nirmatrelvir + ritonavir: prescribing information – dosing, contraindications, interactions, side effects

Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and paediatric patients 6 years of age and older weighing at least 20 kg who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID-19 (see section 5.1).

Posology

Adults
The recommended dose in adults 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.

Paediatric patients 6 years of age and older weighing at least 20 kg
The recommended dose in paediatric patients 6 years of age and older weighing at least 20 kg is shown below in Table 1.

Table 1:
Recommended dose for paediatric patients 6 years of age and older weighing at least 20 kg Patient population Recommended dose Paediatric patients ≥6 years of age weighing ≥40 kg 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 Paediatric patients ≥6 years of age weighing ≥20 to <40 kg 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) taken together orally every 12 hours for 5 days

Special attention for paediatric patients 6 years of age and older weighing at least 20 kg to less than 40 kg There is a pack specific for paediatric patients 6 years of age and older weighing at least 20 kg to less than 40 kg. This pack contains 5 blister cards with two separated parts each containing one tablet of nirmatrelvir and one tablet of ritonavir for administration every 12 hours.

Paxlovid should be administered as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptom onset. Completion of the full 5-day treatment course is recommended even if the patient requires hospitalisation due to severe or critical COVID-19 after starting treatment with this medicinal product.

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

Special populations

Renal impairment
No dose adjustment is needed in patients with mild renal impairment [estimated glomerular filtration rate (eGFR) ≥ 60 to < 90 mL/min]. In adult 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 2 to avoid over-exposure. The treatment should be administered at approximately the same time each day for 5 days. On days patients with severe renal impairment undergo haemodialysis, the dose should be administered after haemodialysis (see section 5.2).

Table 2:
Recommended dose and regimen for adult patients with renal impairment
Renal function
Days of treatment
Dose and dose frequency
Moderate renal impairment
(eGFR ≥ 30 to < 60 mL/min)
Days 1-5
150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) every 12 hours Severe renal impairment (eGFR < 30 mL/min) including those requiring haemodialysis Day 1 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) once Days 2-5 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet) once daily Abbreviation: eGFR=estimated glomerular filtration rate.

Special attention for patients with MODERATE renal impairment
There is a pack specific for patients with moderate renal impairment. This pack contains 5 blister cards with two separated parts each containing one tablet of nirmatrelvir and one tablet of ritonavir for administration every 12 hours.

Special attention for patients with SEVERE renal impairment
There is a pack specific for patients with severe renal impairment. This pack contains 1 blister card with one separated part containing two tablets of nirmatrelvir and one tablet of ritonavir for administration once on Day 1, and four additional separated parts each containing one tablet of nirmatrelvir and one tablet of ritonavir for administration once daily on Days 2 to 5.

Although the safety and pharmacokinetics of nirmatrelvir/ritonavir have not been studied in paediatric patients with renal impairment, dose reduction in paediatric patients 6 years of age and older weighing at least 40 kg with renal impairment should parallel that recommended for adults with the same degree of renal impairment (see Table 2) (see section 5.2).

Dose in paediatric patients with renal impairment weighing less than 40 kg has not been determined.

Hepatic impairment
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).

Severely immunocompromised population
Data are limited in severely immunocompromised individuals. A treatment duration of 10 days may help to mitigate the risk of virological rebound in patients with severe immunodepression (e.g. active haematologic malignancies, haematopoietic stem cell transplantation, CAR T-cell therapy or B-cell depleting therapies) (see section 5.1).

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

Paediatric population
The safety and efficacy of Paxlovid in paediatric patients below 6 years of age or weighing less than 20 kg have not been established.

Paediatric dosing for paediatric patients 6 years of age and older weighing at least 20 kg is based on the results from a paediatric study (see sections 5.1 and 5.2).

Method of administration

For oral use.

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

This medicinal product can be taken with or without food (see section 5.2). The tablets should be swallowed 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 possible medicinal products that are contraindicated with Paxlovid.

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

- 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, simvastatin o
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 and triazolam
- Vasopressin receptor antagonists: tolvaptan

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

• 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 delayed offset 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 the delayed offset of the recently discontinued CYP3A inducer and the need to initiate Paxlovid within 5 days of symptom onset.

Summary of the safety profile

The most common adverse reactions reported during treatment with Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) were dysgeusia (4.6%), diarrhoea (3.0%), headache (1.2%) and vomiting (1.2%).

Tabulated list of adverse reactions

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

The adverse reactions in Table 4 are listed below by system organ class and frequency. Frequencies are defined as follows: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); not known (frequency cannot be estimated from the available data).

Table 4:
Adverse reactions with Paxlovid
System organ class
Frequency 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 disorders
Uncommon
Myalgia
General disorders and administration site conditions
Rare
Malaise
* These adverse reactions are also manifestations of hypersensitivity reaction.

Description of selected adverse reactions

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

Paediatric population
The safety of Paxlovid in paediatric patients was evaluated in a Phase 2/3, open-label, single-arm study (see section 5.1).

In the study analysis, 75 participants 6 to less than 18 years of age weighing at least 20 kg were included in the assessment of safety. The adverse reaction profile observed in this study is similar to that in the adult population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix Ⅴ.

Risk of serious adverse reactions due to interactions with other medicinal products

Management of drug-drug interactions (DDIs) in high-risk COVID-19 patients receiving multiple concomitant medications can be complex and require a thorough understanding of the nature and magnitude of interaction with all concomitant medications. In certain patients, a multi-disciplinary

approach (e.g., involving physicians and specialists in clinical pharmacology) should be considered for management of DDIs especially if concomitant medications are withheld, their dose is reduced, or if monitoring 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 (see section 4.5).

Coadministration of Paxlovid with calcineurin inhibitors and mTOR inhibitors
Consultation of a multidisciplinary group (e.g., involving physicians, specialists in immunosuppressive therapy, and/or specialists in clinical pharmacology) is required to handle the complexity of this coadministration by closely and regularly monitoring immunosuppressant blood concentrations and adjusting the dose of the immunosuppressant in accordance with the latest guidelines (see section 4.5).

Effects of other medicinal products on Paxlovid
Initiation of medicinal products that inhibit or induce CYP3A may increase or decrease concentrations of Paxlovid, respectively.

These interactions may lead to:

• Clinically significant adverse reactions with severe, life-threatening or fatal events from greater exposures of concomitant medicinal products.
• Clinically significant adverse reactions from greater exposures of Paxlovid.
• Loss of therapeutic effect of Paxlovid and possible development of viral resistance.

See Table 3 for medicinal products that are contraindicated for concomitant use with nirmatrelvir/ritonavir and for potentially significant interactions with other medicinal products (see section 4.5). Potential for interactions should be considered with other medicinal products prior to and during Paxlovid therapy; concomitant medicinal products should be reviewed during Paxlovid therapy and the patient should be monitored for the adverse reactions associated with the concomitant medicinal products.

Hypersensitivity reactions

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

Severe hepatic impairment

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.

Hepatotoxicity

Hepatic transaminase elevations, clinical hepatitis and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering this medicinal product to patients with 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 to elderly patients since they are at higher risk of experiencing serious complications of hypertension.

Risk of HIV-1 resistance development

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

Excipients

Lactose
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.

Sodium
Nirmatrelvir and ritonavir tablets each contain less than 1 mmol sodium (23 mg) per tablet, that is to say 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 nirmatrelvir and ritonavir plasma concentrations and reduce Paxlovid therapeutic effect.

Coadministration of Paxlovid with medicinal product that inhibits CYP3A4 may increase nirmatrelvir and 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 concentrations of medicinal products that are primarily metabolised by CYP3A. Thus, coadministration of nirmatrelvir/ritonavir with medicinal products highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated (see Table 3). Coadministration of other CYP3A4 substrates that may lead to potentially significant interaction (see Table 3) should be considered only if the benefits outweigh the risks.

Medicinal products CYP2D6 substrates
Based on in vitro studies, ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and 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 should thus be exercised in case of concomitant treatment. Close drug monitoring for safety and efficacy should 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 these

pathways and may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.

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

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

Medicinal products listed in Table 3 are a guide and not considered a comprehensive list of all possible medicinal products that are contraindicated or may interact with nirmatrelvir/ritonavir.

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments
Alpha1-adrenoreceptor antagonist
↑Alfuzosin
Increased plasma concentrations of alfuzosin may lead to severe hypotension and is therefore contraindicated (see section 4.3).
↑Tamsulosin
Tamsulosin is extensively metabolised, mainly by CYP3A4 and CYP2D6, both of which are inhibited by ritonavir. Avoid concomitant use with Paxlovid.
Amphetamine derivatives
↑Amphetamine

Ritonavir administered at high dose in accordance with its previous use as an antiretroviral agent is likely to inhibit CYP2D6 and as a result is expected to increase concentrations of amphetamine and its derivatives. Careful monitoring of adverse effects is recommended when these medicines are coadministered with Paxlovid.
Analgesics

↑Buprenorphine (57%, 77%)
The increases of plasma levels of buprenorphine and its active metabolite did not lead to clinically significant pharmacodynamic changes in a population of opioid tolerant patients. Adjustment to the dose of buprenorphine may therefore not be necessary when the two are dosed together.
↑Fentanyl,
↑Oxycodone
Ritonavir inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of these narcotic analgesics.
If concomitant use with Paxlovid is necessary, consider a dose reduction of these narcotic analgesics and closely monitor therapeutic and adverse effects (including respiratory depression). Refer to the individual SmPCs for more information.
↓Methadone (36%, 38%)

Increased methadone dose may be necessary when coadministered with ritonavir dosed as a pharmacokinetic enhancer due to induction of glucuronidation. Monitor

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments methadone-maintained patients closely for evidence of withdrawal effects. Dose adjustment should be considered based on the patient’s clinical response to methadone therapy.
↓Morphine

Morphine levels may be decreased due to induction of glucuronidation by coadministered ritonavir dosed as a pharmacokinetic enhancer.
↑Pethidine
Coadministration could result in increased or prolonged opioid effects. If concomitant use is necessary, consider dose reduction of pethidine. Monitor for respiratory depression and sedation.
↓Piroxicam
Decreased piroxicam exposure due to
CYP2C9 induction by Paxlovid.
Antianginal
↑Ranolazine
Due to CYP3A inhibition by ritonavir, concentrations of ranolazine are expected to increase. The concomitant administration with ranolazine is contraindicated (see section 4.3).
Antiarrhythmics
↑Amiodarone
↑Flecainide
Given the risk of substantial increase in amiodarone or flecainide exposure and thus of its related adverse events, coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it.
↑Digoxin
This interaction may be due to modification of P-gp mediated digoxin efflux by ritonavir dosed as a pharmacokinetic enhancer. Digoxin drug concentration is expected to increase.
Monitor digoxin levels if possible and digoxin safety and efficacy.
↑Disopyramide
Ritonavir may increase plasma concentrations of disopyramide which could result in an increased risk of adverse events such as cardiac arrhythmias.
Caution is warranted and therapeutic concentration monitoring is recommended for disopyramide if available.
↑Dronedarone,
↑Propafenone,
↑Quinidine

Ritonavir coadministration is likely to result in increased plasma concentrations of dronedarone, propafenone and quinidine and is therefore contraindicated (see section 4.3).
Antiasthmatic
↓Theophylline (43%, 32%)

An increased dose of theophylline may be required when coadministered with ritonavir, due to induction of CYP1A2.
Anticancer agents
↑Abemaciclib
Serum concentrations may be increased due to CYP3A4 inhibition by ritonavir.
Coadministration of abemaciclib and

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments
Paxlovid should be avoided. If this coadministration is judged unavoidable, refer to the abemaciclib SmPC for dose adjustment recommendations. Monitor for ADRs related to abemaciclib.
↑Afatinib

Serum concentrations may be increased due to Breast Cancer Resistance Protein
(BCRP) and acute P-gp inhibition by ritonavir. The extent of increase in AUC and Cmax depends on the timing of ritonavir administration. Caution should be exercised 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 a decreased exposure of nirmatrelvir/ritonavir and potential loss of virologic response. In addition, serum concentrations of apalutamide may be increased when coadministered with ritonavir resulting in the potential for serious adverse events including seizure.
Concomitant use of Paxlovid with apalutamide is contraindicated (see section
4.3).
↑Ceritinib

Serum concentrations of ceritinib may be increased due to CYP3A and P-gp inhibition by ritonavir. Caution should be exercised in administering ceritinib with Paxlovid. Refer to the ceritinib SmPC for dose adjustment recommendations.
Monitor for ADRs related to ceritinib.
↑Dasatinib,
↑Nilotinib,
↑Vinblastine,
↑Vincristine
Serum concentrations may be increased when coadministered with ritonavir resulting in the potential for increased incidence of adverse events.
↑Encorafenib,
↑Ivosidenib

Serum concentrations of encorafenib or ivosidenib may be increased when coadministered with ritonavir which may increase the risk of toxicity, including the risk of serious adverse events such as QT interval prolongation. Avoid coadministration of encorafenib or ivosidenib. If the benefit is considered to outweigh the risk and ritonavir must be used, patients should be carefully monitored for safety.
Enzalutamide
Enzalutamide is a strong CYP3A4 inducer, and this may lead to decreased exposure of Paxlovid, potential loss of virologic response, and possible resistance.
Concomitant use of enzalutamide with

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments
Paxlovid is contraindicated (see section 4.3).
↑Fostamatinib

Coadministration of fostamatinib with ritonavir may increase fostamatinib metabolite R406 exposure resulting in dose-related adverse events such as hepatotoxicity, neutropenia, hypertension or diarrhoea. Refer to the fostamatinib SmPC for dose reduction recommendations if such events occur.
↑Ibrutinib

Serum concentrations of ibrutinib may be increased due to CYP3A inhibition by ritonavir, resulting in increased risk for toxicity including risk of tumour lysis syndrome. Coadministration of ibrutinib and ritonavir should be avoided. If the benefit is considered to outweigh the risk and ritonavir must be used, reduce the ibrutinib dose to 140 mg and monitor patient closely for toxicity.
↑Neratinib

Serum concentrations may be increased due to CYP3A4 inhibition by ritonavir.
Concomitant use of neratinib with
Paxlovid is contraindicated due to serious and/or life-threatening potential reactions including hepatotoxicity (see section 4.3).
↑Venetoclax
Serum concentrations may be increased due to CYP3A inhibition by ritonavir, resulting in increased risk of tumour lysis syndrome at the dose initiation and during the ramp-up phase and is therefore contraindicated (see section 4.3 and refer to the venetoclax SmPC). For patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax, reduce the venetoclax dose to 100 mg or less (or by at least 75% if already modified for other reasons) when used with strong CYP3A inhibitors.
Anticoagulants
↑Apixaban
Combined P-gp and strong CYP3A4 inhibitors increase blood levels of apixaban and increase the risk of bleeding. Dosing recommendations for coadministration of apixaban with Paxlovid depend on the apixaban dose. For apixaban doses of 5 mg or 10 mg twice daily, reduce the apixaban dose by 50%. In patients already taking apixaban 2.5 mg twice daily, avoid coadministration with Paxlovid.
↑Dabigatran (94%, 133%)*
Concomitant administration of Paxlovid is expected to increase dabigatran concentrations resulting in increased risk

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments of bleeding. Reduce dose of dabigatran or avoid concomitant use.
↑Rivaroxaban (153%, 53%)

Inhibition of CYP3A and P-gp lead to increased plasma levels and pharmacodynamic effects of rivaroxaban which may lead to an increased bleeding risk. Therefore, the use of Paxlovid is not recommended in patients receiving rivaroxaban.
Warfarin,
↑↓S-Warfarin (9%, 9%),
↓↔R-Warfarin (33%)
Induction of CYP1A2 and CYP2C9 lead to decreased levels of R-warfarin while little pharmacokinetic effect is noted on S-warfarin when coadministered with ritonavir. Decreased R-warfarin levels may lead to reduced anticoagulation, therefore it is recommended that anticoagulation parameters are monitored when warfarin is coadministered with ritonavir.
Anticonvulsants

Carbamazepine*,
Phenobarbital,
Phenytoin,
Primidone
Carbamazepine decreases AUC and Cmax of nirmatrelvir by 55% and 43%, respectively. Phenobarbital, phenytoin and primidone are strong CYP3A4 inducers, and this may lead to a decreased exposure of nirmatrelvir and ritonavir and potential loss of virologic response. Concomitant use of carbamazepine, phenobarbital, phenytoin and primidone with Paxlovid is contraindicated (see section 4.3).
↑Clonazepam
A dose decrease may be needed for clonazepam when coadministered with
Paxlovid and clinical monitoring is recommended.
↓Divalproex,
Lamotrigine
Ritonavir dosed as a pharmacokinetic enhancer induces oxidation by CYP2C9 and glucuronidation and as a result is expected to decrease the plasma concentrations of anticonvulsants. Careful monitoring of serum levels or therapeutic effects is recommended when these medicines are coadministered with ritonavir.
Anticorticosteroids
↑Ketoconazole (3.4-fold, 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.

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments
Antidepressants
↑Amitriptyline,
Fluoxetine,
Imipramine,
Nortriptyline,
Paroxetine,
Sertraline
Ritonavir administered at high dose in accordance with its previous use as an antiretroviral agent is likely to inhibit CYP2D6 and as a result is expected to increase concentrations of imipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine or sertraline. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with antiretroviral doses of ritonavir.
Anti-gout
↑Colchicine
Concentrations of colchicine are expected to increase 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 with
Paxlovid is contraindicated (see section 4.3).
Anti-HCV
↑Glecaprevir/pibrentasvir
Serum concentrations may be increased due to P-gp, BCRP and OATP1B inhibition by ritonavir. Concomitant administration of glecaprevir/pibrentasvir and Paxlovid is not recommended due to an increased risk of ALT elevations associated with increased glecaprevir exposure.
↑Sofosbuvir/velpatasvir/ voxilaprevir

Serum concentrations may be increased due to OATP1B inhibition by ritonavir.
Concomitant administration of sofosbuvir/velpatasvir/voxilaprevir and
Paxlovid is not recommended. Refer to the sofosbuvir/velpatasvir/voxilaprevir SmPC for further information.
Antihistamines
↑Fexofenadine
Ritonavir may modify P-gp mediated fexofenadine efflux when dosed as a pharmacokinetic enhancer resulting in increased concentrations of fexofenadine.
↑Loratadine

Ritonavir dosed as a pharmacokinetic enhancer inhibits CYP3A and as a result is expected to increase the plasma concentrations of loratadine. Careful monitoring of therapeutic and adverse effects is recommended when loratadine is coadministered with ritonavir.
↑Terfenadine
Increased plasma concentrations of terfenadine. Thereby, increasing the risk of serious arrhythmias from this agent and therefore concomitant use with Paxlovid is contraindicated (see section 4.3).

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments
Anti-HIV
↑Bictegravir/
↔Emtricitabine/
↑Tenofovir
Ritonavir may significantly increase the plasma concentrations of bictegravir through CYP3A inhibition. Ritonavir is expected to increase the absorption of tenofovir alafenamide by inhibition of P-gp, thereby increasing the systemic concentration of tenofovir.
↑Efavirenz (21%)
A higher frequency of adverse reactions
(e.g., dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes) have been observed when efavirenz is coadministered with ritonavir.
Refer to the efavirenz SmPC for more information.
↑Maraviroc (161%, 28%)

Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition.
Maraviroc may be given with ritonavir to increase the maraviroc exposure. For further information, refer to the maraviroc SmPC.
↓Raltegravir (16%, 1%)

Coadministration of ritonavir and raltegravir results in a minor reduction in raltegravir levels.
↓Zidovudine (25%, ND)
Ritonavir may induce the glucuronidation of zidovudine, resulting in slightly decreased levels of zidovudine. Dose alterations should not be necessary.
Anti-infectives
↓Atovaquone
Ritonavir dosed as a pharmacokinetic enhancer induces glucuronidation and as a result is expected to decrease the plasma concentrations of atovaquone. Careful monitoring of serum levels or therapeutic effects is recommended when atovaquone is coadministered with ritonavir.
↑Bedaquiline
No interaction study is available with ritonavir only. Due to the risk of bedaquiline related adverse events, coadministration should be avoided. If the benefit outweighs the risk, coadministration of bedaquiline with ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (refer to the bedaquiline SmPC).
↑Clarithromycin (77%, 31%),
↓14-OH clarithromycin metabolite (100%, 99%)
Due to the large therapeutic window of clarithromycin no dose reduction should be necessary in patients with normal renal function. Clarithromycin doses greater than 1 g per day should not be coadministered with ritonavir dosed as a pharmacokinetic enhancer. For patients with renal impairment, a clarithromycin dose

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments reduction should be considered: for patients with creatinine clearance of 30 to 60 mL/min the dose should be reduced by 50% (see section 4.2 for patients with severe renal impairment).
Delamanid

No interaction study is available with ritonavir only. In a healthy volunteer drug interaction study of delamanid 100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 14 days, the exposure of the delamanid metabolite DM-6705 was 30% increased. Due to the risk of QTc prolongation associated with DM-6705, if coadministration of delamanid with ritonavir is considered necessary, very frequent ECG monitoring throughout the full Paxlovid treatment period is recommended (see section 4.4 and refer to the delamanid SmPC).
↑Erythromycin,
↑Itraconazole*
Itraconazole increases AUC and Cmax of nirmatrelvir by 39% and 19%, respectively. Ritonavir dosed as a pharmacokinetic enhancer inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of itraconazole and erythromycin. Careful monitoring of therapeutic and adverse effects is recommended when erythromycin or itraconazole is coadministered with ritonavir.
↑Fusidic acid (systemic route)
Given the risk of substantial increase in fusidic acid (systemic route) exposure and thus of its related adverse events, coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it.
↑Rifabutin (4-fold, 2.5-fold),
↑25-O-desacetyl rifabutin metabolite (38-fold, 16-fold)
An increase in rifabutin exposure is expected due to the inhibition of CYP3A4 by ritonavir. The consultation of a multidisciplinary group is recommended to safely guide the co-administration and the need of a reduction of the rifabutin dose.
Rifampicin,
Rifapentine
Rifampicin and rifapentine are strong
CYP3A4 inducers, and this may lead to a decreased exposure of nirmatrelvir/ritonavir, potential loss of virologic response and possible resistance.
Concomitant use of rifampicin or rifapentine with Paxlovid is contraindicated (see section 4.3).
Sulfamethoxazole/trimethoprim

Dose alteration of sulfamethoxazole/trimethoprim during

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments concomitant ritonavir therapy should not be necessary.
↓Voriconazole (39%, 24%)
Coadministration of voriconazole and ritonavir dosed as a pharmacokinetic enhancer should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Antiparasitic agent
↓Albendazole

Significant decreases in plasma concentrations of albendazole and its active metabolite may occur due to induction by ritonavir, with a risk of decreased albendazole efficacy. Clinical monitoring of therapeutic response and possible adjustment of albendazole dosage during treatment with Paxlovid and following discontinuation is recommended.
Antipsychotics

↑Clozapine
Given the risk of increase in clozapine exposure and thus of its related adverse events, coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it.
↑Haloperidol,
↑Risperidone,
↑Thioridazine

Ritonavir is likely to inhibit CYP2D6 and as a result is expected to increase concentrations of haloperidol, risperidone and thioridazine. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with antiretroviral doses of ritonavir.
↑Lurasidone

Due to CYP3A inhibition by ritonavir, concentrations of lurasidone are expected to increase. The concomitant administration with lurasidone is contraindicated (see section 4.3).
↑Pimozide
Ritonavir coadministration is likely to result in increased plasma concentrations of pimozide and is therefore contraindicated (see section 4.3).
↑Quetiapine
Due to CYP3A inhibition by ritonavir, concentrations of quetiapine are expected to increase. Concomitant administration of Paxlovid and quetiapine is contraindicated as it may increase quetiapine-related toxicity (see section 4.3).
Benign prostatic hyperplasia agents
↑Silodosin
Coadministration is contraindicated due to potential for postural hypotension (see section 4.3).
β2-agonist (long acting)
↑Salmeterol
Ritonavir inhibits CYP3A4 and as a result a pronounced increase in the plasma concentrations of salmeterol is expected, resulting in increased risk of

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Therefore, avoid concomitant use with Paxlovid.
Calcium channel antagonists
↑Amlodipine,
↑Diltiazem,
↑Felodipine,
↑Nicardipine,
↑Nifedipine,
↑Verapamil
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of calcium channel antagonists. Consultation of a multidisciplinary group should be obtained to guide on the best way to handle the drug interaction by dose decrease or even temporary discontinuation of calcium channel antagonist when coadministered with Paxlovid. Moreover, if coadministered, patients should be carefully monitored for therapeutic and adverse effects during the coadministration. Refer to the individual calcium channel antagonist SmPCs for more information.
↑Lercanidipine
Given the risk of significant increase in lercanidipine exposure and thus of its related adverse events, coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it.
Cardiovascular agents
↑Aliskiren
Avoid concomitant use with Paxlovid.
↑Cilostazol
Dose adjustment of cilostazol is recommended. Refer to the cilostazol
SmPC for more information.
Clopidogrel
Coadministration with clopidogrel may decrease levels of clopidogrel active metabolite. Avoid concomitant use with Paxlovid.
↑Eplerenone
Coadministration with eplerenone is contraindicated due to potential for hyperkalemia (see section 4.3).
↑Ivabradine
Coadministration with ivabradine is contraindicated due to potential for bradycardia or conduction disturbances (see section 4.3).
↑Mavacamten
Coadministration with mavacamten may increase mavacamten plasma concentration and increase the risk of heart failure, particularly in CYP2C19 poor metabolisers. Discontinue mavacamten for the duration of Paxlovid treatment. Due to the persistent inhibitory effect of ritonavir, mavacamten should not be resumed for at

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments least 5 days following the last dose of
Paxlovid to avoid elevated mavacamten exposure. Adequate monitoring may be necessary, please refer to the mavacamten SmPC for more information.
↑Ticagrelor
Given the risk of substantial increase in ticagrelor exposure and thus of its related adverse events, coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it.
Cystic fibrosis transmembrane conductance regulator potentiators
↑Elexacaftor/ tezacaftor/ivacaftor,
↑Ivacaftor,
↑Tezacaftor/ivacaftor
Reduce dose when coadministered with
Paxlovid. Refer to the individual SmPCs for more information.
Lumacaftor/ivacaftor
Coadministration contraindicated due to potential loss of virologic response and possible resistance (see section 4.3).
Dipeptidyl peptidase 4
(DPP4) inhibitors
↑Saxagliptin
Dose adjustment of saxagliptin to 2.5 mg once daily is recommended.
Endothelin antagonists
↑Bosentan
Coadministration of bosentan and ritonavir resulted in an increase of steady-state bosentan maximum concentrations (Cmax) and AUC. Avoid concomitant use with Paxlovid. Refer to the bosentan SmPC for more information.
↑Riociguat
Serum concentrations may be increased due to CYP3A and P-gp inhibition by ritonavir. The coadministration of riociguat with Paxlovid is not recommended (refer to the riociguat SmPC).
Ergot derivatives
↑Dihydroergotamine,
↑Ergonovine,
↑Ergotamine,
↑Methylergonovine
Ritonavir coadministration is likely to result in increased plasma concentrations of ergot derivatives and is therefore contraindicated (see section 4.3).
GI motility agent
↑Cisapride
Increased plasma concentrations of cisapride. Thereby, increasing the risk of serious arrhythmias from this agent and therefore concomitant use with Paxlovid is contraindicated (see section 4.3).
Herbal products
St. John’s Wort
Herbal preparations containing St John’s wort (Hypericum perforatum) due to the risk of decreased plasma concentrations and reduced clinical effects of nirmatrelvir and ritonavir and therefore concomitant use with Paxlovid is contraindicated (see section 4.3).
HMG Co-A reductase inhibitors
↑Lovastatin,
Simvastatin
HMG-CoA reductase inhibitors which are highly dependent on CYP3A metabolism, such as lovastatin and simvastatin, are

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments expected to have markedly increased plasma concentrations when coadministered with ritonavir at high dose in accordance with its previous use as an antiretroviral agent or as a pharmacokinetic enhancer. Since increased concentrations of lovastatin and simvastatin may predispose patients to myopathies, including rhabdomyolysis, the combination of these medicinal products with ritonavir is contraindicated (see section 4.3).
↑Atorvastatin,
Rosuvastatin (31%, 112%)*

Atorvastatin is less dependent on CYP3A for metabolism. While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with ritonavir coadministration. The mechanism of this interaction is not clear, but may be the result of transporter inhibition. When used with ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent, the lowest possible doses of atorvastatin or rosuvastatin should be administered.
↑Fluvastatin,
Pravastatin
While not dependent on CYP3A for metabolism, pravastatin and fluvastatin exposure may be increased due to transporter inhibition. Consider temporary discontinuation of pravastatin and fluvastatin during treatment with Paxlovid.
Hormonal contraceptive
↓Ethinyl Estradiol (40%, 32%)
Due to reductions in ethinyl estradiol concentrations, barrier or other non-hormonal methods of contraception should be considered with concomitant Paxlovid use and until one menstrual cycle after stopping Paxlovid. Ritonavir is likely to change the uterine bleeding profile and reduce the effectiveness of estradiol- containing contraceptives.
Immunosuppressants
↑Voclosporin
Coadministration is contraindicated due to potential for acute and/or chronic nephrotoxicity (see section 4.3).
Immunosuppressants
Calcineurin inhibitors:
↑Cyclosporine,
↑Tacrolimus

mTOR inhibitors:
↑Everolimus,
↑Sirolimus

Ritonavir dosed as a pharmacokinetic enhancer inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of cyclosporine, everolimus, sirolimus and tacrolimus. This coadministration should only be considered with close and regular monitoring of immunosuppressant blood concentrations, to reduce the dose of the immunosuppressant in accordance with the latest guidelines and to avoid over-exposure and subsequent increase of

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments serious adverse reactions of the immunosuppressant. It is important that the close and regular monitoring is performed not only during the coadministration with Paxlovid but is also pursued after the treatment with Paxlovid. As overall recommended for managing the drug-drug interaction, consultation of a multidisciplinary group is required to handle the complexity of this coadministration (see section 4.4).
Janus kinase (JAK) inhibitors
↑Tofacitinib

Dose adjustment of tofacitinib is recommended. Refer to the tofacitinib
SmPC for more information.
↑Upadacitinib

Dosing recommendations for coadministration of upadacitinib with
Paxlovid depends on the upadacitinib indication. Refer to the upadacitinib SmPC for more information.
Lipid-modifying agents
↑Lomitapide
CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Due to CYP3A inhibition by ritonavir, concentrations of lomitapide are expected to increase. Concomitant use of Paxlovid with lomitapide is contraindicated (refer to the lomitapide SmPC) (see section 4.3).
Migraine medicinal products
↑Eletriptan

Coadministration of eletriptan within at least 72 hours of Paxlovid is contraindicated due to potential for serious adverse reactions including cardiovascular and cerebrovascular events (see section 4.3).
↑Rimegepant
Avoid concomitant use with Paxlovid.
Mineralocorticoid receptor antagonists
↑Finerenone
Coadministration contraindicated due to potential for serious adverse reactions including hyperkalemia, hypotension and hyponatremia (see section 4.3).
Muscarinic receptor antagonists
↑Darifenacin
Given the risk of substantial increase in darifenacin exposure and thus of its related adverse events, coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it.
↑Solifenacine
Given the risk of substantial increase in solifenacine exposure and thus of its related adverse events, coadministration should not be used unless a multidisciplinary consultation could be obtained to safely guide it.

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments
Neuropsychiatric agents
↑Aripiprazole,
↑Brexpiprazole

Dose adjustment of aripiprazole and brexpiprazole is recommended. Refer to the aripiprazole or brexpiprazole SmPCs for more information.
↑Cariprazine
Coadministration is contraindicated due to increased plasma exposure of cariprazine and its active metabolites (see section 4.3).
Opioid antagonists
↑Naloxegol
Coadministration contraindicated due to the potential for opioid withdrawal symptoms (see section 4.3).
Phosphodiesterase
(PDE5) inhibitors
↑Avanafil (13-fold, 2.4-fold),
↑Sildenafil (11-fold, 4-fold),
↑Tadalafil (124%, ↔),
↑Vardenafil (49-fold, 13-fold)
Concomitant use of avanafil, sildenafil, tadalafil and vardenafil with Paxlovid is contraindicated (see section 4.3).
Sedatives/hypnotics
↑Alprazolam (2.5-fold, ↔)
Alprazolam metabolism is inhibited following the introduction of ritonavir.
Caution is warranted during the first several days when alprazolam is coadministered with ritonavir at high dose in accordance with its previous use as an antiretroviral agent or as a pharmacokinetic enhancer, before induction of alprazolam metabolism develops.
↑Buspirone
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A and as a result is expected to increase the plasma concentrations of buspirone. Careful monitoring of therapeutic and adverse effects is recommended when buspirone concomitantly administered with ritonavir.
↑Clorazepate,
↑Diazepam,
↑Estazolam,
↑Flurazepam
Ritonavir coadministration is likely to result in increased plasma concentrations of clorazepate, diazepam, estazolam, and flurazepam and is therefore contraindicated (see section 4.3).
↑Oral Midazolam (1330%,
268%)* and parenteral
Midazolam
Midazolam is extensively metabolised by
CYP3A4. Coadministration with Paxlovid may cause a large increase in the concentration of midazolam. Plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore, coadministration of Paxlovid with orally administered midazolam is contraindicated (see section 4.3), whereas caution should be used with coadministration of Paxlovid and parenteral midazolam. Data from concomitant use of parenteral midazolam with other protease inhibitors suggests a possible 3- to 4-fold increase in midazolam plasma levels. If Paxlovid is

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments coadministered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.
Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
↑Triazolam (> 20-fold, 87%)
Ritonavir coadministration is likely to result in increased plasma concentrations of triazolam and is therefore contraindicated (see section 4.3).
Sleeping agent
↑Zolpidem (28%, 22%)

Zolpidem and ritonavir may be coadministered with careful monitoring for excessive sedative effects.
Smoke cessation
↓Bupropion (22%, 21%)
Bupropion is primarily metabolised by
CYP2B6. Concurrent administration 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 dose of bupropion should not be exceeded. In contrast to long-term administration of ritonavir, there was no significant interaction with bupropion after short-term administration of low doses of ritonavir (200 mg twice daily for 2 days), suggesting reductions in bupropion concentrations may have onset several days after initiation of ritonavir coadministration.
Steroids
Budesonide,
Inhaled, injectable or intranasal fluticasone propionate,
Triamcinolone
Systemic corticosteroid effects including
Cushing's syndrome and adrenal suppression (plasma cortisol levels were noted to be decreased 86%) have been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate; similar effects could also occur with other corticosteroids metabolised by CYP3A e.g., budesonide and triamcinolone. Consequently, concomitant administration of ritonavir at high dose in accordance with its previous use as an antiretroviral agent or as a pharmacokinetic enhancer and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of the glucocorticoid should be considered with close monitoring of local and

Table 3:
Interaction with other medicinal products and other forms of interaction
Medicinal product class
Medicinal product within class
(AUC change, Cmax Change)
Clinical comments systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g., beclomethasone).
Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may be required over a longer period.
↑Dexamethasone

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits CYP3A and as a result is expected to increase the plasma concentrations of dexamethasone. Careful monitoring of therapeutic and adverse effects is recommended when dexamethasone is concomitantly administered with ritonavir.
↑Prednisolone (28%, 9%)
Careful monitoring of therapeutic and adverse effects is recommended when prednisolone is concomitantly administered with ritonavir. The AUC of the metabolite prednisolone increased by 37% and 28% after 4 and 14 days ritonavir, respectively.
Thyroid hormone replacement therapy
Levothyroxine
Post-marketing cases have been reported indicating a potential interaction between ritonavir containing products and levothyroxine. Thyroid-stimulating hormone (TSH) should be monitored in patients treated with levothyroxine at least the first month after starting and/or ending ritonavir treatment.
Vasopressin receptor antagonists
↑Tolvaptan
Coadministration is contraindicated due to potential for dehydration, hypovolemia and hyperkalemia (see section 4.3).
Abbreviations: ATL=alanine aminotransferase; AUC=area under the curve.
* Results from DDI studies conducted with Paxlovid (see section 5.2).

Women of childbearing potential

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

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

Pregnancy

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 body weights) 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 of birth 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 using contraception unless the clinical condition requires treatment with this medicinal product.

Breast-feeding

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-fed newborn/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 hours after completing the treatment.

Fertility

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

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

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

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

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

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

Antiviral activity

Nirmatrelvir exhibited antiviral activity against SARS-CoV-2 infection of differentiated normal human bronchial epithelial (dNHBE) cells, a primary human lung alveolar epithelial cell line (EC50 value of 61.8 nM and EC90 value of 181 nM) after 3 days of drug exposure.

The antiviral activity of nirmatrelvir against the Omicron sub-variants BA.2, BA.2.12.1, BA.4, BA.4.6, BA.5, BF.7 (P252L+F294L), BF.7 (T243I), BQ.1.11, BQ.1, XBB.1.5, EG.5, and JN.1 was assessed in Vero E6-TMPRSS2 cells in the presence of a P-gp inhibitor. Nirmatrelvir had a median EC50 value of 88 nM (range: 39-146 nM) against the Omicron sub-variants, reflecting EC50 value fold- changes ≤ 1.8 relative to the USA-WA1/2020 isolate.

In addition, the antiviral activity of nirmatrelvir against the SARS-CoV-2 Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1 variants was assessed in Vero E6 P-gp knockout cells. Nirmatrelvir had a median EC50 value of 25 nM (range: 16-141 nM). The Beta variant was the least susceptible variant tested, with an EC50 value fold-change of 3.7 relative to USA-WA1/2020. The other variants had EC50 value fold-changes ≤ 1.1 relative to USA-WA1/2020.

Antiviral resistance in cell cultures and biochemical assays
SARS-CoV-2 Mpro residues potentially associated with nirmatrelvir resistance have been identified using a variety of methods, including SARS-CoV-2 resistance selection, testing of recombinant SARS-CoV-2 viruses with Mpro substitutions, and biochemical assays with recombinant SARS-CoV-2 Mpro containing amino acid substitutions. Table 5 indicates Mpro substitutions and combinations of Mpro substitutions that have been observed in nirmatrelvir-selected SARS-CoV-2 in cell culture. Individual Mpro substitutions are listed regardless of whether they occurred alone or in combination with other Mpro substitutions. Note that the Mpro S301P and T304I substitutions overlap the P6 and P3 positions of the nsp5/nsp6 cleavage site located at the C-terminus of Mpro. Substitutions at other Mpro cleavage sites have not been associated with nirmatrelvir resistance in cell culture. The clinical significance of these substitutions is unknown.

Table 5:

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

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

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

Absorption

Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean nirmatrelvir 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 elimination half-life was 6.1 hours.

Following oral administration of nirmatrelvir/ritonavir 300 mg/100 mg after a single dose, the geometric mean ritonavir Cmax and AUCinf was 0.36 µg/mL and 3.60 µg*hr/mL, respectively. The median time to Cmax (Tmax) was 3.98 hrs. The arithmetic mean terminal elimination half-life was 6.1 hours.

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

Distribution

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

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

Biotransformation