PAXLOVID 150mg+100mg 150mcg / 100mcg tablets medication leaflet

Paxlovid 150 mg + 100 mg film-coated tablets

Each pink film-coated tablet contains 150 mg of nirmatrelvir.

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

Each pink 150 mg film-coated tablet of nirmatrelvir contains 176 mg of lactose.

For the full list of excipients, see section 6.1.

Nirmatrelvir

Film-coated tablet (tablet).

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.

Film-coated tablet (tablet).

White to off white, capsule shaped tablets, with a dimension of approximately 17.1 mm in length and9.1 mm in width, debossed with 'H' on one side and 'R9' on other side.

Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults who do notrequire supplemental oxygen and who are at increased risk for progressing to severe COVID-19 (seesection 5.1).

The recommended dose is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir(one 100 mg tablet) all taken together orally every 12 hours for 5 days. Paxlovid should beadministered as soon as possible after a diagnosis of COVID-19 has been made and within 5 days ofsymptom onset. Completion of the full 5-day treatment course is recommended even if the patientrequires hospitalisation due to severe or critical COVID-19 after starting treatment with this medicinalproduct.

If the patient misses a dose within 8 hours of the time it is usually taken, the patient should take it assoon as possible and resume the normal dosing schedule. If the patient misses a dose by more than8 hours, the patient should not take the missed dose and instead take the next dose at the regularlyscheduled time. The patient should not double the dose to make up for a missed dose.

No dose adjustment is needed in patients with mild renal impairment [estimated glomerular filtrationrate (eGFR) ≥ 60 to < 90 mL/min]. In patients with moderate renal impairment (eGFR ≥ 30 to< 60 mL/min) or with severe renal impairment [eGFR < 30 mL/min, including patients with End Stage

Renal Disease (ESRD) under haemodialysis], the dose should be reduced as shown in Table 1 to avoidover-exposure. The treatment should be administered at approximately the same time each day for5 days. On days patients with severe renal impairment undergo haemodialysis, the dose should beadministered after haemodialysis (see section 5.2).

Table 1: Recommended dose and regimen for patients with renal impairment

Renal function Days of Dose and dose frequencytreatment

Moderate renal impairment Days 1-5 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg(eGFR ≥ 30 to < 60 mL/min) ritonavir (one 100 mg tablet) every 12 hours

Severe renal impairment Day 1 300 mg nirmatrelvir (two 150 mg tablets) with(eGFR < 30 mL/min) 100 mg ritonavir (one 100 mg tablet) onceincluding those requiringhaemodialysis

Days 2-5 150 mg nirmatrelvir (one 150 mg tablet) with 100 mgritonavir (one 100 mg tablet) once daily

Abbreviation: eGFR=estimated glomerular filtration rate.

Special attention for patients with MODERATE renal impairment

The daily blister contains two separated parts each containing two tablets of nirmatrelvir and onetablet of ritonavir corresponding to the daily administration at the standard dose.

Therefore, patients with moderate renal impairment should be alerted on the fact that only one tabletof nirmatrelvir with the tablet of ritonavir should be taken every 12 hours.

Special attention for patients with SEVERE renal impairment

There is a daily blister specific for patients with severe renal impairment that contains two tablets ofnirmatrelvir and one tablet of ritonavir for administration once on Day 1, and one tablet of nirmatrelvirand one tablet of ritonavir for administration once daily on Days 2 to 5.

No dose adjustment is needed for patients with either mild (Child-Pugh Class A) or moderate (Child-

Pugh Class B) hepatic impairment. Paxlovid should not be used in patients with severe (Child-Pugh

Class C) hepatic impairment (see sections 4.4 and 5.2).

No dose adjustment is needed. Patients diagnosed with human immunodeficiency virus (HIV) orhepatitis C virus (HCV) infection who are receiving ritonavir- or cobicistat-containing regimen shouldcontinue their treatment as indicated.

The safety and efficacy of Paxlovid in patients below 18 years of age have not been established. Nodata are available.

For oral use.

Nirmatrelvir must be coadministered with ritonavir. Failure to correctly coadminister nirmatrelvir withritonavir will result in plasma levels of this active substance that will be insufficient to achieve thedesired therapeutic effect.

This medicinal product can be taken with or without food (see section 5.2). The tablets should beswallowed whole and not chewed, broken or crushed, as no data is currently available.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Medicinal products listed below are a guide and not considered a comprehensive list of all possiblemedicinal products that are contraindicated with Paxlovid.

Medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasmaconcentrations are associated with serious and/or life-threatening reactions.

- Alpha1-adrenoreceptor antagonist: alfuzosin

- Antianginal: ranolazine

- Antiarrhythmic: dronedarone, propafenone, quinidine

- Anticancer drugs: neratinib, venetoclax

- Anti-gout: colchicine

- Antihistamines: terfenadine

- Antipsychotics/neuroleptics: lurasidone, pimozide, quetiapine

- Benign prostatic hyperplasia medicinal products: silodosin

- Cardiovascular medicinal products: eplerenone, ivabradine

- Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine

- GI motility agents: cisapride

- Immunosuppressants: voclosporin

- Lipid-modifying agents:

o HMG Co-A reductase inhibitors: lovastatin, simvastatino Microsomal triglyceride transfer protein (MTTP) inhibitor: lomitapide

- Migraine medicinal products: eletriptan

- Mineralocorticoid receptor antagonists: finerenone

- Neuropsychiatric agents: cariprazine

- Opioid antagonists: naloxegol

- PDE5 inhibitor: avanafil, sildenafil, tadalafil, vardenafil

- Sedative/hypnotics: clorazepate, diazepam, estazolam, flurazepam, oral midazolam andtriazolam

- Vasopressin receptor antagonists: tolvaptan

Medicinal products that are potent CYP3A inducers where significantly reduced nirmatrelvir/ritonavirplasma concentrations may be associated with the potential for loss of virologic response and possibleresistance.

- Antibiotics: rifampicin, rifapentine

- Anticancer drugs: apalutamide, enzalutamide

- Anticonvulsants: carbamazepine, phenobarbital, phenytoin, primidone

- Cystic fibrosis transmembrane conductance regulator potentiators: lumacaftor/ivacaftor

- Herbal products: St. John’s wort (Hypericum perforatum)

Paxlovid cannot be started immediately after discontinuation of CYP3A4 inducers due to the delayedoffset of the recently discontinued CYP3A4 inducer (see section 4.5).

A multi-disciplinary approach (e.g., involving physicians and specialists in clinical pharmacology)should be considered to determine the adequate timing for Paxlovid initiation taking into account thedelayed offset of the recently discontinued CYP3A inducer and the need to initiate Paxlovid within5 days of symptom onset.

Management of drug-drug interactions (DDIs) in high-risk COVID-19 patients receiving multipleconcomitant medications can be complex and require a thorough understanding of the nature andmagnitude of interaction with all concomitant medications. In certain patients, a multi-disciplinaryapproach (e.g., involving physicians and specialists in clinical pharmacology) should be considered formanagement of DDIs especially if concomitant medications are withheld, their dose is reduced, or ifmonitoring of side effects is necessary.

Effects of Paxlovid on 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 (seesection 4.5).

Coadministration of Paxlovid with calcineurin inhibitors and mTOR inhibitors

Consultation of a multidisciplinary group (e.g., involving physicians, specialists inimmunosuppressive therapy, and/or specialists in clinical pharmacology) is required to handle thecomplexity of this coadministration by closely and regularly monitoring immunosuppressant bloodconcentrations and adjusting the dose of the immunosuppressant in accordance with the latestguidelines (see section 4.5).

Effects of other medicinal products on Paxlovid

Initiation of medicinal products that inhibit or induce CYP3A may increase or decrease concentrationsof Paxlovid, respectively.

These interactions may lead to:

- Clinically significant adverse reactions with severe, life-threatening or fatal events fromgreater 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 2 for medicinal products that are contraindicated for concomitant use withnirmatrelvir/ritonavir and for potentially significant interactions with other medicinal products (seesection 4.5). Potential for interactions should be considered with other medicinal products prior to andduring Paxlovid therapy; concomitant medicinal products should be reviewed during Paxlovid therapyand the patient should be monitored for the adverse reactions associated with the concomitantmedicinal products.

Anaphylaxis, hypersensitivity reactions and serious skin reactions (including toxic epidermalnecrolysis and Stevens-Johnson syndrome) have been reported with Paxlovid (see section 4.8). If signsand symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediatelydiscontinue this medicinal product and initiate appropriate medications and/or supportive care.

No pharmacokinetic and clinical data are available in patients with severe hepatic impairment.

Therefore, this medicinal product should not be used in patients with severe hepatic impairment.

Hepatic transaminase elevations, clinical hepatitis and jaundice have occurred in patients receivingritonavir. Therefore, caution should be exercised when administering this medicinal product to patientswith pre-existing liver diseases, liver enzyme abnormalities or hepatitis.

Elevation in blood pressure

Cases of hypertension, generally non serious and transient, have been reported during treatment with

Paxlovid. Specific attention including regular monitoring of blood pressure should be paid notably toelderly patients since they are at higher risk of experiencing serious complications of hypertension.

Because nirmatrelvir is coadministered with ritonavir, there may be a risk of HIV-1 developingresistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

Nirmatrelvir tablets contain lactose. Patients with rare hereditary problems of galactose intolerance,total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Nirmatrelvir and ritonavir tablets each contain less than 1 mmol sodium (23 mg) per tablet, that is tosay essentially ‘sodium-free’.

Effect of other medicinal products on Paxlovid

Nirmatrelvir and ritonavir are CYP3A substrates.

Coadministration of Paxlovid with medicinal products that induce CYP3A may decrease nirmatrelvirand ritonavir plasma concentrations and reduce Paxlovid therapeutic effect.

Coadministration of Paxlovid with medicinal product that inhibits CYP3A4 may increase nirmatrelvirand ritonavir plasma concentrations.

Effects of Paxlovid on other medicinal products

Medicinal products CYP3A4 substrates

Paxlovid (nirmatrelvir/ritonavir) is a strong inhibitor of CYP3A and increases plasma concentrationsof medicinal products that are primarily metabolised by CYP3A. Thus, coadministration ofnirmatrelvir/ritonavir with medicinal products highly dependent on CYP3A for clearance and forwhich elevated plasma concentrations are associated with serious and/or life-threatening events iscontraindicated (see Table 2). Coadministration of other CYP3A4 substrates that may lead topotentially significant interaction (see Table 2) should be considered only if the benefits outweigh therisks.

Medicinal products CYP2D6 substrates

Based on in vitro studies, ritonavir has a high affinity for several cytochrome P450 (CYP) isoformsand may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Coadministration of

Paxlovid with drug substrates of CYP2D6 may increase the CYP2D6 substrate concentration.

Medicinal products P-glycoprotein substrates

Paxlovid also has a high affinity for P-glycoprotein (P-gp) and inhibits this transporter; caution shouldthus be exercised in case of concomitant treatment. Close drug monitoring for safety and efficacyshould be performed, and dose reduction may be adjusted accordingly, or avoid concomitant use.

Paxlovid may induce glucuronidation and oxidation by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and

CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by thesepathways and may result in decreased systemic exposure to such medicinal products, which coulddecrease or shorten their therapeutic effect.

Based on in vitro studies there is a potential for nirmatrelvir to inhibit MDR1 and OATP1B1 atclinically relevant concentrations.

Dedicated drug-drug interactions studies conducted with Paxlovid indicate that the drug interactionsare primarily due to ritonavir. Hence, drug interactions pertaining to ritonavir are applicable for

Paxlovid.

Medicinal products listed in Table 2 are a guide and not considered a comprehensive list of allpossible medicinal products that are contraindicated or may interact with nirmatrelvir/ritonavir.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments

Alpha1-adrenoreceptor ↑Alfuzosin Increased plasma concentrations ofantagonist alfuzosin may lead to severe hypotensionand is therefore contraindicated (seesection 4.3).

↑Tamsulosin Tamsulosin is extensively metabolized,mainly by CYP3A4 and CYP2D6, both ofwhich are inhibited by ritonavir. Avoidconcomitant use with Paxlovid.

Amphetamine ↑Amphetamine Ritonavir administered at high dose inderivatives accordance with its previous use as anantiretroviral agent is likely to inhibit

CYP2D6 and as a result is expected toincrease concentrations of amphetamineand its derivatives. Careful monitoring ofadverse effects is recommended whenthese medicines are coadministered with

Paxlovid.

Analgesics ↑Buprenorphine (57%, 77%) The increases of plasma levels ofbuprenorphine and its active metabolite didnot lead to clinically significantpharmacodynamic changes in a populationof opioid tolerant patients. Adjustment tothe dose of buprenorphine may thereforenot be necessary when the two are dosedtogether.

↑Fentanyl, Ritonavir inhibits CYP3A4 and as a result↑Oxycodone is expected to increase the plasmaconcentrations of these narcotic analgesics.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments

If concomitant use with Paxlovid isnecessary, consider a dose reduction ofthese narcotic analgesics and closelymonitor therapeutic and adverse effects(including respiratory depression). Refer tothe individual SmPCs for moreinformation.

↓Methadone (36%, 38%) Increased methadone dose may benecessary when coadministered withritonavir dosed as a pharmacokineticenhancer due to induction ofglucuronidation. Dose adjustment shouldbe considered based on the patient’sclinical response to methadone therapy.

↓Morphine Morphine levels may be decreased due toinduction of glucuronidation bycoadministered ritonavir dosed as apharmacokinetic enhancer.

↑Pethidine Coadministration could result in increasedor prolonged opioid effects. If concomitantuse is necessary, consider dose reductionof pethidine. Monitor for respiratorydepression and sedation.

↓Piroxicam Decreased piroxicam exposure due to

CYP2C9 induction by Paxlovid.

Antianginal ↑Ranolazine Due to CYP3A inhibition by ritonavir,concentrations of ranolazine are expectedto increase. The concomitantadministration with ranolazine iscontraindicated (see section 4.3).

Antiarrhythmics ↑Amiodarone Given the risk of substantial increase in↑Flecainide amiodarone or flecainide exposure andthus of its related adverse events,coadministration should not be used unlessa multidisciplinary consultation could beobtained to safely guide it.

↑Digoxin This interaction may be due tomodification of P-gp mediated digoxinefflux by ritonavir dosed as apharmacokinetic enhancer. Digoxin drugconcentration is expected to increase.

Monitor digoxin levels if possible anddigoxin safety and efficacy.

↑Disopyramide Ritonavir may increase plasmaconcentrations of disopyramide whichcould result in an increased risk of adverseevents such as cardiac arrhythmias.

Caution is warranted and therapeuticconcentration monitoring is recommendedfor disopyramide if available.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments↑Dronedarone, Ritonavir coadministration is likely to↑Propafenone, result in increased plasma concentrations↑Quinidine of dronedarone, propafenone and quinidineand is therefore contraindicated (seesection 4.3).

Antiasthmatic ↓Theophylline (43%, 32%) An increased dose of theophylline may berequired when coadministered withritonavir, due to induction of CYP1A2.

Anticancer agents ↑Abemaciclib Serum concentrations may be increaseddue to CYP3A4 inhibition by ritonavir.

Coadministration of abemaciclib and

Paxlovid should be avoided. If thiscoadministration is judged unavoidable,refer to the abemaciclib SmPC for doseadjustment recommendations. Monitor for

ADRs related to abemaciclib.

↑Afatinib Serum concentrations may be increaseddue to Breast Cancer Resistance Protein(BCRP) and acute P-gp inhibition byritonavir. The extent of increase in AUCand Cmax depends on the timing of ritonaviradministration. Caution should beexercised in administering afatinib with

Paxlovid (refer to the afatinib SmPC).

Monitor for ADRs related to afatinib.

↑Apalutamide Apalutamide is a moderate to strong

CYP3A4 inducer and this may lead to adecreased exposure ofnirmatrelvir/ritonavir and potential loss ofvirologic response. In addition, serumconcentrations of apalutamide may beincreased when coadministered withritonavir resulting in the potential forserious adverse events including seizure.

Concomitant use of Paxlovid withapalutamide is contraindicated (see section4.3).

↑Ceritinib Serum concentrations of ceritinib may beincreased due to CYP3A and P-gpinhibition by ritonavir. Caution should beexercised in administering ceritinib with

Paxlovid. Refer to the ceritinib SmPC fordose adjustment recommendations.

Monitor for ADRs related to ceritinib.

↑Dasatinib, Serum concentrations may be increased↑Nilotinib, when coadministered with ritonavir↑Vinblastine, resulting in the potential for increased↑Vincristine incidence of adverse events.↑Encorafenib, Serum concentrations of encorafenib or↑Ivosidenib ivosidenib may be increased whencoadministered with ritonavir which mayincrease the risk of toxicity, including therisk of serious adverse events such as QT

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical commentsinterval prolongation. Avoidcoadministration of encorafenib orivosidenib. If the benefit is considered tooutweigh the risk and ritonavir must beused, patients should be carefullymonitored for safety.

Enzalutamide Enzalutamide is a strong CYP3A4 inducer,and this may lead to decreased exposure of

Paxlovid, potential loss of virologicresponse, and possible resistance.

Concomitant use of enzalutamide with

Paxlovid is contraindicated (seesection 4.3).

↑Fostamatinib Coadministration of fostamatinib withritonavir may increase fostamatinibmetabolite R406 exposure resulting indose-related adverse events such ashepatotoxicity, neutropenia, hypertensionor diarrhoea. Refer to the fostamatinib

SmPC for dose reductionrecommendations if such events occur.

↑Ibrutinib Serum concentrations of ibrutinib may beincreased due to CYP3A inhibition byritonavir, resulting in increased risk fortoxicity including risk of tumour lysissyndrome. Coadministration of ibrutiniband ritonavir should be avoided. If thebenefit is considered to outweigh the riskand ritonavir must be used, reduce theibrutinib dose to 140 mg and monitorpatient closely for toxicity.

↑Neratinib Serum concentrations may be increaseddue to CYP3A4 inhibition by ritonavir.

Concomitant use of neratinib with

Paxlovid is contraindicated due to seriousand/or life-threatening potential reactionsincluding hepatotoxicity (see section 4.3).

↑Venetoclax Serum concentrations may be increaseddue to CYP3A inhibition by ritonavir,resulting in increased risk of tumour lysissyndrome at the dose initiation and duringthe ramp-up phase and is thereforecontraindicated (see section 4.3 and referto the venetoclax SmPC). For patients whohave completed the ramp-up phase and areon a steady daily dose of venetoclax,reduce the venetoclax dose to 100 mg orless (or by at least 75% if already modifiedfor other reasons) when used with strong

Anticoagulants ↑Apixaban Combined P-gp and strong CYP3A4inhibitors increase blood levels of apixabanand increase the risk of bleeding. Dosing

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical commentsrecommendations for coadministration ofapixaban with Paxlovid depend on theapixaban dose. For apixaban doses of 5 mgor 10 mg twice daily, reduce the apixabandose by 50%. In patients already takingapixaban 2.5 mg twice daily, avoidcoadministration with Paxlovid.

↑Dabigatran (94%, 133%)* Concomitant administration of Paxlovid isexpected to increase dabigatranconcentrations resulting in increased riskof bleeding. Reduce dose of dabigatran oravoid concomitant use.

↑Rivaroxaban (153%, 53%) Inhibition of CYP3A and P-gp lead toincreased plasma levels andpharmacodynamic effects of rivaroxabanwhich may lead to an increased bleedingrisk. Therefore, the use of Paxlovid is notrecommended in patients receivingrivaroxaban.

Warfarin, Induction of CYP1A2 and CYP2C9 lead to↑↓S-Warfarin (9%, 9%), decreased levels of R-warfarin while little↓↔R-Warfarin (33%) pharmacokinetic effect is noted on

S-warfarin when coadministered withritonavir. Decreased R-warfarin levels maylead to reduced anticoagulation, thereforeit is recommended that anticoagulationparameters are monitored when warfarin iscoadministered with ritonavir.

Anticonvulsants Carbamazepine*, Carbamazepine decreases AUC and Cmax

Phenobarbital, of nirmatrelvir by 55% and 43%,

Phenytoin, respectively. Phenobarbital, phenytoin and

Primidone primidone are strong CYP3A4 inducers,and this may lead to a decreased exposureof nirmatrelvir and ritonavir and potentialloss of virologic response. Concomitantuse of carbamazepine, phenobarbital,phenytoin and primidone with Paxlovid iscontraindicated (see section 4.3).

↑Clonazepam A dose decrease may be needed forclonazepam when coadministered with

Paxlovid and clinical monitoring isrecommended.

↓Divalproex, Ritonavir dosed as a pharmacokinetic

Lamotrigine enhancer induces oxidation by CYP2C9and glucuronidation and as a result isexpected to decrease the plasmaconcentrations of anticonvulsants. Carefulmonitoring of serum levels or therapeuticeffects is recommended when thesemedicines are coadministered withritonavir.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments

Anticorticosteroids ↑Ketoconazole (3.4-fold, 55%) Ritonavir inhibits CYP3A-mediatedmetabolism of ketoconazole. Due to anincreased incidence of gastrointestinal andhepatic adverse reactions, a dose reductionof ketoconazole should be consideredwhen coadministered with ritonavir.

Antidepressants ↑Amitriptyline, Ritonavir administered at high dose in

Fluoxetine, accordance with its previous use as an

Imipramine, antiretroviral agent is likely to inhibit

Nortriptyline, CYP2D6 and as a result is expected to

Paroxetine, increase concentrations of imipramine,

Sertraline amitriptyline, nortriptyline, fluoxetine,paroxetine or sertraline. Carefulmonitoring of therapeutic and adverseeffects is recommended when thesemedicines are concomitantly administeredwith antiretroviral doses of ritonavir.

Anti-gout ↑Colchicine Concentrations of colchicine are expectedto increase when coadministered withritonavir. Life-threatening and fatal druginteractions have been reported in patientstreated with colchicine and ritonavir(CYP3A4 and P-gp inhibition).

Concomitant use of colchicine with

Paxlovid is contraindicated (seesection 4.3).

Anti-HCV ↑Glecaprevir/pibrentasvir Serum concentrations may be increaseddue to P-gp, BCRP and OATP1Binhibition by ritonavir. Concomitantadministration of glecaprevir/pibrentasvirand Paxlovid is not recommended due toan increased risk of ALT elevationsassociated with increased glecaprevirexposure.

↑Sofosbuvir/velpatasvir/ Serum concentrations may be increasedvoxilaprevir due to OATP1B inhibition by ritonavir.

Concomitant administration ofsofosbuvir/velpatasvir/voxilaprevir and

Paxlovid is not recommended. Refer to thesofosbuvir/velpatasvir/voxilaprevir SmPCfor further information.

Antihistamines ↑Fexofenadine Ritonavir may modify P-gp mediatedfexofenadine efflux when dosed as apharmacokinetic enhancer resulting inincreased concentrations of fexofenadine.

↑Loratadine Ritonavir dosed as a pharmacokineticenhancer inhibits CYP3A and as a result isexpected to increase the plasmaconcentrations of loratadine. Carefulmonitoring of therapeutic and adverseeffects is recommended when loratadine iscoadministered with ritonavir.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments↑Terfenadine Increased plasma concentrations ofterfenadine. Thereby, increasing the risk ofserious arrhythmias from this agent andtherefore concomitant use with Paxlovid iscontraindicated (see section 4.3).

Anti-HIV ↑Bictegravir/ Ritonavir may significantly increase the↔Emtricitabine/ plasma concentrations of bictegravir↑Tenofovir through CYP3A inhibition. Ritonavir isexpected to increase the absorption oftenofovir alafenamide by inhibition of

P-gp, thereby increasing the systemicconcentration of tenofovir.

↑Efavirenz (21%) A higher frequency of adverse reactions(e.g., dizziness, nausea, paraesthesia) andlaboratory abnormalities (elevated liverenzymes) have been observed whenefavirenz is coadministered with ritonavir.

Refer to efavirenz SmPC for moreinformation.

↑Maraviroc (161%, 28%) Ritonavir increases the serum levels ofmaraviroc as a result of CYP3A inhibition.

Maraviroc may be given with ritonavir toincrease the maraviroc exposure. Forfurther information, refer to the Summaryof Product Characteristics for maraviroc.

↓Raltegravir (16%, 1%) Coadministration of ritonavir andraltegravir results in a minor reduction inraltegravir levels.

↓Zidovudine (25%, ND) Ritonavir may induce the glucuronidationof zidovudine, resulting in slightlydecreased levels of zidovudine. Dosealterations should not be necessary.

Anti-infectives ↓Atovaquone Ritonavir dosed as a pharmacokineticenhancer induces glucuronidation and as aresult is expected to decrease the plasmaconcentrations of atovaquone. Carefulmonitoring of serum levels or therapeuticeffects is recommended when atovaquoneis coadministered with ritonavir.

↑Bedaquiline No interaction study is available withritonavir only. Due to the risk ofbedaquiline related adverse events,coadministration should be avoided. If thebenefit outweighs the risk,coadministration of bedaquiline withritonavir must be done with caution. Morefrequent electrocardiogram monitoring andmonitoring of transaminases isrecommended (see bedaquiline Summaryof Product Characteristics).

↑Clarithromycin (77%, 31%), Due to the large therapeutic window of↓14-OH clarithromycin clarithromycin no dose reduction should bemetabolite (100%, 99%) necessary in patients with normal renal

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical commentsfunction. Clarithromycin doses greater than1 g per day should not be coadministeredwith ritonavir dosed as a pharmacokineticenhancer. For patients with renalimpairment, a clarithromycin dosereduction should be considered: forpatients with creatinine clearance of 30 to60 mL/min the dose should be reduced by50% (see section 4.2 for patients withsevere renal impairment).

Delamanid No interaction study is available withritonavir only. In a healthy volunteer druginteraction study of delamanid 100 mgtwice daily and lopinavir/ritonavir400/100 mg twice daily for 14 days, theexposure of the delamanid metabolite

DM-6705 was 30% increased. Due to therisk of QTc prolongation associated with

DM-6705, if coadministration ofdelamanid with ritonavir is considerednecessary, very frequent ECG monitoringthroughout the full Paxlovid treatmentperiod is recommended (see section 4.4and refer to the delamanid Summary of

Product Characteristics).

↑Erythromycin, Itraconazole increases AUC and Cmax of↑Itraconazole* nirmatrelvir by 39% and 19%,respectively. Ritonavir dosed as apharmacokinetic enhancer inhibits

CYP3A4 and as a result is expected toincrease the plasma concentrations ofitraconazole and erythromycin. Carefulmonitoring of therapeutic and adverseeffects is recommended whenerythromycin or itraconazole iscoadministered with ritonavir.

↑Fusidic acid (systemic route) Given the risk of substantial increase infusidic acid (systemic route) exposure andthus of its related adverse events,coadministration should not be used unlessa multidisciplinary consultation could beobtained to safely guide it.

↑Rifabutin (4-fold, 2.5-fold), An increase in rifabutin exposure is↑25-O-desacetyl rifabutin expected due to the inhibition of CYP3A4metabolite (38-fold, 16-fold) by ritonavir. The consultation of amultidisciplinary group is recommended tosafely guide the co-administration and theneed of a reduction of the rifabutin dose.

Rifampicin, Rifampicin and rifapentine are strong

Rifapentine CYP3A4 inducers, and this may lead to adecreased exposure ofnirmatrelvir/ritonavir, potential loss ofvirologic response and possible resistance.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments

Concomitant use of rifampicin orrifapentine with Paxlovid iscontraindicated (see section 4.3).

Sulfamethoxazole/trimethoprim Dose alteration ofsulfamethoxazole/trimethoprim duringconcomitant ritonavir therapy should notbe necessary.

↓Voriconazole (39%, 24%) Coadministration of voriconazole andritonavir dosed as a pharmacokineticenhancer should be avoided unless anassessment of the benefit/risk to the patientjustifies the use of voriconazole.

Antipsychotics ↑Clozapine Given the risk of increase in clozapineexposure and thus of its related adverseevents, coadministration should not beused unless a multidisciplinaryconsultation could be obtained to safelyguide it.

↑Haloperidol, Ritonavir is likely to inhibit CYP2D6 and↑Risperidone, as a result is expected to increase↑Thioridazine concentrations of haloperidol, risperidoneand thioridazine. Careful monitoring oftherapeutic and adverse effects isrecommended when these medicines areconcomitantly administered withantiretroviral doses of ritonavir.

↑Lurasidone Due to CYP3A inhibition by ritonavir,concentrations of lurasidone are expectedto increase. The concomitantadministration with lurasidone iscontraindicated (see section 4.3).

↑Pimozide Ritonavir coadministration is likely toresult in increased plasma concentrationsof pimozide and is thereforecontraindicated (see section 4.3).

↑Quetiapine Due to CYP3A inhibition by ritonavir,concentrations of quetiapine are expectedto increase. Concomitant administration of

Paxlovid and quetiapine is contraindicatedas it may increase quetiapine-relatedtoxicity (see section 4.3).

Benign prostatic ↑Silodosin Coadministration is contraindicated due tohyperplasia agents potential for postural hypotension (seesection 4.3).β2-agonist (long ↑Salmeterol Ritonavir inhibits CYP3A4 and as a resultacting) a pronounced increase in the plasmaconcentrations of salmeterol is expected,resulting in increased risk ofcardiovascular adverse events associatedwith salmeterol, including QTprolongation, palpitations and sinus

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical commentstachycardia. Therefore, avoid concomitantuse with Paxlovid.

Calcium channel ↑Amlodipine, Ritonavir dosed as a pharmacokineticantagonists ↑Diltiazem, enhancer or as an antiretroviral agent↑Felodipine, inhibits CYP3A4 and as a result is↑Nicardipine, expected to increase the plasma↑Nifedipine, concentrations of calcium channel↑Verapamil antagonists. Careful monitoring oftherapeutic and adverse effects isrecommended when amlodipine, diltiazem,felodipine, nicardipine, nifedipine orverapamil are concomitantly administeredwith ritonavir.

↑Lercanidipine Given the risk of significant increase inlercanidipine exposure and thus of itsrelated adverse events, coadministrationshould not be used unless amultidisciplinary consultation could beobtained to safely guide it.

Cardiovascular agents ↑Aliskiren Avoid concomitant use with Paxlovid.

↑Cilostazol Dose adjustment of cilostazol isrecommended. Refer to the cilostazol

SmPC for more information.

Clopidogrel Coadministration with clopidogrel maydecrease levels of clopidogrel activemetabolite. Avoid concomitant use with

Paxlovid.

↑Eplerenone Coadministration with eplerenone iscontraindicated due to potential forhyperkalemia (see section 4.3).

↑Ivabradine Coadministration with ivabradine iscontraindicated due to potential forbradycardia or conduction disturbances(see section 4.3).

↑Ticagrelor Given the risk of substantial increase inticagrelor exposure and thus of its relatedadverse events, coadministration shouldnot be used unless a multidisciplinaryconsultation could be obtained to safelyguide it.

Cystic fibrosis ↑Elexacaftor/ Reduce dose when coadministered withtransmembrane tezacaftor/ivacaftor, Paxlovid. Refer to individual SmPCs forconductance regulator ↑Ivacaftor, more information.potentiators ↑Tezacaftor/ivacaftor

Lumacaftor/ivacaftor Coadministration contraindicated due topotential loss of virologic response andpossible resistance (see section 4.3).

Dipeptidyl peptidase 4 ↑Saxagliptin Dose adjustment of saxagliptin to 2.5 mg(DPP4) inhibitors once daily is recommended.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments

Endothelin antagonists ↑Bosentan Coadministration of bosentan and ritonavirresulted in an increase of steady-statebosentan maximum concentrations (Cmax)and AUC. Avoid concomitant use with

Paxlovid. Refer to bosentan SmPC formore information.

↑Riociguat Serum concentrations may be increaseddue to CYP3A and P-gp inhibition byritonavir. The coadministration of riociguatwith Paxlovid is not recommended (referto riociguat SmPC).

Ergot derivatives ↑Dihydroergotamine, Ritonavir coadministration is likely to↑Ergonovine, result in increased plasma concentrations↑Ergotamine, of ergot derivatives and is therefore↑Methylergonovine contraindicated (see section 4.3).

GI motility agent ↑Cisapride Increased plasma concentrations ofcisapride. Thereby, increasing the risk ofserious arrhythmias from this agent andtherefore concomitant use with Paxlovid iscontraindicated (see section 4.3).

Herbal products St. John’s Wort Herbal preparations containing St John’swort (Hypericum perforatum) due to therisk of decreased plasma concentrationsand reduced clinical effects of nirmatrelvirand ritonavir and therefore concomitantuse with Paxlovid is contraindicated (seesection 4.3).

HMG Co-A reductase ↑Lovastatin, HMG-CoA reductase inhibitors which areinhibitors Simvastatin highly dependent on CYP3A metabolism,such as lovastatin and simvastatin, areexpected to have markedly increasedplasma concentrations whencoadministered with ritonavir at high dosein accordance with its previous use as anantiretroviral agent or as a pharmacokineticenhancer. Since increased concentrationsof lovastatin and simvastatin maypredispose patients to myopathies,including rhabdomyolysis, the combinationof these medicinal products with ritonaviris contraindicated (see section 4.3).

↑Atorvastatin, Atorvastatin is less dependent on CYP3A

Rosuvastatin (31%, 112%)* for metabolism. While rosuvastatinelimination is not dependent on CYP3A,an elevation of rosuvastatin exposure hasbeen reported with ritonavircoadministration. The mechanism of thisinteraction is not clear, but may be theresult of transporter inhibition. When usedwith ritonavir dosed as a pharmacokineticenhancer or as an antiretroviral agent, thelowest possible doses of atorvastatin orrosuvastatin should be administered.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments↑Fluvastatin, While not dependent on CYP3A for

Pravastatin metabolism, pravastatin and fluvastatinexposure may be increased due totransporter inhibition. Consider temporarydiscontinuation of pravastatin andfluvastatin during treatment with Paxlovid.

Hormonal ↓Ethinyl Estradiol (40%, 32%) Due to reductions in ethinyl estradiolcontraceptive concentrations, barrier or othernon-hormonal methods of contraceptionshould be considered with concomitantritonavir use at high dose in accordancewith its previous use as an antiretroviralagent or as a pharmacokinetic enhancer.

Ritonavir is likely to change the uterinebleeding profile and reduce theeffectiveness of estradiol-containingcontraceptives.

Immunosuppressants ↑Voclosporin Coadministration is contraindicated due topotential for acute and/or chronicnephrotoxicity (see section 4.3).

Immunosuppressants Calcineurin inhibitors: Ritonavir dosed as a pharmacokinetic↑Cyclosporine, enhancer inhibits CYP3A4 and as a result↑Tacrolimus is expected to increase the plasmaconcentrations of cyclosporine,mTOR inhibitors: everolimus, sirolimus and tacrolimus. This↑Everolimus, coadministration should only be↑Sirolimus considered with close and regularmonitoring of immunosuppressant bloodconcentrations, to reduce the dose of theimmunosuppressant in accordance with thelatest guidelines and to avoidover-exposure and subsequent increase ofserious adverse reactions of theimmunosuppressant. It is important that theclose and regular monitoring is performednot only during the coadministration with

Paxlovid but is also pursued after thetreatment with Paxlovid. As overallrecommended for managing the drug-druginteraction, consultation of amultidisciplinary group is required tohandle the complexity of thiscoadministration (see section 4.4).

Janus kinase (JAK) ↑Tofacitinib Dose adjustment of tofacitinib isinhibitors recommended. Refer to the tofacitinib

SmPC for more information.↑Upadacitinib Dosing recommendations forcoadministration of upadacitinib with

Paxlovid depends on the upadacitinibindication. Refer to the upadacitinib SmPCfor more information.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments

Lipid-modifying ↑Lomitapide CYP3A4 inhibitors increase the exposureagents of lomitapide, with strong inhibitorsincreasing exposure approximately27-fold. Due to CYP3A inhibition byritonavir, concentrations of lomitapide areexpected to increase. Concomitant use of

Paxlovid with lomitapide iscontraindicated (see prescribinginformation for lomitapide) (seesection 4.3).

Migraine medicinal ↑Eletriptan Coadministration of eletriptan within atproducts least 72 hours of Paxlovid iscontraindicated due to potential for seriousadverse reactions including cardiovascularand cerebrovascular events (see section4.3).

↑Rimegepant Avoid concomitant use with Paxlovid.

Mineralocorticoid ↑Finerenone Coadministration contraindicated due toreceptor antagonists potential for serious adverse reactionsincluding hyperkalemia, hypotension andhyponatremia (see section 4.3).

Muscarinic receptor ↑Darifenacin Given the risk of substantial increase inantagonists darifenacin exposure and thus of its relatedadverse events, coadministration shouldnot be used unless a multidisciplinaryconsultation could be obtained to safelyguide it.

↑Solifenacine Given the risk of substantial increase insolifenacine exposure and thus of itsrelated adverse events, coadministrationshould not be used unless amultidisciplinary consultation could beobtained to safely guide it.

Neuropsychiatric ↑Aripiprazole, Dose adjustment of aripiprazole andagents ↑Brexpiprazole brexpiprazole is recommended. Refer toaripiprazole or brexpiprazole SmPCs formore information.

↑Cariprazine Coadministration is contraindicated due toincreased plasma exposure of cariprazineand its active metabolites (see section 4.3).

Opioid antagonists ↑Naloxegol Coadministration contraindicated due tothe potential for opioid withdrawalsymptoms (see section 4.3).

Phosphodiesterase ↑Avanafil (13-fold, 2.4-fold), Concomitant use of avanafil, sildenafil,(PDE5) inhibitors ↑Sildenafil (11-fold, 4-fold), tadalafil and vardenafil with Paxlovid is↑Tadalafil (124%, ↔), contraindicated (see section 4.3).↑Vardenafil (49-fold, 13-fold)

Sedatives/hypnotics ↑Alprazolam (2.5-fold, ↔) Alprazolam metabolism is inhibitedfollowing the introduction of ritonavir.

Caution is warranted during the firstseveral days when alprazolam iscoadministered with ritonavir at high dose

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical commentsin accordance with its previous use as anantiretroviral agent or as a pharmacokineticenhancer, before induction of alprazolammetabolism develops.

↑Buspirone Ritonavir dosed as a pharmacokineticenhancer or as an antiretroviral agentinhibits CYP3A and as a result is expectedto increase the plasma concentrations ofbuspirone. Careful monitoring oftherapeutic and adverse effects isrecommended when buspironeconcomitantly administered with ritonavir.

↑Clorazepate, Ritonavir coadministration is likely to↑Diazepam, result in increased plasma concentrations↑Estazolam, of clorazepate, diazepam, estazolam, and↑Flurazepam flurazepam and is therefore contraindicated(see section 4.3).↑Oral Midazolam (1330%, Midazolam is extensively metabolised by268%)* and parenteral CYP3A4. Coadministration with Paxlovid

Midazolam may cause a large increase in theconcentration of midazolam. Plasmaconcentrations of midazolam are expectedto be significantly higher when midazolamis given orally. Therefore, coadministrationof Paxlovid with orally administeredmidazolam is contraindicated (see section4.3), whereas caution should be used withcoadministration of Paxlovid andparenteral midazolam. Data fromconcomitant use of parenteral midazolamwith other protease inhibitors suggests apossible 3- to 4-fold increase in midazolamplasma levels. If Paxlovid iscoadministered with parenteral midazolam,it should be done in an intensive care unit(ICU) or similar setting which ensuresclose clinical monitoring and appropriatemedical management in case of respiratorydepression and/or prolonged sedation.

Dose adjustment for midazolam should beconsidered, especially if more than a singledose of midazolam is administered.

↑Triazolam (> 20-fold, 87%) Ritonavir coadministration is likely toresult in increased plasma concentrationsof triazolam and is thereforecontraindicated (see section 4.3).

Sleeping agent ↑Zolpidem (28%, 22%) Zolpidem and ritonavir may becoadministered with careful monitoring forexcessive sedative effects.

Smoke cessation ↓Bupropion (22%, 21%) Bupropion is primarily metabolised by

CYP2B6. Concurrent administration ofbupropion with repeated doses of ritonaviris expected to decrease bupropion levels.

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments

These effects are thought to representinduction of bupropion metabolism.

However, because ritonavir has also beenshown to inhibit CYP2B6 in vitro, therecommended dose of bupropion shouldnot be exceeded. In contrast to long-termadministration of ritonavir, there was nosignificant interaction with bupropion aftershort-term administration of low doses ofritonavir (200 mg twice daily for 2 days),suggesting reductions in bupropionconcentrations may have onset severaldays after initiation of ritonavircoadministration.

Steroids Budesonide, Systemic corticosteroid effects including

Inhaled, injectable or intranasal Cushing's syndrome and adrenalfluticasone propionate, suppression (plasma cortisol levels were

Triamcinolone noted to be decreased 86%) have beenreported in patients receiving ritonavir andinhaled or intranasal fluticasonepropionate; similar effects could also occurwith other corticosteroids metabolised by

CYP3A e.g., budesonide andtriamcinolone. Consequently, concomitantadministration of ritonavir at high dose inaccordance with its previous use as anantiretroviral agent or as a pharmacokineticenhancer and these glucocorticoids is notrecommended unless the potential benefitof treatment outweighs the risk of systemiccorticosteroid effects. A dose reduction ofthe glucocorticoid should be consideredwith close monitoring of local andsystemic effects or a switch to aglucocorticoid, which is not a substrate for

CYP3A4 (e.g., beclomethasone).

Moreover, in case of withdrawal ofglucocorticoids progressive dose reductionmay be required over a longer period.

↑Dexamethasone Ritonavir dosed as a pharmacokineticenhancer or as an antiretroviral agentinhibits CYP3A and as a result is expectedto increase the plasma concentrations ofdexamethasone. Careful monitoring oftherapeutic and adverse effects isrecommended when dexamethasone isconcomitantly administered with ritonavir.

↑Prednisolone (28%, 9%) Careful monitoring of therapeutic andadverse effects is recommended whenprednisolone is concomitantlyadministered with ritonavir. The AUC ofthe metabolite prednisolone increased by

Table 2: Interaction with other medicinal products and other forms of interaction

Medicinal product within

Medicinal product classclass (AUC change, Cmax Change) Clinical comments37% and 28% after 4 and 14 days ritonavir,respectively.

Thyroid hormone Levothyroxine Post-marketing cases have been reportedreplacement therapy indicating a potential interaction betweenritonavir containing products andlevothyroxine. Thyroid-stimulatinghormone (TSH) should be monitored inpatients treated with levothyroxine at leastthe first month after starting and/or endingritonavir treatment.

Vasopressin receptor ↑Tolvaptan Coadministration is contraindicated due toantagonists potential for dehydration, hypovolemia andhyperkalemia (see section 4.3).

Abbreviations: ATL=alanine aminotransferase; AUC=area under the curve.

* Results from DDI studies conducted with Paxlovid (see section 5.2).

There are limited data on the use of Paxlovid in pregnant women to inform the drug-associated risk ofadverse developmental outcomes; women of childbearing potential should avoid becoming pregnantduring treatment with this medicinal product and as a precautionary measure for 7 days aftercompleting the treatment.

Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Patients usingcombined hormonal contraceptives should be advised to use an effective alternative contraceptivemethod or an additional barrier method of contraception during treatment with this medicinal product,and until one menstrual cycle after stopping the treatment (see section 4.5).

There are limited data from the use of Paxlovid in pregnant women.

Animal data with nirmatrelvir have shown developmental toxicity in the rabbit (lower foetal bodyweights) but not in the rat (see section 5.3).

A large number of women exposed to ritonavir during pregnancy indicate no increase in the rate ofbirth defects compared to rates observed in population-based birth defect surveillance systems.

Animal data with ritonavir have shown reproductive toxicity (see section 5.3).

Paxlovid is not recommended during pregnancy and in women of childbearing potential not usingcontraception unless the clinical condition requires treatment with this medicinal product.

Nirmatrelvir and ritonavir are excreted in breast milk (see section 5.2).

There are no available data on the effects of nirmatrelvir and ritonavir on the breast-fednewborn/infant or on milk production. A risk to the newborn/infant cannot be excluded.

Breast-feeding should be discontinued during treatment and as a precautionary measure for 48 hoursafter completing the treatment.

There are no human data on the effect of Paxlovid (nirmatrelvir and ritonavir) or ritonavir alone onfertility. Both nirmatrelvir and ritonavir, tested separately, produced no effects on fertility in rats (seesection 5.3).

Paxlovid is expected to have no influence on the ability to drive and use machines.

The most common adverse reactions reported during treatment with Paxlovid (nirmatrelvir/ritonavir300 mg/100 mg) were dysgeusia (4.6%), diarrhoea (3.0%), headache (1.2%) and vomiting (1.2%).

The safety profile of the product is based on adverse reactions reported in clinical trials andspontaneous reporting.

The adverse reactions in Table 3 are listed below by system organ class and frequency. Frequenciesare defined as follows: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to< 1/100); rare (≥ 1/10,000 to < 1/1000); not known (frequency cannot be estimated from the availabledata).

Table 3: Adverse reactions with Paxlovid

Frequency

System organ class category Adverse reactions

Immune system disorders Uncommon Hypersensitivity

Rare Anaphylaxis

Nervous system disorders Common Dysgeusia, headache

Vascular disorders Uncommon Hypertension

Gastrointestinal disorders Common Diarrhoea, vomiting, nausea

Uncommon Abdominal pain

Skin and subcutaneous tissue disorders Uncommon Rash*

Rare Toxic epidermal necrolysis,

Stevens-Johnson syndrome,

Pruritus*

Musculoskeletal and connective tissue Uncommon Myalgiadisorders

General disorders and administration site Rare Malaiseconditions

* These adverse reactions are also manifestations of hypersensitivity reaction.

Patients with severe renal impairment

Based on limited data from a Phase 1, open-label study, the safety profile of Paxlovid in participantswith severe renal impairment, including those requiring haemodialysis, was consistent with the safetyprofile observed in clinical trials.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix Ⅴ.

Treatment of overdose with Paxlovid should consist of general supportive measures includingmonitoring of vital signs and observation of the clinical status of the patient. There is no specificantidote for overdose with this medicinal product.

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE30

Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred toas 3C-like protease (3CLpro) or nsp5 protease. Inhibition of the SARS-CoV-2 Mpro renders theprotein incapable of processing polyprotein precursors which leads to the prevention of viralreplication.

Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, thereby providing increasedplasma concentrations of nirmatrelvir.

Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 infection of differentiated normalhuman bronchial epithelial (dNHBE) cells, a primary human lung alveolar epithelial cell line (EC50value of 61.8 nM and EC90 value of 181 nM) after 3 days of drug exposure.

The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4,

BA.4.6, BA.5, BF.7 (P252L+F294L), BF.7 (T243I), BQ.1.11, BQ.1, XBB.1.5, EG.5, and JN.1 wasassessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median

EC50 value of 88 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC50 value fold-changes ≤ 1.8 relative to the USA-WA1/2020 isolate.

In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta,

Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvirhad a median EC50 value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptiblevariant tested, with an EC50 value fold-change of 3.7 relative to USA-WA1/2020. The other variantshad EC50 value fold-changes ≤ 1.1 relative to USA-WA1/2020.

Antiviral resistance in cell cultures and biochemical assays

SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identifiedusing a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant

SARS-CoV-2 viruses with Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2

Mpro containing amino acid substitutions. Table 4 indicates Mpro substitutions and combinations of Mprosubstitutions that have been observed in nirmatrelvir-selected SARS-CoV-2 in cell culture. Individual

Mpro substitutions are listed regardless of whether they occurred alone or in combination with other

Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions ofthe nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro cleavage siteshave not been associated with nirmatrelvir resistance in cell culture. The clinical significance of thesesubstitutions is unknown.

Table 4: SARS-CoV-2 Mpro amino acid substitutions selected by nirmatrelvir in cell culture(with EC50 fold change > 5)

S144A (2.2-5.3), E166V (25-288), P252L (5.9), T304I (1.4-5.5), T21I+S144A (9.4), T21I+E166V(83), T21I+A173V (3.1-8.9), T21I+T304I (3.0-7.9), L50F+E166V (34-175), L50F+T304I (5.9),

F140L+A173V (10.1), A173V+T304I (20.2), T21+L50F+A193P+S301P (28.8),

T21I+S144A+T304I (27.8), T21I+C160F+A173V+V186A+T304I (28.5), T21I+A173V+T304I(15), L50F+F140L+L167F+T304I (54.7)

Most single and some double Mpro amino acid substitutions identified which reduced the susceptibilityof SARS-CoV-2 to nirmatrelvir resulted in an EC50 shift of < 5-fold compared to wild type

SARS-CoV-2. In general, triple and some double Mpro amino acid substitutions led to EC50 changes of> 5-fold to that of wild type. The clinical significance of these substitutions needs to be furtherunderstood.

Viral load rebound

Post-treatment viral nasal RNA rebounds were observed on Day 10 and/or Day 14 in a subset of

Paxlovid and placebo recipients in EPIC-HR, irrespective of COVID-19 symptoms. The incidence ofviral rebound in EPIC-HR occurred in both the Paxlovid treated participants and the untreated(placebo) participants, but at a numerically higher incidence in the Paxlovid arm (6.3% vs. 4.2%).

Viral rebound and recurrence of COVID-19 symptoms were not associated with progression to severedisease including hospitalisation, death or emergence of resistance.

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 forprogression to severe disease: diabetes, overweight (BMI > 25 kg/m2), chronic lung disease (includingasthma), chronic kidney disease, current smoker, immunosuppressive disease or immunosuppressivetreatment, cardiovascular disease, hypertension, sickle cell disease, neurodevelopmental disorders,active cancer, medically-related technological dependence, or were 60 years of age and olderregardless of comorbidities. Participants with COVID-19 symptom onset of ≤ 5 days were included inthe study. The study excluded individuals with a history of prior COVID-19 infection or vaccination.

Participants were randomised (1:1) to receive Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) orplacebo orally every 12 hours for 5 days. The primary efficacy endpoint was the proportion ofparticipants with COVID-19 related hospitalisation or death from any cause through Day 28. Theanalysis was conducted in the modified intent-to-treat (mITT) analysis set (all treated participants withonset of symptoms ≤ 3 days who at baseline did not receive nor were expected to receive COVID-19therapeutic mAb treatment), the mITT1 analysis set (all treated participants with onset of symptoms≤ 5 days who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAbtreatment), and the mITT2 analysis set (all treated participants with onset of symptoms ≤ 5 days).

A total of 2113 participants were randomised to receive either Paxlovid or placebo. At baseline, meanage was 45 years with 12% of participants 65 years of age and older (3% were 75 years of age andolder); 51% were male; 71% were White, 4% were Black or African American, and 15% were Asian;41% were Hispanic or Latino; 67% of participants had onset of symptoms ≤ 3 days before initiation ofstudy treatment; 80% had a BMI > 25 kg/m2 (36% a BMI > 30 kg/m2); 11% had diabetes mellitus; lessthan 1% of the study population had immune deficiency, 49% of participants were serologicalnegative at baseline and 49% were serological positive. The mean (SD) baseline viral load was4.71 log10 copies/mL (2.89); 27% of participants had a baseline viral load of > 10^7 (copies/mL);6.0% of participants either received or were expected to receive COVID-19 therapeutic mAb treatmentat 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 (99%), mostly clade 21J.

The baseline demographic and disease characteristics were balanced between the Paxlovid andplacebo groups.

The determination of primary efficacy was based on a planned interim analysis of 754 participants inmITT population. The estimated risk reduction was -6.5% with unadjusted 95% CI of (-9.3%, -3.7%)and a 95% CI of (-10.92%, -2.09%) when adjusting for multiplicity. The 2-sided p-value was < 0.0001with 2-sided significance level of 0.002.

Table 5 provides results of the primary endpoint in the mITT1 analysis population for the full data setat final study completion.

Table 5: Efficacy results in non-hospitalised adults with COVID-19 dosed within 5 days ofsymptom onset who did not receive COVID-19 mAb treatment at baseline (mITT1analysis setb)

Paxlovid Placebo(N=977) (N=989)

COVID-19 related hospitalisation or death from any cause through Day 28n (%) 9 (0.9%) 64 (6.5%)

Reduction relative to placeboa (95% CI), % -5.64 (-7.31, -3.97)p-value < 0.0001

All-cause mortality through Day 28, % 0 12 (1.2%)

Abbreviations: CI=confidence interval; COVID-19=Coronavirus Disease 2019; mAb=monoclonalantibody; mITT1=modified intent-to-treat 1 (all participants randomly assigned to studyintervention, who took at least 1 dose of study intervention, with at least 1 post-baseline visitthrough Day 28, who at baseline did not receive nor were expected to receive COVID-19therapeutic mAb treatment and were treated ≤ 5 days after COVID-19 symptom onset).

a. The estimated cumulative proportion of participants hospitalised or death by Day 28 was calculated foreach treatment group using the Kaplan-Meier method, where participants without hospitalisation anddeath status through Day 28 were censored at the time of study discontinuation.

b. Data analysis set was updated after post-hoc removal of data for 133 participants due to GCP qualityissues

The estimated risk reduction was -6.1% with 95% CI of (-8.2%, -4.1%) in participants dosed within3 days of symptom onset, and -4.6% with 95% CI of (-7.4%, -1.8%) in the mITT1 subset ofparticipants dosed > 3 days from symptom onset.

Consistent results were observed in the final mITT and mITT2 analysis populations. A total of1318 participants were included in the mITT analysis population. The event rates were 5/671 (0.75%)in the Paxlovid group, and 44/647 (6.80%) in the placebo group.

Table 6: Progression of COVID-19 (hospitalisation or death) through Day 28 in symptomatic adultsat increased risk of progression to severe illness; mITT1 analysis set

Paxlovid 300 mg/100 mg Placebo

Number of patients N=977 N=989

Serology Negative n=475 n=497

Patients with hospitalisation or deatha (%) 8 (1.7%) 56 (11.3%)

Estimated proportion over 28 days [95% CI], % 1.72 (0.86, 3.40) 11.50 (8.97, 14.68)

Estimated reduction relative to placebo (95% CI) -9.79 (-12.86, -6.72)

Serology Positive n=490 n=479

Patients with hospitalisation or deatha (%) 1 (0.2%) 8 (1.7%)

Estimated proportion over 28 days [95% CI], % 0.20 (0.03, 1.44) 1.68 (0.84, 3.33)

Estimated reduction relative to placebo (95% CI) -1.5 (-2.70, -0.25)

Table 6: Progression of COVID-19 (hospitalisation or death) through Day 28 in symptomatic adultsat increased risk of progression to severe illness; mITT1 analysis set

Abbreviations: CI=confidence interval; COVID-19=Coronavirus Disease 2019; mITT1=modifiedintent-to-treat 1 (all participants randomly assigned to study intervention, who took at least 1 dose of studyintervention, who at baseline did not receive nor were expected to receive COVID-19 therapeutic monoclonalantibody treatment, and were treated ≤ 5 days after COVID-19 symptom onset).

Seropositivity was defined if results were positive in a serological immunoassay specific for host antibodies toeither S or N viral proteins.

The difference between the proportions in the 2 treatment groups and its 95% confidence interval based onnormal approximation of the data are presented.

a. COVID-19 related hospitalisation or death from any cause.

Efficacy results for mITT1 were consistent across subgroups of participants including age (≥ 65 years)and BMI (BMI > 25 and BMI > 30) and diabetes.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Paxlovid in one or more subsets of the paediatric population in treatment of COVID-19 (seesection 4.2 for information on paediatric use).

The pharmacokinetics of nirmatrelvir/ritonavir have been studied in healthy participants and inparticipants with mild-to-moderate COVID-19.

Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemicconcentrations and longer half-life of nirmatrelvir.

Upon repeat-dose of nirmatrelvir/ritonavir 75 mg/100 mg, 250 mg/100 mg, and 500 mg/100 mgadministered twice daily, the increase in systemic exposure at steady-state appears to be less than doseproportional. Multiple dosing over 10 days achieved steady-state on Day 2 with approximately 2-foldaccumulation. Systemic exposures on Day 5 were similar to Day 10 across all doses.

Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, thegeometric mean nirmatrelvir Cmax and AUCinf at steady-state was 2.21 µg/mL and 23.01 µg*hr/mL,respectively. The median time to Cmax (Tmax) was 3.00 hrs. The arithmetic mean terminal eliminationhalf-life was 6.1 hours.

Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, thegeometric mean ritonavir Cmax and AUCinf was 0.36 µg/mL and 3.60 µg*hr/mL, respectively. Themedian time to Cmax (Tmax) was 3.98 hrs. The arithmetic mean terminal elimination half-life was6.1 hours.

Dosing with a high fat meal increased the exposure of nirmatrelvir (approximately 61% increase inmean Cmax and 20% increase in mean AUClast) relative to fasting conditions following administrationof 300 mg nirmatrelvir (2 × 150 mg)/100 mg ritonavir tablets.

The protein binding of nirmatrelvir in human plasma is approximately 69%.

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

In vitro studies assessing nirmatrelvir without concomitant ritonavir suggest that nirmatrelvir isprimarily metabolised by cytochrome P450 (CYP) 3A4. However, administration of nirmatrelvir withritonavir inhibits the metabolism of nirmatrelvir. In plasma, the only medicinal product-related entityobserved was unchanged nirmatrelvir. Minor oxidative metabolites were observed in the faeces andurine.

In vitro studies utilising human liver microsomes have demonstrated that CYP3A is the major isoforminvolved in ritonavir metabolism, although CYP2D6 also contributes to the formation of oxidationmetabolite M-2.

The primary route of elimination of nirmatrelvir when administered with ritonavir was renal excretionof intact medicinal product. Approximately 49.6% and 35.3% of the administered dose of nirmatrelvir300 mg was recovered in urine and faeces, respectively. Nirmatrelvir was the predominantdrug-related entity with small amounts of metabolites arising from hydrolysis reactions in excreta. Inplasma, the only drug-related entity quantifiable was unchanged nirmatrelvir.

Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir wasprimarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool,part of which is expected to be unabsorbed ritonavir.

Age and gender

The pharmacokinetics of nirmatrelvir/ritonavir based on age and gender have not been evaluated.

Systemic exposure in Japanese participants was numerically lower but not clinically meaningfullydifferent than those in Western participants.

Compared to healthy controls with no renal impairment, the Cmax and AUC of nirmatrelvir in patientswith mild renal impairment was 30% and 24% higher, in patients with moderate renal impairment was38% and 87% higher, and in patients with severe renal impairment was 48% and 204% higher,respectively.

Severe renal impairment including those requiring haemodialysis

The pharmacokinetics of nirmatrelvir in participants with mild-to-moderate COVID-19 and severerenal impairment (eGFR< 30 mL/min) either requiring haemodialysis (n=12) or not requiringhaemodialysis (n=2) were evaluated after administration of 300 mg/100 mg nirmatrelvir/ritonavir onceon Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on Days 2-5 for a total of5 doses.

During a 4-hour haemodialysis session, approximately 6.9% of nirmatrelvir dose was cleared throughdialysis. Haemodialysis clearance was 1.83 L/h.

Population pharmacokinetic model-based simulations showed that administration of 300 mg/100 mgnirmatrelvir/ritonavir once on Day 1 followed by 150 mg/100 mg nirmatrelvir/ritonavir once daily on

Days 2-5 in participants with severe renal impairment resulted in comparable exposures on Day 1 andat steady-state (AUC0-24 and Cmax) to those observed in participants with normal renal functionreceiving 300 mg/100 mg nirmatrelvir/ritonavir twice daily for 5 days.

Compared to healthy controls with no hepatic impairment, the pharmacokinetics of nirmatrelvir inparticipants with moderate hepatic impairment was not significantly different. Adjusted geometricmean ratio (90% CI) of AUCinf and Cmax of nirmatrelvir comparing moderate hepatic impairment (test)to normal hepatic function (reference) was 98.78% (70.65%, 138.12%) and 101.96% (74.20%,140.11%), respectively.

Nirmatrelvir/ritonavir has not been studied in patients with severe hepatic impairment.

Following 3 doses of nirmatrelvir/ritonavir 300 mg/100 mg administered twice daily in 8 healthylactating women, under high-fat high-calorie fed conditions, both nirmatrelvir and ritonavir wereexcreted into breast milk. The estimated milk to plasma ratios for Cmax and AUC were 0.27 and 0.26,respectively for nirmatrelvir and 0.06 and 0.07, respectively for ritonavir.

Interaction studies conducted with nirmatrelvir/ritonavir

CYP3A4 was the major contributor to the oxidative metabolism of nirmatrelvir when nirmatrelvir wastested alone in human liver microsomes. Ritonavir is an inhibitor of CYP3A and increases plasmaconcentrations of nirmatrelvir and other drugs that are primarily metabolised by CYP3A. Despitebeing coadministered with ritonavir as a pharmacokinetic enhancer, there is potential for stronginhibitors and inducers to alter the pharmacokinetics of nirmatrelvir.

Nirmatrelvir does not reversibly inhibit CYP2B6, CYP2D6, CYP2C9, CYP2C19, CYP2C8, or

CYP1A2 in vitro at clinically relevant concentrations. In vitro study results showed nirmatrelvir maybe inducer of CYP3A4, CYP2B6, CYP2C8 and CYP2C9. The clinical relevance is unknown. Basedon in vitro data, nirmatrelvir has a low potential to inhibit BCRP, MATE1, MATE2K, OAT1, OAT3,

OATP1B3, OCT1 and OCT2. There is a potential for nirmatrelvir to inhibit MDR1 and OATP1B1 atclinically relevant concentrations.

The effect on the pharmacokinetics of nirmatrelvir/ritonavir was assessed with itraconazole (CYP3Ainhibitor) and carbamazepine (CYP3A inducer). The test/reference ratios of the adjusted geometricmeans for nirmatrelvir AUCinf and Cmax were 44.50% and 56.82%, respectively, followingnirmatrelvir/ritonavir 300 mg/100 mg coadministration with multiple oral doses of carbamazepine.

The test/reference ratios of the adjusted geometric means for nirmatrelvir AUCtau and Cmax were138.82% and 118.57%, respectively, when nirmatrelvir/ritonavir was coadministered with multipledoses of itraconazole as compared to nirmatrelvir/ritonavir administered alone.

The effect of nirmatrelvir/ritonavir on other drugs was assessed with midazolam (CYP3A substrate),dabigatran (P-gp substrate), and rosuvastatin (OATP1B1 substrate). The test/reference ratios of theadjusted geometric means for midazolam AUCinf and Cmax were 1430.02% and 368.33%, respectively,when midazolam was coadministered with multiple doses of nirmatrelvir/ritonavir compared tomidazolam administered alone. The test/reference ratios of the adjusted geometric means fordabigatran AUCinf and Cmax were 194.47% and 233.06%, respectively, following dabigatranadministration with multiple doses of nirmatrelvir/ritonavir as compared to administration ofdabigatran alone. The test/reference ratios of the adjusted geometric means for rosuvastatin AUCinfand Cmax were 131.18% and 212.44%, respectively, following rosuvastatin administration withmultiple doses of nirmatrelvir/ritonavir as compared to administration of rosuvastatin alone.

No nonclinical safety studies have been conducted with nirmatrelvir in combination with ritonavir.

Nirmatrelvir

Studies of repeated dose toxicity and genotoxicity revealed no risk due to nirmatrelvir. No adverseeffects were observed in fertility, embryo-foetal development, or pre- and postnatal developmentstudies in rats. A study in pregnant rabbits showed an adverse decrease in foetal body weight, in theabsence of significant maternal toxicity. Systemic exposure (AUC24) in rabbits at the maximum dosewithout adverse effect in foetal body weight was estimated to be approximately 3 times higher thanexposure in humans at recommended therapeutic dose of Paxlovid.

No carcinogenicity studies have been conducted with nirmatrelvir.

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 elementsand were accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigmentepithelium and retinal degeneration have been seen in all of the rodent studies conducted withritonavir, but have not been seen in dogs. Ultrastructural evidence suggests that these retinal changesmay be secondary to phospholipidosis. However, clinical trials revealed no evidence of medicinalproduct-induced ocular changes in humans. All thyroid changes were reversible upondiscontinuation of ritonavir. Clinical investigation in humans has revealed no clinically significantalteration in thyroid function tests.

Renal changes including tubular degeneration, chronic inflammation and proteinuria were noted inrats and are considered to be attributable to species-specific spontaneous disease. Furthermore, noclinically significant renal abnormalities were noted in clinical trials.

Genotoxicity studies revealed no risk due to ritonavir. Long-term carcinogenicity studies of ritonavirin mice and rats revealed tumourigenic potential specific for these species, but are regarded as of norelevance for humans. Ritonavir produced no effects on fertility in rats. Developmental toxicityobserved in rats (embryo-lethality, decreased foetal body weight and ossification delays and visceralchanges, including delayed testicular descent) occurred mainly at a maternally toxic dose.

Developmental toxicity in rabbits (embryo-lethality, decreased litter size and decreased foetal weights)occurred at a maternally toxic dose.

Nirmatrelvir film-coated tablets

Microcrystalline cellulose

Lactose monohydrate

Croscarmellose sodium

Colloidal silicon dioxide

Sodium stearyl fumarate

Hydroxypropyl methylcellulose (E464)

Titanium dioxide (E171)

Macrogol/polyethylene glycol (E1521)

Iron oxide red (E172)

Copovidone

Sorbitan laurate

Silica, colloidal anhydrous (E551)

Calcium hydrogen phosphate

Sodium stearyl fumarate

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol/polyethylene glycol (E1521)

Hydroxypropyl cellulose (E463)

Talc (E553b)

Silica, colloidal anhydrous (E551)

Polysorbate 80 (E433)

Not applicable.

2 years.

This medicinal product does not require any special storage conditions.

OPA/Al/PVC foil blister cards.

Twice daily dose blister card

Pack size of 5 blister cards each containing 4 nirmatrelvir tablets and 2 ritonavir tablets for morningand evening dose (total of 30 tablets).

Once daily dose blister card

Pack size of one blister card of 11 tablets. The blister card contains 6 nirmatrelvir tablets and5 ritonavir tablets for once daily dose.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Brussels

Belgium

EU/1/22/1625/001

EU/1/22/1625/002

Date of first authorisation: 28 January 2022

Date of latest renewal: 28 November 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.