Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

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 1). Coadministration of other CYP3A4 substrates that may lead to potentially significant interaction (see Table 1) 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 1 are a guide and not considered a comprehensive list of all possible medicinal products that are contraindicated or may interact with nirmatrelvir/ritonavir.

Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments Alpha1-adrenorecepto ↑Alfuzosin                      Increased plasma concentrations of r antagonist                                         alfuzosin may lead to severe hypotension and is therefore contraindicated (see section 4.3).
↑Tamsulosin                     Tamsulosin is extensively metabolized, mainly by CYP3A4 and CYP2D6, both of which are inhibited by ritonavir. Avoid concomitant use with Paxlovid.
Amphetamine          ↑Amphetamine                    Ritonavir administered at high dose in derivatives                                          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,                             Ritonavir inhibits CYP3A4 and as a result ↑Oxycodone                             is expected to increase the plasma concentrations of these narcotic analgesics.
If concomitant use with Paxlovid is necessary, consider a dosage reduction of these narcotic analgesics and closely monitor therapeutic and adverse effects
(including respiratory depression). Refer to the individual SmPCs for more information.




Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments ↓Methadone (36%, 38%)           Increased methadone dose may be necessary when coadministered with ritonavir dosed as a pharmacokinetic enhancer due to induction of glucuronidation. 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 dosage 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                            Given the risk of substantial increase in ↑Flecainide                            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,                          Ritonavir coadministration is likely to ↑Propafenone,                          result in increased plasma concentrations ↑Quinidine                             of dronedarone, propafenone and quinidine and is therefore contraindicated (see section 4.3).



Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments 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
Paxlovid should be avoided. If this coadministration is judged unavoidable,
refer to the abemaciclib SmPC for dosage 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 dosage 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.




Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments ↑Encorafenib,                   Serum concentrations of encorafenib or ↑Ivosidenib                     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
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).




Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments ↑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 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,                              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 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*,                        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 exposure of nirmatrelvir and ritonavir and potential loss of virologic response. Concomitant


Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                  Clinical comments 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,                           Ritonavir dosed as a pharmacokinetic Lamotrigine                            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.
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. 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


Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                  Clinical comments associated with increased glecaprevir exposure.


↑Sofosbuvir/velpatasvir/               Serum concentrations may be increased voxilaprevir                           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).
Anti-HIV                  ↑Bictegravir/                          Ritonavir may significantly increase the ↔Emtricitabine/                        plasma concentrations of bictegravir ↑Tenofovir                             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 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 Summary of Product Characteristics for maraviroc.
↓Raltegravir (16%, 1%)                 Coadministration of ritonavir and raltegravir results in a minor reduction in raltegravir levels.



Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments ↓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 (see bedaquiline Summary of Product Characteristics).
↑Clarithromycin (77%, 31%),            Due to the large therapeutic window of ↓14-OH clarithromycin                  clarithromycin no dose reduction should be metabolite (100%, 99%)                 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 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 Summary of
Product Characteristics).



Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments ↑Erythromycin,                  Itraconazole increases AUC and Cmax of ↑Itraconazole*                  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),         An increase in rifabutin exposure is ↑25-O-desacetyl rifabutin              expected due to the inhibition of CYP3A4 metabolite (38-fold, 16-fold)          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,                            Rifampicin and rifapentine are strong Rifapentine                            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 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.
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,                          Ritonavir is likely to inhibit CYP2D6 and ↑Risperidone,                          as a result is expected to increase ↑Thioridazine                          concentrations of haloperidol, risperidone 

Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                    Clinical comments 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     ↑Silodosin                      Coadministration is contraindicated due to hyperplasia agents                                   potential for postural hypotension (see section 4.3).
β2-agonist (long     ↑Salmeterol                     Ritonavir   inhibits CYP3A4 and as a result acting)                                              a pronounced increase in the plasma concentrations of salmeterol is expected,
resulting in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Therefore, avoid concomitant use with Paxlovid.
Calcium channel      ↑Amlodipine,                    Ritonavir dosed as a pharmacokinetic antagonists          ↑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 of therapeutic and adverse effects is recommended when amlodipine, diltiazem,
felodipine, nicardipine, nifedipine or verapamil are concomitantly administered with ritonavir.
↑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.
↑Aliskiren                      Avoid concomitant use with Paxlovid.



Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                  Clinical comments Cardiovascular       ↑Cilostazol                     Dosage adjustment of cilostazol is agents                                               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).
↑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           ↑Elexacaftor/                          Reduce dosage when coadministered with transmembrane             tezacaftor/ivacaftor,                  Paxlovid. Refer to individual SmPCs for conductance               ↑Ivacaftor,                            more information.
regulator potentiators    ↑Tezacaftor/ivacaftor
Lumacaftor/ivacaftor                   Coadministration contraindicated due to potential loss of virologic response and possible resistance (see section 4.3).
Dipeptidyl peptidase      ↑Saxagliptin                           Dosage adjustment of saxagliptin to 2.5 mg 4 (DPP4) inhibitors                                              once daily is recommended.
Endothelin                ↑Bosentan                              Coadministration of bosentan and ritonavir antagonists                                                      resulted in an increase of steady-state bosentan maximum concentrations (Cmax) and AUC. Avoid concomitant use with
Paxlovid. Refer to 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 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 of cisapride. Thereby, increasing the risk of serious arrhythmias from this agent and therefore concomitant use with Paxlovid is contraindicated (see section 4.3).



Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments 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 ↑Lovastatin,                      HMG-CoA reductase inhibitors which are inhibitors           Simvastatin                     highly dependent on CYP3A metabolism, such as lovastatin and simvastatin, are 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,                  Atorvastatin is less dependent on CYP3A for metabolism. While rosuvastatin
Rosuvastatin, (31%, 112%)*      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,                   While not dependent on CYP3A for
Pravastatin                     metabolism, pravastatin and fluvastatin exposure may be increased due to transporter inhibition. Consider temporary discontinuation of pravastatin and fluvastatin during treatment with Paxlovid.
Hormonal             ↓Ethinyl Estradiol (40%, 32%)   Due to reductions in ethinyl estradiol contraceptive                                        concentrations, barrier or other non-hormonal methods of contraception should be considered with concomitant ritonavir use at high dose in accordance with its previous use as an antiretroviral agent or as a pharmacokinetic enhancer.
Ritonavir is likely to change the uterine bleeding profile and reduce the effectiveness of estradiol-containing contraceptives.



Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments Immunosuppressants ↑Voclosporin                      Coadministration is contraindicated due to potential for acute and/or chronic nephrotoxicity (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 plasma concentrations of cyclosporine,
mTOR inhibitors:                everolimus, sirolimus and tacrolimus. This ↑Everolimus,                    coadministration should only be
↑Sirolimus                      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 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)   ↑Tofacitinib                    Dosage adjustment of tofacitinib is inhibitors                                           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      ↑Lomitapide                     CYP3A4 inhibitors increase the exposure agents                                               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 (see prescribing information for lomitapide) (see section 4.3).
Migraine medicinal   ↑Eletriptan                     Coadministration of eletriptan within at products                                             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.


Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments Mineralocorticoid    ↑Finerenone                     Coadministration contraindicated due to receptor antagonists                                 potential for serious adverse reactions including hyperkalemia, hypotension and hyponatremia (see section 4.3).
Muscarinic receptor  ↑Darifenacin                    Given the risk of substantial increase in antagonists                                          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.
Neuropsychiatric     ↑Aripiprazole,                  Dosage adjustment of aripiprazole and agents               ↑Brexpiprazole,                 brexpiprazole is recommended. Refer to 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         ↑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 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.




Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                 (AUC change, Cmax Change)                   Clinical comments ↑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 by 268%)* and parenteral                  CYP3A4. Coadministration with Paxlovid Midazolam                              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 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.
Dosage 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),


Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product    Medicinal product within class class                  (AUC change, Cmax Change)                    Clinical comments suggesting reductions in bupropion concentrations may have onset several days after initiation of ritonavir coadministration.
Steroids             Budesonide,                       Systemic corticosteroid effects including Inhaled, injectable or intranasal Cushing's syndrome and adrenal fluticasone propionate,           suppression (plasma cortisol levels were Triamcinolone                     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 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           Levothyroxine                          Post-marketing cases have been reported replacement therapy                                              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.


Table 1: Interaction with other medicinal products and other forms of interaction
Medicinal product      Medicinal product within class class                    (AUC change, Cmax Change)                     Clinical comments Vasopressin receptor ↑Tolvaptan                           Coadministration is contraindicated due to antagonists                                               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).