Leaflet NORVIR 100mg film-coated tablets

Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidationwith the following ranked order: CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinalproducts primarily metabolised by CYP3A may result in increased plasma concentrations of the othermedicinal product, which could increase or prolong its therapeutic and adverse effects. For selectedmedicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease overtime. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. Theinhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decreaseover time (e.g. digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinalproducts” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8,

CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal productsmetabolised by these pathways, and may result in decreased systemic exposure to such medicinalproducts, which could decease or shorten their therapeutic effect.

Important information regarding medicinal product interactions when ritonavir is used as apharmacokinetic enhancer is also contained in the SmPC 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 productmetabolising enzymes by St John’s wort. Herbal preparations containing St John’s wort must not beused in combination with ritonavir. If a patient is already taking St John’s wort, St John’s wort shouldbe 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 aftercessation 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. phenytoinand rifampicin). These interactions are noted in the medicinal product interaction tables below.

Medicinal product that are affected by the use of ritonavir

Interactions between ritonavir and protease inhibitors, antiretroviral agents other than proteaseinhibitors and other non-antiretroviral medicinal products are listed in the tables below. This list is notintended to be inclusive or comprehensive. Individual SmPCs should be consulted.

Medicinal Product Interactions - Ritonavir with Protease Inhibitors

Co-administered Dose of Co- Dose of Medicinal Product AUC Cmin

Medicinal Product administered NORVIR Assessed

Medicinal (mg)

Product(mg)

Atazanavir 300 q24h 100 q24h Atazanavir ↑ 86% ↑ 11 fold

Atazanavir1 ↑ 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 withritonavir 100 mg once daily in treatment experienced patients. For further information,physicians should refer to the SmPC for atazanavir.

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 doseshigher than 100 mg twice daily have not been studied with darunavir. For furtherinformation, refer to the SmPC for darunavir.

Fosamprenavir 700 q12h 100 q12h Amprenavir ↑ 2.4 ↑ 11 foldfold

Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of

CYP3A4 inhibition. Fosamprenavir must be given with ritonavir to ensure its therapeuticeffect. Clinical trials confirmed the safety and efficacy of fosamprenavir 700 mg twicedaily with ritonavir 100 mg twice daily. Ritonavir doses higher than 100 mg twice dailyhave not been studied with fosamprenavir. For further information, physicians should referto the SmPC for fosamprenavir.

Indinavir 800 100 q12h Indinavir2 ↑ 178% NDq12h

Ritonavir ↑ 72% ND

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 beenestablished. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement isachieved with doses higher than 100 mg twice daily. In cases of co-administration ofritonavir (100 mg twice daily) and indinavir (800 mg twice daily) caution is warranted asthe risk of nephrolithiasis may be increased.

Nelfinavir 1250 100 q12h Nelfinavir ↑ NDq12h 20to39%

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 beenestablished. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement isachieved with doses higher than 100 mg twice daily.

Tipranavir 500 200 q12h Tipranavir ↑ 11 fold ↑ 29 foldq12h

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 ofritonavir less than 200 mg twice daily should not be used with tipranavir as they might alterthe efficacy of the combination. For further information, physicians should refer to the

SmPC for tipranavir.

ND: Not determined.

1. Based on cross-study comparison to 400 mg atazanavir once daily alone.

2. Based on cross-study comparison to 800 mg indinavir three times daily alone.

Medicinal product interactions - Ritonavir with antiretroviral agents other than proteaseinhibitors

Co- Dose of Co- Dose of Medicinal Product AUC Cminadministered administered NORVIR (mg) Assessed

Medicinal Medicinal

Product Product(mg)

Maraviroc 100 q12h 100 q12h Maraviroc ↑161% ↑28%

Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition. Maravirocmay be given with ritonavir to increase the maraviroc exposure. For further information, refer tothe SmPC for maraviroc.

Raltegravir 400 single 100 q12h Raltegravir ↓ 16% ↓ 1%

Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir levels

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Alpha1-Adrenoreceptor

Antagonist

Alfuzosin Ritonavir co-administration is likely to result in increased plasma concentrations ofalfuzosin 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 resultis expected to increase concentrations of amphetamine and its derivatives. Carefulmonitoring of therapeutic and adverse effects is recommended when these medicinesare concomitantly administered with antiretroviral doses of ritonavir (see section4.4).

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 notlead to clinically significant pharmacodynamic changes in a population of opioidtolerant patients. Adjustment to the dose of buprenorphine or ritonavir may thereforenot be necessary when the two are dosed together. When ritonavir is used incombination with another protease inhibitor and buprenorphine, the SmPC of theco-administered protease inhibitor should be reviewed for specific dosinginformation.

Pethidine, propoxyphene Ritonavir co-administration is likely to result in increased plasma concentrations ofnorpethidine 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 offentanyl. Careful monitoring of therapeutic and adverse effects (includingrespiratory depression) is recommended when fentanyl is concomitantlyadministered with ritonavir.

Methadone1 5, single dose 500 q12h, ↓ 36% ↓ 38%

Increased methadone dose may be necessary when concomitantly administered withritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer due toinduction of glucuronidation. Dose adjustment should be considered based on thepatient’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 pharmacokineticenhancer.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Antianginal

Ranolazine Due to CYP3A inhibition by ritonavir, concentrations of ranolazine are expected toincrease. The concomitant administration with ranolazine is contraindicated (seesection 4.3).

Antiarrthymics

Amiodarone, bepridil, dronedarone, Ritonavir co-administration is likely to result in increased plasma concentrations ofencainide, flecainide, propafenone, amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, andquinidine quinidine and is therefore contraindicated (see section 4.3).

Digoxin 0.5 single IV dose 300 q12h, 3 days ↑ 86% ND0.4 single oral dose 200 q12h, 13 days ↑ 22% 

This interaction may be due to modification of P-glycoprotein mediated digoxinefflux by ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer.

Increased digoxin levels observed in patients receiving ritonavir may lessen overtime as induction develops (see section 4.4).

Antiasthmatic

Theophylline1 3 mg/kg q8h 500 q12h ↓ 43% ↓ 32%

An increased dose of theophylline may be required when co-administered withritonavir, due to induction of CYP1A2.

Anticancer agents and kinaseinhibitors

Afatinib 20 mg, single dose 200 q12h/1h ↑ 48% ↑ 39%40 mg, single dose before40 mg, single dose 200 q12h/ co- ↑ 19% ↑ 4%administered200 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 exercisedin administering afatinib with ritonavir (refer to the afatinib SmPC). Monitor for

ADRs related to afatinib.

Abemaciclib Serum concentrations may be increased due to CYP3A4 inhibition by ritonavir.

Co-administration of abemaciclib and ritonavir should be avoided. If thisco-administration is judged unavoidable, refer to the abemaciclib SmPC for dosageadjustment recommendations. Monitor for ADRs related to abemaciclib.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Apalutamide Apalutamide is a moderate to strong CYP3A4 inducer and this may lead to adecreased exposure of ritonavir and potential loss of virologic response. In addition,serum concentrations may be increased when co-administered with ritonavirresulting 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 byritonavir. Caution should be exercised in administering ceritinib with ritonavir.

Refer to the ceritinib SmPC for dosage adjustment recommendations. Monitor for

ADRs related to ceritinib.

Dasatinib, nilotinib, vincristine, Serum concentrations may be increased when co-administered with ritonavirvinblastine resulting in the potential for increased incidence of adverse events.

Encorafenib Serum concentrations may be increased when co-administered with ritonavir whichmay increase the risk of toxicity, including the risk of serious adverse events such as

QT interval prolongation. Co-administration of encorafenib and ritonavir should beavoided. 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 fostamatinibmetabolite R406 exposure resulting in dose-related adverse events such ashepatotoxicity, 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 byritonavir, resulting in increased risk for toxicity including risk of tumor lysissyndrome. Co-administration of ibrutinib and ritonavir should be avoided. If thebenefit is considered to outweigh the risk and ritonavir must be used, reduce theibrutinib 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 ritonavir is contraindicated due to serious and/orlife-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 duringthe ramp-up phase (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 doseof venetoclax, reduce the venetoclax dose by at least 75% when used with strong

CYP3A inhibitors (refer to the venetoclax SmPC for dosing instructions).

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Anticoagulants

Dabigatran etexilate Serum concentrations may be increased due to P-gp inhibition by ritonavir. Clinical

Edoxaban monitoring and/or dose reduction of the direct oral anticoagulants (DOAC) shouldbe 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 andpharmacodynamic effects of rivaroxaban which may lead to an increased bleedingrisk. Therefore, the use of ritonavir is not recommended in patients receivingrivaroxaban.

Vorapaxar Serum concentrations may be increased due to CYP3A inhibition by ritonavir. Theco-administration of vorapaxar with ritonavir is not recommended (see section 4.4and refer to the vorapaxar SmPC).

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 whilelittle pharmacokinetic effect is noted on S- warfarin when co-administered withritonavir. Decreased R-warfarin levels may lead to reduced anticoagulation,therefore it is recommended that anticoagulation parameters are monitored whenwarfarin is co-administered with ritonavir dosed as an antiretroviral agent or as apharmacokinetic 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 ofcarbamazepine. Careful monitoring of therapeutic and adverse effects isrecommended when carbamazepine is concomitantly administered with ritonavir.

Divalproex, lamotrigine, phenytoin Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inducesoxidation by CYP2C9 and glucuronidation and as a result is expected to decreasethe plasma concentrations of anticonvulsants. Careful monitoring of serum levels ortherapeutic effects is recommended when these medicines are concomitantlyadministered with ritonavir. Phenytoin may decrease serum levels of ritonavir.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Antidepressants

Amitriptyline, fluoxetine, imipramine, Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a resultnortriptyline, paroxetine, sertraline is expected to increase concentrations of imipramine, amitriptyline, nortriptyline,fluoxetine, paroxetine or sertraline. Careful monitoring of therapeutic and adverseeffects is recommended when these medicines are concomitantly administered withantiretroviral doses of ritonavir (see section 4.4).

Desipramine 100, single oral dose 500 q12h ↑ 145% ↑ 22%

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 whenco-administered with ritonavir dosed as an antiretroviral agent or as apharmacokinetic enhancer. If trazodone is co-administered with ritonavir, thecombination should be used with caution, initiating trazodone at the lowest dosageand monitoring for clinical response and tolerability.

Anti-gout treatments

Colchicine Concentrations of colchicine are expected to increase when co-administered withritonavir.

Life-threatening and fatal drug interactions have been reported in patients treatedwith colchicine and ritonavir (CYP3A4 and P-gp inhibition) in patients with renaland/or hepatic impairment (see sections 4.3 and 4.4). Refer to the colchicine SmPC.

Antihistamines

Astemizole, terfenadine Ritonavir co-administration is likely to result in increased plasma concentrations ofastemizole and terfenadine and is therefore contraindicated (see section 4.3).

Fexofenadine Ritonavir may modify P-glycoprotein mediated fexofenadine efflux when dosed asan antriretroviral agent or as a pharmacokinetic enhancer resulting in increasedconcentrations of fexofenadine. Increased fexofenadine levels may lessen over timeas 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 ofloratadine. Careful monitoring of therapeutic and adverse effects is recommendedwhen loratidine is concomitantly administered with ritonavir.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Anti-infectives

Fusidic Acid Ritonavir co-administration is likely to result in increased plasma concentrations ofboth fusidic acid and ritonavir and is therefore contraindicated (see section 4.3).

Rifabutin1 150 daily 500 q12h ↑ 4-fold ↑ 2.5-fold25-O-desacetyl rifabutin metabolite ↑ 38-fold ↑ 16-fold

The reduction of the rifabutin dose to 150 mg 3 times per week may be indicated forselect PIs when co-administered with ritonavir as a pharmacokinetic enhancer. The

SmPC of the co-administered protease inhibitor should be consulted for specificrecommendations. Consideration should be given to official guidance on theappropriate treatment of tuberculosis in HIV-infected patients.

Rifampicin Although rifampicin may induce metabolism of ritonavir, limited data indicate thatwhen high doses of ritonavir (600 mg twice daily) is co-administered withrifampicin, the additional inducing effect of rifampicin (next to that of ritonaviritself) 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.

Voriconazole200 q12h 100 q12h ↓ 39% ↓ 24%

Co-administration of voriconazole and ritonavir dosed as a pharmacokineticenhancer should be avoided, unless an assessment of the benefit/risk to the patientjustifies the use of voriconazole.

Atovaquone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inducesglucuronidation and as a result is expected to decrease the plasma concentrations ofatovaquone. Careful monitoring of serum levels or therapeutic effects isrecommended when atovaquone is concomitantly administered with ritonavir.

Bedaquiline No interaction study is available with ritonavir only. In an interaction study ofsingle-dose bedaquiline and multiple dose lopinavir/ritonavir, the AUC ofbedaquiline was increased by 22%. This increase is likely due to ritonavir and amore pronounced effect may be observed during prolonged co-administration. Dueto the risk of bedaquiline related adverse events, co-administration should beavoided. If the benefit outweighs the risk, co-administration of bedaquiline withritonavir must be done with caution. More frequent electrocardiogram monitoringand monitoring of transaminases is recommended (see section 4.4 and refer to thebedaquiline SmPC).

Clarithromycin 500 q12h 200 q8h ↑ 77% ↑ 31%14-OH clarithromycin metabolite ↓ 100% ↓ 99%

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Due to the large therapeutic window of clarithromycin no dose reduction should benecessary in patients with normal renal function. Clarithromycin doses greater than1 g per day should not be co-administered with ritonavir dosed as an antiretroviralagent or as a pharmacokinetic enhancer. For patients with renal impairment, aclarithromycin dose reduction should be considered: for patients with creatinineclearance of 30 to 60 ml/min the dose should be reduced by 50%, for patients withcreatinine 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 druginteraction study of delamanid 100 mg twice daily and lopinavir/ritonavir400/100 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 isrecommended (see section 4.4 and refer to the delamanid SmPC).

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 oferythromycin and itraconazole. Careful monitoring of therapeutic and adverseeffects is recommended when erythromycin or itraconazole is used concomitantlyadministered with ritonavir.

Ketoconazole 200 daily 500 q12h ↑ 3.4-fold ↑ 55%

Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole. Due to anincreased incidence of gastrointestinal and hepatic adverse reactions, a dosereduction of ketoconazole should be considered when co-administered with ritonavirdosed as an antiretroviral agent or as a pharmacokinetic enhancer.

Sulfamethoxazole/Trimethoprim2 800/160, single dose 500 q12h ↓ 20%/↑ 20% ↔

Dose alteration of sulfamethoxazole/trimethoprim during concomitant ritonavirtherapy should not be necessary.

Antipsychotics/Neuroleptics

Clozapine, pimozide Ritonavir co-administration is likely to result in increased plasma concentrations ofclozapine or pimozide and is therefore contraindicated (see section 4.3).

Haloperidol, risperidone, thioridazine Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 and as a resultis expected to increase concentrations of haloperidol, risperidone and thioridazine.

Careful monitoring of therapeutic and adverse effects is recommended when thesemedicines are concomitantly administered with antiretroviral doses of ritonavir.

Lurasidone Due to CYP3A inhibition by ritonavir, concentrations of lurasidone are expected toincrease. The concomitant administration with lurasidone is contraindicated (seesection 4.3).

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Quetiapine Due to CYP3A inhibition by ritonavir, concentrations of quetiapine are expected toincrease. Concomitant administration of ritonavir and quetiapine is contraindicatedas 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 plasmaconcentrations of salmeterol is expected. Therefore concomitant use is notrecommended.

Calcium channel antagonists

Amlodipine, diltiazem, nifedipine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A4 and as a result is expected to increase the plasma concentrations ofcalcium channel antagonists. Careful monitoring of therapeutic and adverse effectsis recommended when these medicines are concomitantly administered withritonavir.

Endothelin antagonists

Co-administration of bosentan and ritonavir may increase steady state

Bosentanbosentan maximum concentrations (Cmax) and area under the curve (AUC)

Serum concentrations may be increased due to CYP3A and P-gp inhibition by

Riociguatritonavir. The co-administration of riociguat with ritonavir is not recommended (seesection 4.4 and refer to riociguat SmPC).

Ergot Derivatives

Dihydroergotamine, ergonovine, Ritonavir co-administration is likely to result in increased plasma concentrations ofergotamine, methylergonovine ergot derivatives and is therefore contraindicated (see section 4.3).

GI motility agent

Cisapride Ritonavir co-administration is likely to result in increased plasma concentrations ofcisapride 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 OATP1Binhibition by ritonavir.

Concomitant administration of glecaprevir/pibrentasvir and ritonavir is notrecommended due to an increased risk of ALT elevations associated with increasedglecaprevir exposure.

HCV Protease Inhibitor

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Simeprevir 200 qd 100 q12h ↑ 7.2-fold ↑ 4.7-fold

Ritonavir increases plasma concentrations of simeprevir as a result of CYP3A4inhibition. It is not recommended to co-administer ritonavir with simeprevir.

HMG Co-A Reductase

Atorvastatin, Fluvastatin, Lovastatin, HMG-CoA reductase inhibitors which are highly dependent on CYP3A metabolism,

Pravastatin, Rosuvastatin, Simvastatin such as lovastatin and simvastatin, are expected to have markedly increased plasmaconcentrations when co-administered with ritonavir dosed as an antiretroviral agentor as a pharmacokinetic enhancer. Since increased concentrations of lovastatin andsimvastatin may predispose patients to myopathies, including rhabdomyolysis, thecombination of these medicinal products with ritonavir is contraindicated (seesection 4.3). Atorvastatin is less dependent on CYP3A for metabolism. Whilerosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatinexposure has been reported with ritonavir co-administration. The mechanism of thisinteraction is not clear, but may be the result of transporter inhibition. When usedwith ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent, thelowest possible doses of atorvastatin or rosuvastatin should be administered. Themetabolism of pravastatin and fluvastatin is not dependent on CYP3A, andinteractions are not expected with ritonavir. If treatment with an HMG-CoAreductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

Hormonal contraceptive

Ethinyl oestradiol 50 µg, single dose 500 q12h ↓ 40% ↓ 32%

Due to reductions in ethinyl oestradiol concentrations, barrier or other non-hormonalmethods of contraception should be considered with concomitant ritonavir use whendosed as an antiretroviral agent or as a pharmacokinetic enhancer. Ritonavir is likelyto change the uterine bleeding profile and reduce the effectiveness of oestradiol-containing contraceptives (see section 4.4).

Immunosupressants

Cyclosporine, tacrolimus, everolimus Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent inhibits

CYP3A4 and as a result is expected to increase the plasma concentrations ofcyclosporine, tacrolimus or everolimus. Careful monitoring of therapeutic andadverse effects is recommended when these medicines are concomitantlyadministered with ritonavir.

Lipid-modifying agents

Lomitapide CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitorsincreasing exposure approximately 27-fold. Due to CYP3A inhibition by ritonavir,concentrations of lomitapide are expected to increase. Concomitant use of ritonavirwith lomitapide is contraindicated (see the SmPC for lomitapide) (see section 4.3).

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

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 ritonavirdosed as an antiretroviral agent or as a pharmacokinetic enhancer should be usedwith 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 iscontraindicated 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 withritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer should bewith caution at reduced doses of no more than 10 mg tadalafil every 72 hours withincreased monitoring for adverse reactions (see section 4.4).

When tadalafil is used concurrently with ritonavir in patients withpulmonary arterial hypertension, refer to the tadalafil SmPC.

Vardenafil 5, single dose 600 q12h ↑ 49-fold ↑ 13-fold

Concomitant use of vardenafil with ritonavir is contraindicated (see section 4.3).

Sedatives/hynoptics

Clorazepate, diazepam, estazolam, Ritonavir co-administration is likely to result in increased plasma concentrations offlurazepam, oral and parenteral clorazepate, diazepam, estazolam and flurazepam and is therefore contraindicatedmidazolam (see section 4.3).

Midazolam is extensively metabolised by CYP3A4. Co-administration withritonavir may cause a large increase in the concentration of this benzodiazepine. Nomedicinal product interaction study has been performed for the co-administration ofritonavir with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasmaconcentrations of midazolam are expected to be significantly higher whenmidazolam is given orally. Therefore, ritonavir should not be co-administered withorally administered midazolam (see section 4.3), whereas caution should be usedwith co-administration of ritonavir and parenteral midazolam. Data fromconcomitant use of parenteral midazolam with other protease inhibitors suggest apossible 3 - 4 fold increase in midazolam plasma levels. If ritonavir isco-administered with parenteral midazolam, it should be done in an intensive careunit (ICU) or similar setting which ensures close clinical monitoring and appropriatemedical management in case of respiratory depression and/or prolonged sedation.

Dosage adjustment for midazolam should be considered, especially if more than asingle dose of midazolam is administered.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Triazolam 0.125, single dose 200, 4 doses ↑ > 20 fold ↑ 87%

Ritonavir co-administration is likely to result in increased plasma concentrations oftriazolam and is therefore contraindicated (see section 4.3).

Pethidine 50, oral single dose 500 q12h ↓ 62% ↓ 59%

Norpethidine metabolite ↑ 47% ↑ 87%

The use of pethidine and ritonavir is contraindicated due to the increasedconcentrations of the metabolite, norpethidine, which has both analgesic and CNSstimulant 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 ↓ 12% ↓ 16%days

Alprazolam metabolism was inhibited following the introduction of ritonavir. Afterritonavir use for 10 days, no inhibitory effect of ritonavir was observed. Caution iswarranted during the first several days when alprazolam is co-administered withritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer, beforeinduction 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 ofbuspirone. Careful monitoring of therapeutic and adverse effects is recommendedwhen buspirone concomitantly administered with ritonavir.

Sleeping agent

Zolpidem 5 200, 4 doses ↑ 28% ↑ 22%

Zolpidem and ritonavir may be co-administered with careful monitoring forexcessive sedative effects.

Smoke cessation

Bupropion 150 100 q12h ↓ 22% ↓ 21%150 600 q12h ↓ 66% ↓ 62%

Bupropion is primarily metabolised by CYP2B6. Concurrent administration ofbupropion 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, therecommended dose of bupropion should not be exceeded. In contrast to long-termadministration of ritonavir, there was no significant interaction with bupropion aftershort-term administration of low doses of ritonavir (200 mg twice daily for 2 days),suggesting reductions in bupropion concentrations may have onset several days afterinitiation of ritonavir co-administration.

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products

Co-administered Medicinal Products Dose of Co- Dose of Effect on Co- Effect on Co-administered NORVIR (mg) administered administered

Medicinal Products Medicinal Medicinal Products(mg) Products Cmax

AUC

Steroids

Inhaled, injectable or intranasal Systemic corticosteroid effects including Cushing's syndrome and adrenalfluticasone propionate, budesonide, suppression (plasma cortisol levels were noted to be decreased 86% in the abovetriamcinolone study) have been reported in patients receiving ritonavir and inhaled or intranasalfluticasone propionate; similar effects could also occur with other corticosteroidsmetabolised by CYP3A e.g., budesonide and triamcinolone. Consequently,concomitant administration of ritonavir dosed as an antiretroviral agent or as apharmacokinetic enhancer and these glucocorticoids is not recommended unless thepotential benefit of treatment outweighs the risk of systemic corticosteroid effects(see section 4.4). A dose reduction of the glucocorticoid should be considered withclose monitoring of local and systemic effects or a switch to a glucocorticoid, whichis not a substrate for CYP3A4 (e.g., beclomethasone). Moreover, in case ofwithdrawal of glucocorticoids progressive dose reduction may be required over alonger 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 ofdexamethasone. Careful monitoring of therapeutic and adverse effects isrecommended when dexamethasone is concomitantly administered with ritonavir.

Prednisolone 20 200 q12h ↑ 28% ↑ 9%

Careful monitoring of therapeutic and adverse effects is recommended whenprednisolone is concomitantly administered with ritonavir. The AUC of themetabolite prednisolone increased by 37 and 28% after 4 and 14 days ritonavir,respectively.

Thyroid hormone replacementtherapy

Levothyroxine Post-marketing cases have been reported indicating a potential interaction betweenritonavir containing products and levothyroxine. Thyroid-stimulating hormone(TSH) should be monitored in patients treated with levothyroxine at least the firstmonth after starting and/or ending ritonavir treatment.

ND: Not determined1. Based on a parallel group comparison2. Sulfamethoxazole was co-administered with trimethoprim.

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

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

Important information regarding medicinal product interactions when ritonavir is used apharmacokinetic enhancer is also contained in the SmPC 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 reduceconcentrations for co-administered protease inhibitors. For specific information regarding the impactof co-administration of acid reducing agents, refer to the SmPC of the co-administered proteaseinhibitor. Based on interaction studies with the ritonavir boosted protease inhibitors(lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does notsignificantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change ofexposure (about 6 - 18%).