Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects. For selected medicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease over time (e.g. digoxin and fexofenadine- see table “Ritonavir effects on non-antiretroviral medicinal products” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products metabolised by these pathways, and may result in decreased systemic exposure to such medicinal products, which could decease or shorten their therapeutic effect.

Important information regarding medicinal product interactions when ritonavir is used as a pharmacokinetic enhancer is also contained in the prescribing information of the co-administered protease inhibitor.

Medicinal products that affect ritonavir levels

Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing St John's wort (Hypericum perforatum). This is due to the induction of medicinal product metabolising enzymes by St John's wort. Herbal preparations containing St John's wort must not be used in combination with ritonavir. If a patient is already taking St John's wort, St John's wort should be stopped and if possible check viral levels.
Ritonavir levels may increase on stopping St John's wort. The dose of ritonavir may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort (see section 4.3).

Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. delavirdine, efavirenz, phenytoin and rifampicin). These interactions are noted in the medicinal product interaction tables below.

Medicinal products that are affected by the use of ritonavir


Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in the tables below. This list is not intended to be inclusive or comprehensive. Individual prescribing informations should be consulted.



Medicinal Product Interactions – Ritonavir with Protease Inhibitors 
Co-administered    Dose of Co-administered Medicinal              Dose of     Medicinal         AUC           Cmin Medicinal          Product (mg)                                   NORVIR      Product Product                                                           (mg)        Assessed 

Amprenavir         600 q12h                                       100 q12h    Amprenavir1       ↑ 64%         ↑ 5 fold Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition. Clinical trials confirmed the safety and efficacy of 600 mg amprenavir twice daily with ritonavir 100 mg twice daily. For further information, physicians should refer to the amprenavir prescribing information.
Atazanavir         300 q24h                                       100 q24h    Atazanavir        ↑ 86%         ↑ 11 fold Atazanavir2       ↑ 2 fold      ↑ 3-7 fold
Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition. Clinical trials confirmed the safety and efficacy of 300 mg atazanavir once daily with ritonavir 100 mg once daily in treatment experienced patients. For further information, physicians should refer to the atazanavir prescribing information.
Darunavir          600, single                                    100 q12h    Darunavir         ↑ 14 fold Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition. Darunavir must be given with ritonavir to ensure its therapeutic effect. Ritonavir doses higher than 100 mg twice daily have not been studied with darunavir. For further information, refer to the prescribing information for draunavir.
Fosamprenavir      700 q12h                                       100 q12h    Amprenavir        ↑ 2.4 fold    ↑ 11 fold Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4 inhibition. Fosamprenavir must be given with ritonavir to ensure its therapeutic effect. Clinical trials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily. Ritonavir doses higher than 100 mg twice daily have not been studied with fosamprenavir. For further information, physicians should refer to the fosamprenavir prescribing information.
Indinavir          800 q12h                                       100 q12h    Indinavir3        ↑ 178%        ND Ritonavir         ↑ 72%         ND
400 q12h                                       400 q12h    Indinavir   3
↔             ↑ 4 fold
Ritonavir         ↔             ↔
Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher than 100 mg twice daily. In cases of co-administration of ritonavir (100 mg twice daily) and indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may be increased.
Nelfinavir         1250 q12h                                      100 q12h    Nelfinavir        ↑ 20 to       ND 39%
750, single                                    500 q12h    Nelfinavir        ↑ 152%        ND Ritonavir         ↔             ↔


Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher than 100 mg twice daily.
Saquinavir         1000 q12h                                       100 q12h     Saquinavir4      ↑ 15-fold   ↑ 5-fold Ritonavir        ↔           ↔
400 q12h                                        400 q12h     Saquinavir   4
↑ 17-fold   ND
Ritonavir        ↔           ↔
Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition. Saquinavir should only be given in combination with ritonavir. Ritonavir 100 mg twice daily with saquinavir 1000 mg twice daily provides saquinavir systemic exposure over 24 hours similar to or greater than those achieved with saquinavir 1200 mg three times daily without ritonavir.

In a clinical study investigating the interaction of rifampicin 600 mg once daily and saquinavir 1000 mg with ritonavir 100 mg twice daily in healthy volunteers, severe hepatocellular toxicity with transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days of co- administration was noted. Due to the risk of severe hepatoxicity, saquinavir/ritonavir should not be given together with rifampicin.

For further information, physicians should refer to saquinavir Prescribing information.
Tipranavir         500 q12h                                        200 q12h     Tipranavir       ↑ 11 fold   ↑ 29 fold Ritonavir        ↓ 40%       ND
Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition. Tipranavir must be given with low dose ritonavir to ensure its therapeutic effect. Doses of ritonavir less than 200 mg twice daily should not be used with tipranavir as they might alter the efficacy of the combination.
For further information, physicians should refer to the tipranavir prescribing information.
ND: Not determined.

1.    Based on cross-study comparison to 1200 mg amprenavir twice daily alone.
2.    Based on cross-study comparison to 400 mg atazanavir once daily alone.
3.    Based on cross-study comparison to 800 mg indinavir three times daily alone.
4.    Based on cross-study comparison to 600 mg saquinavir three times daily alone.
Medicinal product interactions – Ritonavir with antiretroviral agents other than protease inhibitors 
Co-administered   Dose of Co-administered Medicinal               Dose of      Medicinal        AUC         Cmin Medicinal         Product (mg)                                    NORVIR       Product Product                                                           (mg)         Assessed Didanosine        200 q12h                                        600 q12h 2   Didanosine       ↓ 13%       ↔ h later
As ritonavir is recommended to be taken with food and didanosine should be taken on an empty stomach, dosing should be separated by 2.5 h. Dose alterations should not be necessary.
Delavirdine       400 q8h                                         600 q12h     Delavirdine1     ↔           ↔ Ritonavir        ↑ 50%       ↑ 75%
Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to be affected by ritonavir. When used in combination with delavirdine, dose reduction of ritonavir may be considered.
Efavirenz         600 q24h                                        500 q12h     Efavirenz        ↑ 21% Ritonavir        ↑ 17%


A higher frequency of adverse reactions (e.g., dizziness, nausea, paraesthesia) and laboratory abnormalities (elevated liver enzymes) have been observed when efavirenz is co-administered with ritonavir dosed as an antiretroviral agent.


Maraviroc          100 q12h                                        100 q12h    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 prescribing information for Maraviroc.
Nevirapine         200 q12h                                        600 q12h    Nevirapine          ↔          ↔ Ritonavir           ↔          ↔
Co-administration of ritonavir with nevirapine does not lead to clinically relevant changes in the pharmacokinetics of either nevirapine or ritonavir.
Raltegravir        400 single                                      100 q12h    Raltegravir         ↓ 16%      ↓ 1% Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir levels Zidovudine         200 q8h                                     300 q6h         Zidovudine       ↓ 25%          ND Ritonavir may induce the glucuronidation of zidovudine, resulting in slightly decreased levels of zidovudine. Dose alterations should not be necessary.
ND: Not determined

1. Based on parallel group comparison.
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 
Co-administered Medicinal       Dose of Co-administered            Dose of NORVIR          Effect on Co-      Effect on Products                        Medicinal Products (mg)            (mg)                    administered       Co- Medicinal          administer
Products AUC       ed
Medicinal
Products
Cmax
Alpha1-Adrenoreceptor
Antagonist
Alfuzosin                       Ritonavir co-administration is likely to result in increased plasma concentrations of alfuzosin and is therefore contraindicated (see section 4.3).

Amphetamine Derivatives
Amphetamine                     Ritonavir dosed 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 therapeutic and adverse effects is recommended when these medicines are concomitantly administered with antiretroviral doses of ritonavir (see section 4.4).
Analgesics
Buprenorphine                   16 q24h                            100 q12h                ↑ 57%              ↑ 77% Norbuprenorphine                                                                           ↑ 33%              ↑ 108% Glucuronide metabolites                                                                    ↔                  ↔ 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 or ritonavir may therefore not be necessary when the two are dosed together. When ritonavir is used in combination with another protease inhibitor and buprenorphine, the prescribing information of the co- administered protease inhibitor should be reviewed for specific dosing information.


Pethidine, propoxyphene    Ritonavir co-administration is likely to result in increased plasma concentrations of norpethidine and propoxyphene and is therefore contraindicated (see section 4.3).
Fentanyl                   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 fentanyl.
Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when fentanyl is concomitantly administered with ritonavir.
Methadone1                 5, single dose                       500 q12h,            ↓ 36%              ↓ 38% Increased methadone dose may be necessary when concomitantly administered with ritonavir dosed as an antiretroviral agent or 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 co- administered ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.
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).
Antiarrthymics
Amiodarone, bepridil,      Ritonavir co-administration is likely to result in increased plasma concentrations of dronedarone, encainide,    amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, and quinidine flecainide, propafenone,   and is therefore contraindicated (see section 4.3).
quinidine
Digoxin                    0.5 single IV dose                   300 q12h, 3 days     ↑ 86%              ND 0.4 single oral dose                 200 q12h, 13 days    ↑ 22%              ↔ This interaction may be due to modification of P-glycoprotein mediated digoxin efflux by ritonavir dosed as an antriretroviral agent or as a pharmacokinetic enhancer.
Increased digoxin levels observed in patients receiving ritonavir may lessen over time as induction develops (see section 4.4).
Antiasthmatic
Theophylline1              3 mg/kg q8h                          500 q12h             ↓ 43%              ↓ 32% An increased dose of theophyline may be required when co-administered with ritonavir, due to induction of CYP1A2.
Anticancer agents and kinase inhibitors
Afatinib                   20 mg, single dose                   200 q12h/1h before   ↑ 48%              ↑ 39% 40 mg, single dose                   200 q12h/ co- administered         ↑ 19%              ↑ 4%
40 mg, single dose                   200 q12h/6h after

↑ 11%               ↑ 5%
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 Norvir (refer to the afatinib prescribing information).
Monitor for ADRs related to afatinib.
Abemaciclib                Serum concentrations may be increased due to CYP3A4 inhibition by ritonavir.

Co-administration of abemaciclib and Norvir should be avoided. If this co-administration is judged unavoidable, refer to the abemaciclib prescribing information for dosage adjustment recommendations. Monitor for ADRs related to abemaciclib.


Apalutamide                Apalutamide is a moderate to strong CYP3A4 inducer and this may lead to a decreased exposure of ritonavir and potential loss of virologic response. In addition, serum concentrations may be increased when co-administered with ritonavir resulting in the potential for serious adverse events including seizure.

Concomitant use of ritonavir with apalutamide is not recommended.
Ceritinib                  Serum concentrations may be increased due to CYP3A and P-gp inhibition by ritonavir.
Caution should be exercised in administering ceritinib with Norvir. Refer to the ceritinib prescribing information for dosage adjustment recommendations. Monitor for ADRs related to ceritinib.
Dasatinib, nilotinib,      Serum concentrations may be increased when co-administered with ritonavir resulting vincristine, vinblastine   in the potential for increased incidence of adverse reactions.
Encorafenib                Serum concentrations may be increased when co-administered with ritonavir which may increase the risk of toxicity, including the risk of serious adverse events such as QT interval prolongation. Co-administration of encorafenib and ritonavir should be avoided. If the benefit is considered to outweigh the risk and ritonavir must be used, patients should be carefully monitored for safety.
Fostamatinib               Co-administration 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 prescribing information 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 tumor lysis syndrome.
Co-administration 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 Norvir 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 tumor lysis syndrome at the dose initiation and during the ramp-up phase (see section 4.3 and refer to the venetoclax prescribing information).
For patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax, reduce the venetoclax dose by at least 75% when used with strong CYP3A inhibitors (refer to the venetoclax prescribing information for dosing instructions).
Anticoagulants
Dabigatran etexilate       Serum concentrations may be increased due to P gp inhibition by ritonavir. Clinical monitoring and/or dose reduction of the direct oral anticoagulants (DOAC) should be Edoxaban                   considered when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with ritonavir.
Rivaroxaban                10, single dose                    600 q12h              ↑ 153%                ↑ 55% 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 ritonavir is not recommended in patients receiving rivaroxaban.
Vorapaxar                  Serum concentrations may be increased due to CYP3A inhibition by ritonavir. The co- administration of vorapaxar with Norvir is not recommended (see section 4.4 and refer to the vorapaxar prescribing information).


Warfarin                   5, single dose                     400 q12h 
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 co-administered with ritonavir.
Decreased R-warfarin levels may lead to reduced anticoagulation, therefore it is recommended that anticoagulation parameters are monitored when warfarin is co- administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.
Anticonvulsants
Carbamazepine                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 carbamazepine.
Careful monitoring of therapeutic and adverse effects is recommended when carbamazepine is concomitantly administered with ritonavir.
Divalproex, lamotrigine,     Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent induces phenytoin                    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 concomitantly administered with ritonavir. Phenytoin may decrease serum levels of ritonavir.
Antidepressants
Amitriptyline, fluoxetine,   Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a result is imipramine, nortriptyline,   expected to increase concentrations of imipramine, amitriptyline, nortriptyline, paroxetine, sertraline,      fluoxetine, paroxetine, or sertraline. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with antiretroviral doses of ritonavir (see section 4.4).
Desipramine                  100, single oral       500 q12h                          ↑ 145%               ↑ 22% dose
The AUC and Cmax of the 2-hydroxy metabolite were decreased 15 and 67%, respectively. Dosage reduction of desipramine is recommended when co-administered with ritonavir dosed as an antiretroviral agent.
Trazodone                    50, single dose        200 q12h                          ↑ 2.4-fold           ↑ 34% An increase in the incidence in trazodone-related adverse reactions was noted when co- administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer. If trazodone is co-administered with ritonavir, the combination should be used with caution, initiating trazodone at the lowest dosage and monitoring for clinical response and tolerability.
Anti-gout treatments
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) in patients with renal and/or hepatic impairment (see sections 4.3 and 4.4). Refer to the colchicine prescribing information.
Antihistamines
Astemizole, terfenadine      Ritonavir co-administration is likely to result in increased plasma concentrations of astemizole and terfenadine and is therefore contraindicated (see section 4.3).
Fexofenadine                 Ritonavir may modify P-glycoprotein mediated fexofenadine efflux when dosed as an antriretroviral agent or as a pharmacokinetic enhancer resulting in increased concentrations of fexofenadine. Increased fexofenadine levels may lessen over time as induction develops.
Loratadine                   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 loratadine.
Careful monitoring of therapeutic and adverse effects is recommended when loratidine is concomitantly administered with ritonavir.

Anti-infectives
Fusidic Acid               Ritonavir co-administration is likely to result in increased plasma concentrations of both fusidic acid and ritonavir and is therefore contraindicated (see section 4.3).
Rifabutin1                 150 daily                          500 q12h,    ↑ 4-fold                        ↑ 2.5-fold 
25-O-desacetyl rifabutin                                                   ↑ 38-fold                       ↑ 16-fold metabolite                 Due to the large increase in rifabutin AUC, the concomitant use of rifabutin with ritonavir dosed as an antiretroviral agent is contraindicated (see section 4.3). The reduction of the rifabutin dose to 150 mg 3 times per week may be indicated for select PIs when co-administered with ritonavir as a pharmacokinetic enhancer. The prescribing information of the co-administered protease inhibitor should be consulted for specific recommendations. Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV-infected patients.
Rifampicin                 Although rifampicin may induce metabolism of ritonavir, limited data indicate that when high doses of ritonavir (600 mg twice daily) is co-administered with rifampicin, the additional inducing effect of rifampicin (next to that of ritonavir itself) is small and may have no clinical relevant effect on ritonavir levels in high-dose ritonavir therapy.
The effect of ritonavir on rifampicin is not known.
Voriconazole               200 q12h                400 q12h                            ↓ 82%               ↓ 66% 200 q12h                100 q12h                            ↓ 39%               ↓ 24% Concomitant use of ritonavir dosed as an antiretroviral agent and voriconazole is contraindicated due to reduction in voriconazole concentrations (see section 4.3). Co- administration 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.
Atovaquone                 Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent 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 concomitantly administered with ritonavir.
Bedaquiline                No interaction study is available with ritonavir only. In an interaction study of single- dose bedaquiline and multiple dose lopinavir/ritonavir, the AUC of bedaquiline was increased by 22%. This increase is likely due to ritonavir and a more pronounced effect may be observed during prolonged co-administration. Due to the risk of bedaquiline related adverse events, co-administration should be avoided. If the benefit outweighs the risk, co-administration of bedaquiline with ritonavir must be done with caution.
More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.4 and refer to the bedaquiline prescribing information).
Clarithromycin             500 q12h                           200 q8h                  ↑ 77%               ↑ 31% 
14-OH clarithromycin                                                                   ↓ 100%              ↓ 99% metabolite                 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 co-administered with ritonavir dosed as an antiretroviral agent or 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%, for patients with creatinine clearance less than 30 ml/min the dose should be reduced by 75%.
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 co-administration of delamanid with ritonavir is considered necessary, very frequent 

ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.4 and refer to the delamanid prescribing information).


Erythromycin, itraconazole    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 erythromycin and itraconazole. Careful monitoring of therapeutic and adverse effects is recommended when erythromycin or itraconazole is used concomitantly administered with ritonavir.
Ketoconazole                  200 daily                         500 q12h              ↑ 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 co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.
Sulfamethoxazole/Trimethopr   800/160, single dose              500 q12h              ↓ 20% / ↑ 20%        ↔ im2                           Dose alteration of sulfamethoxazole/trimethoprim during concomitant ritonavir therapy should not be necessary.
Antipsychotics/Neuroleptics
Clozapine, pimozide           Ritonavir co-administration is likely to result in increased plasma concentrations of clozapine or pimozide and is therefore contraindicated (see section 4.3).
Haloperidol, risperidone,     Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a result is thioridazine                  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).
Quetiapine                    Due to CYP3A inhibition by ritonavir, concentrations of quetiapine are expected to increase. Concomitant administration of Norvir and quetiapine is contraindicated as it may increase quetiapine-related toxicity (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. Therefore concomitant use is not recommended.
Calcium channel antagonists
Amlodipine, diltiazem,        Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits nifedipine                    CYP3A4 and as a result is expected to increase the plasma concentrations of calcium channel antagonists. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with ritonavir.
Endothelin antagonists
Bosentan                      Co-administration of bosentan and ritonavir may increase steady state bosentan maximum concentrations (Cmax) and area under the curve (AUC).
Riociguat                     Serum concentrations may be increased due to CYP3A and P-gp inhibition by ritonavir.
The co-administration of riociguat with Norvir is not recommended (see section 4.4 and refer to riociguat prescribing information).
Ergot Derivatives
Dihydroergotamine,            Ritonavir co-administration is likely to result in increased plasma concentrations of ergonovine, ergotamine,       ergot derivatives and is therefore contraindicated (see section 4.3).
methylergonovine
GI motility agent


Cisapride                    Ritonavir co-administration is likely to result in increased plasma concentrations of cisapride and is therefore contraindicated (see section 4.3).
HCV Direct Acting
Antiviral
Glecaprevir/pibrentasvir     Serum concentrations may be increased due to P-glycoprotein, BCRP and OATP1B inhibition by ritonavir.

Concomitant administration of glecaprevir/pibrentasvir and Norvir is not recommended due to an increased risk of ALT elevations associated with increased glecaprevir exposure.
HCV Protease Inhibitor
Simeprevir                   200 qd                         100 q12h                ↑ 7.2-fold           ↑ 4.7-fold Ritonavir increases plasma concentrations of simeprevir as a result of CYP3A4 inhibition. It is not recommended to co-administer ritonavir with simeprevir.
HMG Co-A Reductase
Inhibitors
Atorvastatin, Fluvastatin,   HMG-CoA reductase inhibitors which are highly dependent on CYP3A metabolism, Lovastatin, Pravstatin,      such as lovastatin and simvastatin, are expected to have markedly increased plasma Rosuvastatin, Simvastatin    concentrations when co-administered with ritonavir dosed 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 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 co-administration. 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. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A, and interactions are not expected with ritonavir.
If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.
Hormonal contraceptive
Ethinyl estradiol            50 µg, single dose                   500 q12h           ↓ 40%                ↓ 32% Due to reductions in ethinyl estradiol concentrations, barrier or other non-hormonal methods of contraception should be considered with concomitant ritonavir use when dosed 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 (see section 4.4).
Immunosupressants
Cyclosporine, tacrolimus,    Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits everolimus                   CYP3A4 and as a result is expected to increase the plasma concentrations of cyclosporine, tacrolimus or everolimus. Careful monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with ritonavir.

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 Norvir with lomitapide is contraindicated (see prescribing information for lomitapide) (see section 4.3).
Phosphodiesterase (PDE5) inhibitors

Avanafil                      50, single dose                      600 q12h            ↑ 13-fold           ↑ 2.4-fold Concomitant use of avanafil with ritonavir is contraindicated (see section 4.3).
Sildenafil                    100, single dose                     500 q12h            ↑ 11-fold           ↑ 4-fold Concomitant use of sildenafil for the treatment of erectile dysfunction with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer should be with caution and in no instance should sildenafil doses exceed 25 mg in 48 hours (see also section 4.4). Concomitant use of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3).
Tadalafil                     20, single dose                      200 q12h            ↑ 124%              ↔ The concomitant use of tadalafil for the treatment of erectile dysfunction with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer should be with caution at reduced doses of no more than 10 mg tadalafil every 72 hours with increased monitoring for adverse reactions (see section 4.4).

When tadalafil is used concurrently with ritonavir in patients with pulmonary arterial hypertension, refer to the tadalafil prescribing information
Vardenafil                    5, single dose                       600 q12h            ↑ 49-fold           ↑ 13-fold Concomitant use of vardenafil with ritonavir is contraindicated (see section 4.3).
Sedatives/hypnotics
Clorazepate, diazepam,        Ritonavir co-administration is likely to result in increased plasma concentrations of estazolam, flurazepam, oral   clorazepate, diazepam, estazolam and flurazepam and is therefore contraindicated (see and parenteral midazolam      section 4.3).

Midazolam is extensively metabolised by CYP3A4. Co-administration with Norvir may cause a large increase in the concentration of this benzodiazepine. No medicinal product interaction study has been performed for the co-administration of Norvir with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally.
Therefore, Norvir should not be co-administered with orally administered midazolam (see section 4.3), whereas caution should be used with co-administration of Norvir and parenteral midazolam. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3 – 4 fold increase in midazolam plasma levels. If Norvir is co-administered 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                     0.125, single dose                   200, 4 doses        ↑ > 20 fold         ↑ 87% Ritonavir co-administration is likely to result in increased plasma concentrations of triazolam and is therefore contraindicated (see section 4.3).
Pethidine Norpethidine        50, oral single dose                 500 q12h            ↓ 62%               ↓ 59% metabolite                                                                             ↑ 47%               ↑ 87% The use of pethidine and ritonavir is contraindicated due to the increased concentrations of the metabolite, norpethidine, which has both analgesic and CNS stimulant activity. Elevated norpethidine concentrations may increase the risk of CNS effects (e.g., seizures), see section 4.3.
Alprazolam                    1, single dose                       200 q12h, 2 days    ↑2.5 fold           ↔ 500 q12h, 10 days   ↓ 12%               ↓ 16%
Alprazolam metabolism was inhibited following the introduction of ritonavir. After ritonavir use for 10 days, no inhibitory effect of ritonavir was observed. Caution is warranted during the first several days when alprazolam is co-administered with 

ritonavir dosed 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.
Sleeping agent
Zolpidem                   5                                 200, 4 doses           ↑ 28%                ↑ 22% Zolpidem and ritonavir may be co-administered with careful monitoring for excessive sedative effects.
Smoke cessation
Bupropion                  150                               100 q12h               ↓ 22%                ↓ 21% 150                               600 q12h               ↓ 66%                ↓ 62% 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 co-administration.
Steroids
Inhaled, injectable or     Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression intranasal fluticasone     (plasma cortisol levels were noted to be decreased 86% in the above study) have been propionate, budesonide,    reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate; triamcinolone              similar effects could also occur with other corticosteroids metabolised by CYP3A e.g., budesonide and triamcinolone. Consequently, concomitant administration of ritonavir dosed 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 (see section 4.4). 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               20                                200 q12h               ↑ 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.
ND: Not determined
1. Based on a parallel group comparison
2. Sulfamethoxazole was co-administered with trimethoprim.


Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine or nefazodone. The possibility of medicinal product interaction cannot be excluded.

In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of increased therapeutic and toxic effects due to protein binding displacement of concomitant medicinal products should be considered.

Ritonavir dosed as a pharmacokinetic enhancer

Important information regarding medicinal product interactions when ritonavir is used a pharmacokinetic enhancer is also contained in the prescribing information of the co-administered protease inhibitor.

Proton pump inhibitors and H2-receptor antagonists
Proton pump inhibitors and H2-receptor antagonists (e.g. omeprazole or ranitidine) may reduce concentrations for co-administered protease inhibitors. For specific information regarding the impact of co- administration of acid reducing agents, refer to the prescribing information of the co-administered protease inhibitor. Based on interaction studies with the ritonavir boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure (about 6 - 18%).