)	5.46 (2.24)
Day 5, mean (SD)	2.61 (1.90)	3.45 (2.33)
Adjusted change from baseline, mean (SE)	-2.99 (0.12)	-1.96 (0.12)
Reduction relative to placebo, mean (SE)	-1.03 (0.16)

Abbreviation: mITT = modified intention-to-treat. All participants were randomly assigned to the study intervention, who received at least 1 dose of the study intervention, had at least 1 post-baseline visit before Day 28, and who did not receive or expected to receive a COVID-19 therapeutic at baseline. Monoclonal antibody therapy, and treatment received ≤ 3 days after COVID-19 symptom onset; mITT1 = modified intention-to-treat analysis set including all participants randomized to study intervention who received at least 1 dose of study intervention at Have at least 1 post-baseline visit before Day 28, who are not receiving or expected to receive COVID-19 therapeutic monoclonal antibody treatment at baseline, and who receive treatment ≤ 5 days after COVID-19 symptom onset; SD = standard Deviation; SE = standard error.

The drug has been authorized under a so-called "conditional approval" scheme. This means further evidence for the drug is awaited. The agency will review new information about the drug at least annually and will update this SmPC as needed.

pediatric population

The FDA has deferred its obligation to submit results from studies of Paxlovid for the treatment of coronavirus disease 2019 (COVID-19) in one or more pediatric populations (see Section 4.2 for information on pediatric use).

5.2 Pharmacokinetic properties

The pharmacokinetics of PF-07321332/ritonavir have been studied in healthy participants.

Ritonavir is administered with PF-07321332 as a pharmacokinetic enhancer, resulting in higher systemic concentrations of PF-07321332. In healthy participants in the fasted state, the mean half-life (t1/2) was approximately 2 hours after a single dose of 150 mg PF 07321332 alone and 7 hours after a single dose of 250 mg/100 mg PF -07321332/ ritonavir thus supports a twice-daily dosing regimen.

Geometric mean (CV%) maximum concentration (Cmax) and area under the plasma concentration-time curve from 0 to time after administration of a single dose of PF-07321332/ritonavir 250 mg/100 mg to healthy participants in the fasting state The primary measurement values (AUClast) were 2.88 ug/mL (25%) and 27.6 ug*hr/mL (13%) respectively. Following repeated twice daily dosing of PF-07321332/ritonavir at 75 mg/100 mg, 250 mg/100 mg, and 500 mg/100 mg, the increase in systemic exposure at steady state appeared to be less than dose proportional. Multiple dosing over 10 days reached steady state on day 2, with accumulation approximately 2-fold. Systemic exposure on day 5 was similar to that on day 10 for all doses.

absorb

After a single oral dose of PF-07321332/ritonavir 300 mg/100 mg, the geometric mean Cmax and area under the plasma concentration time curve (AUCinf) of PF-07321332 (CV%) at steady state were respectively 2.21 µg/mL (33) and 23.01 µg*hr/mL (23). Median (range) time to reach Cmax (Tmax) was 3.00 hours (1.02-6.00). The arithmetic mean (+SD) terminal elimination half-life is 6.1 (1.8) hours.

After a single oral dose of PF-07321332/ritonavir 300 mg/100 mg, the geometric mean ritonavir (CV%) Cmax and AUCinf were 0.36 µg/mL (46) and 3.60 µg*, respectively hr/mL (47) . Median (range) time to Cmax (Tmax) was 3.98 hours (1.48-4.20). The arithmetic mean (+SD) terminal elimination half-life is 6.1 (2.2) hours.

Effect of food on oral absorption

After coadministration of PF-07321332 suspension with ritonavir tablets, coadministration with a high-fat meal modestly increased PF-07321332 exposure relative to fasting conditions (mean Cmax increased by approximately 15% , the average AUClast increased by 1.6%).

distribute

PF-07321332 is approximately 69% protein bound in human plasma.

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

Biotransformation

In vitro studies evaluating PF-07321332 without concomitant ritonavir demonstrated that PF-07321332 is primarily metabolized by CYP3A4. PF-07321332 irreversibly inhibits CYP2D6, CYP2C9, CYP2C19, CYP2C8, or CYP1A2 in vitro at clinically relevant concentrations. In vitro study results indicate that PF-07321332 may be an inducer of CYP3A4, CYP2B6, CYP2C8 and CYP2C9. Clinical relevance is unknown. Based on in vitro data, PF-07321332 has low potential to inhibit BCRP, MATE2K, OAT1, OAT3, OATP1B3, and OCT2. PF-07321332 has the potential to inhibit MDR1, MATE1, OCT1 and OATP1B1 at clinically relevant concentrations. PF-07321332 Coadministration with ritonavir may inhibit the metabolism of PF-07321332. In plasma, the only drug-related entity observed was unchanged PF 07321332. Small amounts of oxidative metabolites were observed in feces and urine.

In vitro studies using human liver microsomes indicate that cytochrome P450 3A (CYP3A) is the major isomer involved in the metabolism of ritonavir, although CYP2D6 also contributes to the formation of the oxidative metabolite M-2.

Low doses of ritonavir have profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolized by CYP3A4), and other protease inhibitors may affect the pharmacokinetics of ritonavir.

Ritonavir has high affinity for several cytochrome P450 (CYP) isomers and can inhibit oxidation in the following order: CYP3A4 > CYP2D6. Ritonavir also has high affinity for P-glycoprotein (P-gp) and may inhibit this transporter. Ritonavir may induce glucuronidation and oxidation via CYP1A2, CYP2C8, CYP2C9, and CYP2C19, thereby increasing the biotransformation of certain drugs metabolized through these pathways and may result in reduced systemic exposure to these drugs, which may decrease or shorten its therapeutic effect.

disuse

The primary route of elimination of PF-07321332 when administered with ritonavir is renal excretion of the intact drug. Approximately 49.6% and 35.3% of the PF 07321332 300 mg administered dose were recovered in urine and feces, respectively. PF-07321332 is the major drug-related entity and hydrolysis in its excreta produces minor metabolites. In plasma, the only quantifiable drug-related entity was unchanged PF-07321332.

Human studies with radiolabeled ritonavir indicate that ritonavir is eliminated primarily through the hepatobiliary system; approximately 86% of the radiolabel is recovered in feces, a portion of which is expected to be unabsorbed ritonavir .

Specific populations

The age- and sex-based pharmacokinetics of PF-07321332/ritonavir have not been evaluated.

race or ethnicity

Systemic exposure in Japanese participants was numerically lower than in Western participants, but the difference was not clinically significant.

Patients with renal insufficiency

Compared with healthy controls without renal impairment, the Cmax and AUC of PF-07321332 were 30% and 24% higher, respectively, in patients with mild renal impairment, and 38% and 38% higher, respectively, in patients with moderate renal impairment. 87%, and renal impairment was 48% and 204% higher, respectively, in patients with severe renal insufficiency.

Patients with liver damage

There were no significant differences in the pharmacokinetics of PF-07321332 in subjects with moderate hepatic impairment compared with healthy controls without hepatic impairment.

Interaction studies with PF-07321332/ritonavir

When PF-07321332 was tested alone in human liver microsomes, CYP3A4 was a major contributor to the oxidative metabolism of PF-07321332. Ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of PF-07321332 and other drugs primarily metabolized by CYP3A. Although coadministered with ritonavir as a pharmacokinetic enhancer, strong inhibitors and inducers may still alter the pharmacokinetics of PF-07321332.

The effects of coadministration of Paxlovid with itraconazole (CYP3A inhibitor) and carbamazepine (CYP3A inducer) on PF-07321332 AUC and Cmax are summarized in Table 7 (Effects of Other Drugs on PF-07321332).

Table 7: Interactions with other medicinal products: Pharmacokinetic parameters of PF 07321332 in the presence of co-administered medicinal products

#	Dosage (schedule)	Dosage (schedule)	n	PF 07321332 Ratio of pharmacokinetic parameters (90% CI) (combined with coadministered drugs/alone); no effect = 1.00	PF 07321332 Ratio of pharmacokinetic parameters (90% CI) (combined with coadministered drugs/alone); no effect = 1.00
Combination medication	Combination medication	PF 07321332/ritonavir	n	Cmax	area under curve
Carbamazepine ^b	300 mg twice daily (16 doses)	300 mg/100 mg twice daily (5 doses)	9	56.82 (47.04, 68.62)	44.50 (33.77, 58.65)
Itraconazole	200 mg once daily (8 doses)	300 mg/100 mg twice daily (5 doses)	11	118.57 (112.50, 124.97)	138.82 (129.25, 149.11)

Abbreviations: AUC=area under the plasma concentration-time curve; CI=confidence interval; Cmax=maximum plasma concentration.

^aFor carbamazepine, AUC=AUCinf and for itraconazole, AUC=AUCtau. ^{bCarbamazepine} titrated to 300 mg twice daily on days 8 to 15 (e.g., 100 mg twice daily on days 1 to 3, 200 mg twice daily on days 4 to 7) .

5.3 Preclinical Safety Data

toxicology

Repeated-dose toxicity studies of PF-07321332 in rats and monkeys lasting up to 1 month did not result in adverse findings.

Repeated-dose toxicity studies of ritonavir in animals identified the primary target organs as the liver, retina, thyroid, and kidneys. Liver changes involve hepatocellular, biliary, and phagocyte components and are accompanied by elevated liver enzymes. Retinal pigment epithelial cell proliferation and retinal degeneration were observed in all rodent studies with ritonavir but not in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary to phospholipidosis. However, clinical trials found no evidence that the drug caused eye changes in humans. All thyroid changes were reversible after discontinuation of ritonavir. Human clinical studies have shown no clinically significant changes in thyroid function tests.

Renal changes including tubular degeneration, chronic inflammation, and proteinuria have been observed in rats and are thought to be attributable to species-specific spontaneous disease. Additionally, no clinically significant renal abnormalities were identified in clinical trials.

carcinogenesis

The carcinogenicity of Paxlovid has not been evaluated.

PF 07321332 The carcinogenic potential has not been evaluated.

Long-term carcinogenicity studies of ritonavir in mice and rats revealed tumorigenic potential specific to these species but are not considered relevant to humans.

mutagenesis

The mutagenicity potential of Paxlovid has not been evaluated.

PF 07321332 was not genotoxic in a series of assays, including bacterial mutagenicity, chromosomal aberrations using human lymphoblastoid TK6 cells, and in vivo rat micronucleus assays.

Ritonavir was found to be mutagenic or causative in a series of in vitro and in vivo tests, including the Ames bacterial reverse mutation assay using Salmonella typhimurium and E. Cleavage activity was negative in human lymphocytes.

reproductive toxicity

PF 07321332

In a fertility and early embryonic development study, PF 07321332 was administered by oral gavage to male and female rats at doses of 60, 200, or 1,000 mg/kg/day, starting 14 days before mating and throughout the mating period Once daily and continued until day 6 of pregnancy for women and a total of 32 doses for men. Based on predicted human Cmax/AUC24 at 300 mg/100 mg PF twice daily, there is no effect on fertility, reproductive performance, or early embryonic development at doses up to 1,000 mg/kg/day, equivalent to 12x/4.3x 07321332/ritonavir .

The potential embryo-fetal toxicity of PF-07321332 was evaluated in final rat and rabbit studies at doses up to 1,000 mg/kg/day. There were no PF 07321332-related effects on any parameter in a rat embryo-fetal development (EFD) study up to 1,000 mg/kg/day (exposure range 16x/7.8x 300 mg/100 mg based on total Cmax/AUC24 PF 07321332/ritonavir/ritonavir predicted human exposure twice daily). However, in the rabbit EFD study, there were no PF 07321332 related effects on fetal morphology or embryo-fetal viability up to the highest dose of 1,000 mg/kg/day (exposure range 24x/10x based on total Cmax/AUC24). No adverse effects In the case of PF 07321332, lower fetal weights were observed at 1,000 mg/kg/day (0.91x control), with minimal effects on maternal weight changes and food consumption at this dose. Growth delay may be reversible after cessation of exposure in humans and is not present at intermediate doses (10x/2.8x Cmax/AUC24 above predicted clinical exposure). There were no signs of serious developmental toxicity (teratogenesis and embryo-fetal lethality) associated with PF-07321332 at the highest dose tested, 1,000 mg/kg/day.

ritonavir

Ritonavir had no effect on fertility in rats.

during organogenesis (at GD 6 to 17 and 6 to 19, respectively). No evidence of teratogenicity with ritonavir was observed in rats and rabbits. In the presence of maternal toxicity, an increased incidence of early resorption, delayed ossification, and developmental variations, as well as decreased fetal weight, were observed in rats. A slight increase in the incidence of cryptorchidism (at maternally toxic doses) was also noted in rats. In the presence of maternal toxicity, resorption, reduced litter size, and decreased fetal weight were observed in rabbits. In studies on prenatal and postnatal development in rats, doses of 0, 15, 35,

6. Drug details

6.1 List of excipients

PF 07321332

Chip:

microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
colloidal silica
Sodium stearyl fumarate

Thin film coating:

Hypromellose (E464)
Titanium dioxide (E171)
Polyethylene glycol (E1521)
Iron oxide red (E172)

ritonavir

Chip:

Copovidone
Sorbitol laurate
Anhydrous silica colloid (E551)
Calcium hydrogen phosphate anhydrous
Sodium stearyl fumarate

Thin film coating:

Hypromellose (E464)
Titanium dioxide (E171)
Polyethylene glycol (E1521)
Hydroxypropyl cellulose (E463)
Talc (E553b)
Anhydrous silica colloid (E551)
Polysorbate 80 (E433)

6.2 not compatible

not applicable.

6.3 Shelf life

1 year.

6.4 Special precautions for storage

Store below 25 °C.

Do not refrigerate or freeze.

6.5 Nature and contents of container

Paxlovid is packaged in cartons of 5 daily dose OPA/Al/PVC foil blister cards of 30 tablets per box. Each daily blister card contains 4 PF-07321332 tablets and 2 ritonavir tablets.