Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer) Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of these compounds and consequently that of darunavir, leading to loss of therapeutic effect and possible development of resistance (see sections 4.3 and 4.4). CYP3A inducers that are contraindicated include rifampicin, St John’s wort and lopinavir.
Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and ritonavir, which may result in increased plasma concentrations of darunavir and ritonavir. Co-administration with strong CYP3A4 inhibitors is not recommended and caution is warranted, these interactions are described in the interaction table below (e.g. indinavir, azole antifungals like clotrimazole).
Medicinal products that may be affected by darunavir boosted with ritonavir Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ ritonavir with medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased systemic exposure to such medicinal products, which could increase or 
prolong their therapeutic effect and adverse reactions.
Co-administration of boosted darunavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see the Interaction table below).
Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) (see section 4.3).
The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily. Therefore, darunavir must only be used in combination with pharmacokinetic enhancer (see sections 4.4 and 5.2).
A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19 and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir with medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.
Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin, statins and bosentan; see the Interaction table below).
Interaction table
Interaction studies have only been performed in adults.
Several of the interaction studies (indicated by # in the table below) have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The effects on co-administered medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.
Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products are listed in the table below. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range (not determined as "ND").
In the table below the specific pharmacokinetic enhancer is specified when recommendations differ.
When the recommendation is the same for Darunavir Teva when co-administered with a low dose ritonavir, the term “boosted Darunavir Teva” is used.
The below list of examples of drug drug interactions is not comprehensive and therefore the label of each drug that is co-administered with Darunavir Teva should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co- administration.




INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL PRODUCTS

Medicinal products by Interaction                                       Recommendations concerning co- therapeutic areas     Geometric mean change (%)                         administration 
HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors
Dolutegravir              dolutegravir AUC ↓ 22%                        Boosted Darunavir Teva and dolutegravir dolutegravir C24h ↓ 38%                       can be used without dose adjustment.
dolutegravir Cmax ↓11% darunavir ↔*
* Using cross-study comparisons to historical pharmacokinetic data
Raltegravir               Some clinical studies suggest raltegravir     At present the effect of raltegravir on may cause a modest decrease in darunavir      darunavir plasma concentrations does not plasma concentrations.                        appear to be clinically relevant. Boosted Darunavir Teva and raltegravir can be used without dose adjustments.
Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)

Didanosine                didanosine AUC ↓ 9%                           Boosted Darunavir Teva and didanosine can 400 mg once daily         didanosine Cmin ND                            be used without dose adjustments.
didanosine Cmax ↓ 16%                         Didanosine is to be administered on an darunavir AUC ↔                               empty stomach, thus it should be administered 1 hour before or 2 hours after darunavir Cmin ↔ boosted Darunavir Teva given with food.
darunavir Cmax ↔

Tenofovir disoproxil      tenofovir AUC ↑ 22%                           Monitoring of renal function may be 245 mg once daily ‡       tenofovir Cmin ↑ 37%                          indicated when boosted Darunavir Teva is tenofovir Cmax ↑ 24%                          given in combination with tenofovir #                                             disoproxil, particularly in patients with darunavir AUC ↑ 21%
# underlying systemic or renal disease, or in darunavir Cmin ↑ 24%                        patients taking nephrotoxic agents.
# darunavir Cmax ↑ 16%
(↑ tenofovir from effect on MDR -1            Darunavir Teva co-administered with transport in the renal tubules)               cobicistat lowers the creatinine clearance.
Refer to section 4.4 if creatinine clearance is used for dose adjustment of tenofovir disoproxil.

Emtricitabine/tenofovir   Tenofovir alafenamide ↔                       The recommended dose of emtricitabine/ alafenamide                                                             tenofovir alafenamide is 200/10 mg once Tenofovir ↑                                   daily when used with boosted Darunavir Teva.

Abacavir                  Not studied. Based on the different           Boosted Darunavir Teva can be used with Emtricitabine             elimination pathways of the other NRTIs       these NRTIs without dose adjustment.
Lamivudine                zidovudine, emtricitabine, stavudine,
Stavudine                 lamivudine, that are primarily renally
Zidovudine                excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and boosted Darunavir Teva.



Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz                efavirenz AUC ↑ 21%                               Clinical monitoring for central nervous 600 mg once daily        efavirenz Cmin ↑ 17%                              system toxicity associated with increased exposure to efavirenz may be indicated when efavirenz Cmax ↑ 15%
#
Darunavir Teva co-administered with low darunavir AUC ↓ 13%                             dose ritonavir is given in combination with # darunavir Cmin ↓ 31%                            efavirenz.
# darunavir Cmax ↓ 15%                            Efavirenz in combination with Darunavir (↑ efavirenz from CYP3A inhibition)               Teva /ritonavir 800/100 mg once daily may (↓ darunavir from CYP3A induction)                result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with
Darunavir Teva /ritonavir, the Darunavir
Teva /ritonavir 600/100 mg twice daily regimen should be used (see section 4.4).
Co-administration with Darunavir Teva co-administered with cobicistat is not recommended (see section 4.4).

Etravirine               etravirine AUC ↓ 37%                              Darunavir Teva co-administered with low 100 mg twice daily       etravirine Cmin ↓ 49%                             dose ritonavir and etravirine 200 mg twice etravirine Cmax ↓ 32%                             daily can be used without dose adjustments.
darunavir AUC ↑ 15% darunavir Cmin ↔ darunavir Cmax ↔
Nevirapine               nevirapine AUC ↑ 27%                              Darunavir Teva co-administered with low 200 mg twice daily       nevirapine Cmin ↑ 47%                             dose ritonavir and nevirapine can be used nevirapine Cmax ↑ 18%                             without dose adjustments.
# darunavir: concentrations were consistent with historical data
(↑ nevirapine from CYP3A inhibition)
Rilpivirine              rilpivirine AUC ↑ 130%                            Boosted Darunavir Teva and rilpivirine can 150 mg once daily        rilpivirine Cmin ↑ 178%                           be used without dose adjustments.
rilpivirine Cmax ↑ 79% darunavir AUC ↔ darunavir Cmin ↓ 11% darunavir Cmax ↔

HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir† Atazanavir               atazanavir AUC ↔                                  Darunavir Teva co-administered with low 300 mg once daily        atazanavir Cmin ↑ 52%                             dose ritonavir and atazanavir can be used atazanavir Cmax ↓ 11%                             without dose adjustments.
# darunavir AUC ↔
# darunavir Cmin ↔
# darunavir Cmax ↔
Atazanavir: comparison of atazanavir/ritonavir
300/100 mg once daily vs. atazanavir 300 mg once daily in combination with darunavir/ritonavir 400/100 mg twice daily.
Darunavir: comparison of darunavir/ ritonavir 400/100 mg twice daily vs.
darunavir/ritonavir 400/100 mg twice daily in combination with atazanavir 300 mg once daily.


Indinavir                indinavir AUC ↑ 23%                               When used in combination with Darunavir 800 mg twice daily       indinavir Cmin ↑ 125%                             Teva co-administered with low dose indinavir Cmax ↔                                  ritonavir, dose adjustment of indinavir from #                                                 800 mg twice daily to 600 mg twice daily darunavir AUC ↑ 24%
# may be warranted in case of intolerance.
darunavir Cmin ↑ 44%
# darunavir Cmax ↑ 11%
Indinavir: comparison of indinavir/ritonavir
800/100 mg twice daily vs.
indinavir/darunavir/ritonavir    800/400/100 mg twice daily.
Darunavir: comparison of darunavir/ritonavir
400/100 mg twice daily vs. darunavir/ ritonavir
400/100 mg in combination with indinavir 800 mg twice daily.

Saquinavir               #                                                 It is not recommended to combine Darunavir darunavir AUC ↓ 26%
1,000 mg twice daily     # darunavir Cmin ↓ 42%                            Teva co-administered with low dose #                                                 ritonavir with saquinavir.
darunavir Cmax ↓ 17% saquinavir AUC ↓ 6% saquinavir Cmin ↓ 18% saquinavir Cmax ↓ 6%
Saquinavir: comparison of saquinavir/ritonavir
1,000/100 mg twice daily vs.
saquinavir/darunavir/ritonavir 1,000/400/100 mg twice daily
Darunavir: comparison of darunavir/ritonavir
400/100 mg twice daily vs. darunavir/ ritonavir
400/100 mg in combination with saquinavir
1,000 mg twice daily.

HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir† Lopinavir/ritonavir      lopinavir AUC ↑ 9%                                Due to a decrease in the exposure (AUC) of 400/100 mg twice daily   lopinavir Cmin ↑ 23%                              darunavir by 40%, appropriate doses of the lopinavir Cmax ↓ 2%                               combination have not been established.
Hence, concomitant use of boosted darunavir AUC ↓ 38%‡
Darunavir Teva and the combination product darunavir Cmin ↓ 51%‡                             lopinavir/ritonavir is contraindicated (see darunavir Cmax ↓ 21%‡                             section 4.3).
Lopinavir/ritonavir      lopinavir AUC ↔
533/133.3 mg twice daily lopinavir Cmin ↑ 13% lopinavir Cmax ↑ 11% darunavir AUC ↓ 41% darunavir Cmin ↓ 55% darunavir Cmax ↓ 21%
‡ based upon non dose normalised values

CCR5 ANTAGONIST

Maraviroc                maraviroc AUC ↑ 305%                              The maraviroc dose should be 150 mg twice 150 mg twice daily       maraviroc Cmin ND                                 daily when co-administered with boosted maraviroc Cmax ↑ 129%                             Darunavir Teva.
darunavir, ritonavir concentrations were consistent with historical data



α1 -ADRENORECEPTOR ANTAGONIST

Alfuzosin               Based on theoretical considerations Darunavir Co-administration of boosted Darunavir Teva is expected to increase alfuzosin plasma Teva and alfuzosin is contraindicated (see concentrations. (CYP3A inhibition)            section 4.3).
ANAESTHETIC

Alfentanil              Not studied. The metabolism of alfentanil is   The concomitant use with boosted Darunavir mediated via CYP3A, and may as such be         Teva may require to lower the dose of inhibited by boosted Darunavir Teva.           alfentanil and requires monitoring for risks of prolonged or delayed respiratory depression.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide            Not studied. Boosted Darunavir Teva is         Caution is warranted and therapeutic Flecainide              expected to increase these antiarrhythmic      concentration monitoring, if available, is Lidocaine (systemic)    plasma concentrations.                         recommended for these antiarrhythmics Mexiletine              (CYP3A and/or CYP2D6 inhibition)               when co-administered with boosted Propafenone                                                            Darunavir Teva.

Amiodarone                                                             Co-administration of boosted Darunavir Bepridil                                                               Teva and amiodarone, bepridil, dronedarone, Dronedarone                                                            ivabradine, quinidine, or ranolazine is Ivabradine                                                             contraindicated (see section 4.3).
Quinidine
Ranolazine

Digoxin                 digoxin AUC ↑ 61%                              Given that digoxin has a narrow therapeutic 0.4 mg single dose      digoxin Cmin ND                                index, it is recommended that the lowest digoxin Cmax ↑ 29%                             possible dose of digoxin should initially be (↑ digoxin from probable inhibition of P-gp)   prescribed in case digoxin is given to patients on boosted Darunavir Teva therapy.
The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.

ANTIBIOTIC

Clarithromycin          clarithromycin AUC ↑ 57%                       Caution should be exercised when 500 mg twice daily      clarithromycin Cmin ↑ 174%                     clarithromycin is combined with boosted Darunavir Teva.
clarithromycin Cmax ↑ 26%
# darunavir AUC ↓ 13%                        For patients with renal impairment the #                                              Summary of Product Characteristics for darunavir Cmin ↑ 1%                        clarithromycin should be consulted for the # darunavir Cmax ↓ 17%                          recommended dose.
14-OH-clarithromycin concentrations were not detectable when combined with
Darunavir Teva/ritonavir.
(↑ clarithromycin from CYP3A inhibition and possible P-gp inhibition)
ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR

Apixaban                Not studied. Co-administration of boosted     The use of boosted Darunavir Teva and Edoxaban                Darunavir Teva with these anticoagulants may these anticoagulants is not recommended.
Rivaroxaban             increase concentrations of the anticoagulant, which may lead to an increased bleeding risk.
(CYP3A and/or P-gp inhibition).


Dabigatran              Not studied. Co-administration with boosted     Concomitant administration of boosted Ticagrelor              Darunavir Teva may lead to a substantial        Darunavir Teva with dabigatran or ticagrelor increase in exposure to dabigatran or           is contraindicated (see section 4.3).
ticagrelor.
Clopidogrel             Not studied. Co-administration of clopidogrel Co-administration of clopidogrel with with boosted Darunavir Teva is expected to    boosted Darunavir Teva is not decrease clopidogrel active metabolite plasma recommended.
concentration, which may reduce the antiplatelet activity of clopidogrel.
Use of other antiplatelets not affected by
CYP inhibition or induction (e.g. prasugrel) is recommended.
Warfarin                Not studied. Warfarin concentrations may be It is recommended that the international affected when co-administered with boosted    normalised ratio (INR) be monitored when Darunavir Teva.                               warfarin is combined with boosted Darunavir Teva.
ANTICONVULSANTS

Phenobarbital           Not studied. Phenobarbital and phenytoin are    Darunavir Teva co-administered with low Phenytoin               expected to decrease plasma concentrations of   dose ritonavir should not be used in darunavir and its pharmacoenhancer.             combination with these medicines.
(induction of CYP450 enzymes)
Carbamazepine           carbamazepine AUC ↑ 45%                         No dose adjustment for Darunavir 200 mg twice daily      carbamazepine Cmin ↑ 54%                        Teva/ritonavir is recommended.
carbamazepine Cmax ↑ 43%                        If there is a need to combine Darunavir darunavir AUC ↔                                 Teva/ritonavir and carbamazepine, patients should be monitored for potential darunavir Cmin ↓ 15% carbamazepine-related adverse events.
darunavir Cmax ↔                                Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings,
the carbamazepine dose may need to be reduced by 25% to 50% in the presence of
Darunavir Teva/ritonavir.
Clonazepam              Not studied. Co-administration of boosted   Clinical monitoring is recommended when Darunavir Teva with clonazepam may increase co-administering boosted Darunavir Teva concentrations of clonazepam. (CYP3A        and clonazepam.
inhibition)
ANTIDEPRESSANTS

Paroxetine              paroxetine AUC ↓ 39%                            If antidepressants are co-administered with 20 mg once daily        paroxetine Cmin ↓ 37%                           boosted Darunavir Teva, the recommended approach is a dose titration of the paroxetine Cmax ↓ 36%                           antidepressant based on a clinical assessment #darunavir AUC ↔                                of antidepressant response. In addition, #darunavir Cmin ↔                               patients on a stable dose of these antidepressants who start treatment with
#darunavir Cmax ↔                               boosted Darunavir Teva should be monitored Sertraline              sertraline AUC ↓ 49%                            for antidepressant response.
50 mg once daily sertraline Cmin ↓ 49% sertraline Cmax ↓ 44%
#darunavir AUC ↔
#darunavir Cmin ↓ 6%
#darunavir Cmax ↔
Amitriptyline           Concomitant use of boosted Darunavir Teva       Clinical monitoring is recommended when Desipramine             and these antidepressants may increase          co-administering boosted Darunavir Teva Imipramine              concentrations of the antidepressant.           with these antidepressants and a dose Nortriptyline           (CYP2D6 and/or CYP3A inhibition).               adjustment of the antidepressant may be Trazodone                                                               needed.

ANTI-DIABETICS

Metformin               Not studied. Based on theoretical               Careful patient monitoring and considerations Darunavir Teva                   dose adjustment of metformin is co-administered with cobicistat is              recommended in patients who are expected to increase metformin plasma           taking Darunavir Teva co-administered with concentrations.                                 cobicistat.
(MATE1 inhibition)                              (not applicable for Darunavir Teva co- administered with ritonavir)

ANTIEMETICS

Domperidone             Not studied.                                    Co-administration of domperidone with boosted Darunavir Teva is contraindicated.

ANTIFUNGALS

Voriconazole            Not studied. Ritonavir may decrease plasma      Voriconazole should not be combined with concentrations of voriconazole.                 boosted Darunavir Teva unless an (induction of CYP450 enzymes)                   assessment of the benefit/risk ratio justifies the use of voriconazole.
Fluconazole             Not studied. Boosted Darunavir Teva may         Caution is warranted and clinical monitoring Isavuconazole           increase antifungal plasma concentrations and   is recommended. When co-administration is Itraconazole            posaconazole, isavuconazole, itraconazole, or   required the daily dose of itraconazole fluconazole may increase darunavir              should not exceed 200 mg.
Posaconazole concentrations.
(CYP3A and/or P-gp inhibition)
Clotrimazole            Not studied. Concomitant systemic use of clotrimazole and boosted Darunavir Teva may increase plasma concentrations of darunavir and/or clotrimazole.
darunavir AUC24h ↑ 33% (based on population pharmacokinetic model)
ANTIGOUT MEDICINES
Colchicine              Not studied. Concomitant use of colchicine      A reduction in colchicine dosage or an and boosted Darunavir Teva may increase the     interruption of colchicine treatment is exposure to colchicine.                         recommended in patients with normal renal (CYP3A and/ or P-gp inhibition)                 or hepatic function if treatment with boosted Darunavir Teva is required. For patients with renal or hepatic impairment colchicine with boosted Darunavir Teva is contraindicated
(see sections 4.3 and 4.4).

ANTIMALARIALS

Artemether/             artemether AUC ↓ 16%                            The combination of boosted Darunavir Teva Lumefantrine            artemether Cmin ↔                               and artemether/lumefantrine can be used 80/480 mg, 6 doses at                                                   without dose adjustments; however, due to artemether Cmax ↓ 18%
0, 8, 24, 36, 48, and                                                   the increase in lumefantrine exposure, the 60 hours                dihydroartemisinin AUC ↓ 18%                    combination should be used with caution.
dihydroartemisinin Cmin ↔ dihydroartemisinin Cmax ↓ 18% lumefantrine AUC ↑ 175% lumefantrine Cmin ↑ 126% lumefantrine Cmax ↑ 65% darunavir AUC ↔ darunavir Cmin ↓ 13% darunavir Cmax ↔


ANTIMYCOBACTERIALS

Rifampicin               Not studied. Rifapentine and rifampicin are         The combination of rifapentine and boosted Rifapentine              strong CYP3A inducers and have been shown           Darunavir Teva is not recommended.
to cause profound decreases in concentrations
The combination of rifampicin and boosted of other protease inhibitors, which can result in
Darunavir Teva is contraindicated (see virological failure and resistance development section 4.3).
(CYP450 enzyme induction). During attempts to overcome the decreased exposure by increasing the dose of other protease inhibitors with low dose ritonavir, a high frequency of liver reactions was seen with rifampicin.

Rifabutin               rifabutin AUC** ↑ 55%                             A dosage reduction of rifabutin by 75% of 150 mg once every other rifabutin Cmin** ↑ ND                             the usual dose of 300 mg/day (i.e. rifabutin day                     rifabutin Cmax** ↔                                150 mg once every other day) and increased darunavir AUC ↑ 53%                               monitoring for rifabutin related adverse events is warranted in patients receiving the darunavir Cmin ↑ 68% combination with Darunavir Teva co- darunavir Cmax ↑ 39%                              administered with ritonavir. In case of safety ** sum of active moieties of rifabutin (parent    issues, a further increase of the dosing drug + 25-O-desacetyl metabolite)                 interval for rifabutin and/or monitoring of The interaction trial showed a comparable        rifabutin levels should be considered.
daily systemic exposure for rifabutin between Consideration should be given to official treatment at 300 mg once daily alone and 150 guidance on the appropriate treatment of mg once every other day in combination with tuberculosis in HIV infected patients.
Darunavir Teva /ritonavir (600/100 mg twice Based upon the safety profile of Darunavir daily) with an about 10-fold increase in the     Teva /ritonavir, the increase in darunavir daily exposure to the active metabolite 25-O- exposure in the presence of rifabutin does desacetylrifabutin. Furthermore, AUC of the not warrant a dose adjustment for Darunavir sum of active moieties of rifabutin (parent drug Teva /ritonavir.
+ 25-O-desacetyl metabolite) was increased       Based on pharmacokinetic modeling, this 1.6-fold, while Cmax remained comparable.        dosage reduction of 75% is also applicable if Data on comparison with a 150 mg once daily patients receive rifabutin at doses other than reference dose is lacking.                       300 mg/day.
(Rifabutin is an inducer and substrate of
CYP3A.) An increase of systemic exposure to darunavir was observed when Darunavir Teva co-administered with 100 mg ritonavir was co- administered with rifabutin (150 mg once every other day).

ANTINEOPLASTICS

Dasatinib                Not studied. Boosted Darunavir Teva is              Concentrations of these medicinal products Nilotinib                expected to increase these antineoplastic           may be increased when co-administered with Vinblastine              plasma concentrations.                              boosted Darunavir Teva resulting in the Vincristine              (CYP3A inhibition)                                  potential for increased adverse events usually associated with these agents. Caution should be exercised when combining one of these antineoplastic agents with boosted
Darunavir Teva.

Everolimus                                                                   Concominant use of everolimus or irinotecan Irinotecan                                                                   and boosted Darunavir Teva is not recommended.



ANTIPSYCHOTICS/NEUROLEPTICS

Quetiapine                 Not studied. Boosted Darunavir Teva is             Concomitant administration of boosted expected to increase these antipsychotic           Darunavir Teva and quetiapine is plasma concentrations.                             contraindicated as it may increase (CYP3A inhibition)                                 quetiapine-related toxicity. Increased concentrations of quetiapine may lead to coma (see section 4.3).
Perphenazine               Not studied. Boosted Darunavir Teva is             A dose decrease may be needed for these Risperidone                expected to increase these antipsychotic           drugs when co-administered with boosted Thioridazine               plasma concentrations.                             Darunavir Teva.
(CYP3A, CYP2D6 and/or P-gp inhibition)
Concominant administration of boosted
Lurasidone                                                                    Darunavir Teva and lurasidone, pimozide or Pimozide                                                                      sertindole is contraindicated Sertindole                                                                    (see section 4.3).

β-BLOCKERS

Carvedilol                 Not studied. Boosted Darunavir Teva is             Clinical monitoring is recommended when Metoprolol                 expected to increase these β-blocker plasma        co-administering boosted Darunavir Teva Timolol                    concentrations.                                    with β-blockers. A lower dose of the β- (CYP2D6 inhibition)                                blocker should be considered.

CALCIUM CHANNEL BLOCKERS

Amlodipine                 Not studied. Boosted Darunavir Teva can be         Clinical monitoring of therapeutic and Diltiazem                  expected to increase the plasma concentrations     adverse effects is recommended when these Felodipine                 of calcium channel blockers.                       medicines are concomitantly administered Nicardipine                (CYP3A and/or CYP2D6 inhibition)                   with boosted Darunavir Teva.
Nifedipine
Verapamil

CORTICOSTEROIDS

Corticosteroids            Fluticasone: in a clinical study where ritonavir   Concomitant use of boosted Darunavir Teva primarily metabolised by   100 mg capsules twice daily were co-               and corticosteroids that are metabolised by CYP3A (including           administered with 50 µg intranasal fluticasone     CYP3A (e.g. fluticasone propionate or other betamethasone,             propionate (4 times daily) for 7 days in healthy   inhaled or nasal corticosteroids) may budesonide, fluticasone,   subjects, fluticasone propionate plasma            increase the risk of development of systemic mometasone, prednisone,    concentrations increased significantly, whereas    corticosteroid effects, including Cushing’s triamcinolone)             the intrinsic cortisol levels decreased by         syndrome and adrenal suppression.
approximately 86% (90% CI 82-89%). Greater         Co-administration with CYP3A-metabolised effects may be expected when fluticasone is        corticosteroids is not recommended unless inhaled. Systemic corticosteroid effects           the potential benefit to the patient outweighs including Cushing’s syndrome and adrenal           the risk, in which case patients should be suppression have been reported in patients         monitored for systemic corticosteroid receiving ritonavir and inhaled or intranasally    effects. Alternative corticosteroids which are administered fluticasone. The effects of high      less dependent on CYP3A metabolism e.g.
fluticasone systemic exposure on ritonavir         beclomethasone for intranasal or inhalational plasma levels are unknown.                         use should be considered, particularly for long term use.
Other corticosteroids: interaction not studied.
Plasma concentrations of these medicinal products may be increased when co- administered with boosted Darunavir Teva,
resulting in reduced serum cortisol concentrations.

Dexamethasone              Not studied. Dexamethasone may decrease            Systemic dexamethasone should be used (systemic)                 plasma concentrations of darunavir.                with caution when combined with boosted (CYP3A induction)                                  Darunavir Teva.


ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan                 Not studied. Concomitant use of bosentan and   When administered concomitantly with boosted Darunavir Teva may increase plasma     Darunavir Teva and low dose ritonavir, the concentrations of bosentan.                    patient’s tolerability of bosentan should be Bosentan is expected to decrease plasma        monitored.
concentrations of darunavir and/or its pharmacoenhancer. (CYP3A induction)

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A protease inhibitors
Elbasvir/grazoprevir    Boosted Darunavir Teva may increase the         Concomitant use of boosted Darunavir Teva exposure to grazoprevir.                        and elbasvir/grazoprevir is contraindicated (CYP3A and OATP1B inhibition)                   (see section 4.3).

Glecaprevir/pibrentasvir Based on theoretical considerations boosted    It is not recommended to co-administer Darunavir Teva may increase the exposure to    boosted Darunavir Teva with glecaprevir and pibrentasvir.                  glecaprevir/pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3 inhibition)

HERBAL PRODUCTS

St John's wort         Not studied. St John’s wort is expected to       Boosted Darunavir Teva must not be used (Hypericum perforatum) decrease the plasma concentrations of            concomitantly with products containing St darunavir or its pharmacoenhancers.              John’s wort (Hypericum perforatum) (see (CYP450 induction)                               section 4.3). If a patient is already taking St John’s wort, stop St John’s wort and if possible check viral levels. Darunavir exposure (and also ritonavir exposure) may increase on stopping St John’s wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St
John’s wort.
HMG CO-A REDUCTASE INHIBITORS

Lovastatin               Not studied. Lovastatin and simvastatin are    Increased plasma concentrations of Simvastatin              expected to have markedly increased plasma     lovastatin or simvastatin may cause concentrations when co-administered with       myopathy, including rhabdomyolysis.
boosted Darunavir Teva.                        Concomitant use of boosted Darunavir Teva (CYP3A inhibition)                             with lovastatin and simvastatin is therefore contraindicated (see section 4.3).

Atorvastatin             atorvastatin AUC ↑ 3-4 fold                    When administration of atorvastatin and 10 mg once daily         atorvastatin Cmin ↑ ≈5.5-10 fold               boosted Darunavir Teva is desired, it is atorvastatin Cmax ↑ ≈2 fold                    recommended to start with an atorvastatin #                                              dose of 10 mg once daily. A gradual dose darunavir/ritonavir increase of atorvastatin may be tailored to the clinical response.
atorvastatin AUC ↑ 290%Ω atorvastatin Cmax ↑ 319%Ω atorvastatin Cmin NDΩ
Ω with darunavir/cobicistat 800/150 mg

Pravastatin              pravastatin AUC ↑ 81%¶                         When administration of pravastatin and 40 mg single dose        pravastatin Cmin ND                            boosted Darunavir Teva is required, it is recommended to start with the lowest pravastatin Cmax ↑ 63%
¶ possible dose of pravastatin and titrate up to an up to five-fold increase was seen in a    the desired clinical effect while monitoring limited subset of subjects                     for safety.


Rosuvastatin              rosuvastatin AUC ↑ 48%║                       When administration of rosuvastatin and 10 mg once daily          rosuvastatin Cmax ↑ 144%║                     boosted Darunavir Teva is required, it is ║ based on published data with                recommended to start with the lowest darunavir/ritonavir                           possible dose of rosuvastatin and titrate up to the desired clinical effect while monitoring rosuvastatin AUC ↑ 93%§                       for safety.
rosuvastatin Cmax ↑ 277%§ rosuvastatin Cmin ND§
§ with darunavir/cobicistat 800/150 mg
OTHER LIPID MODIFYING AGENTS

Lomitapide                Based on theoretical considerations boosted  Co-administration is contraindicated (see Darunavir Teva is expected to increase the   section 4.3) exposure of lomitapide when co-administered.
(CYP3A inhibition)

H2-RECEPTOR ANTAGONISTS
Ranitidine                #                                             Boosted Darunavir Teva can be co- darunavir AUC ↔
150 mg twice daily        # darunavir Cmin ↔                            administered with H2-receptor antagonists #                                             without dose adjustments.
darunavir Cmax ↔

IMMUNOSUPPRESSANTS
Ciclosporin               Not studied. Exposure to these               Therapeutic drug monitoring of the Sirolimus                 immunosuppressants will be increased when immunosuppressive agent must be done Tacrolimus                co-administered with boosted Darunavir Teva. when co-administration occurs.
(CYP3A inhibition)

Everolimus                                                              Concomitant use of everolimus and boosted Darunavir Teva is not recommended.

INHALED BETA AGONISTS

Salmeterol                Not studied. Concomitant use of salmeterol    Concomitant use of salmeterol and boosted and boosted darunavir may increase plasma     Darunavir Teva is not recommended. The concentrations of salmeterol.                 combination may result in increased risk of cardiovascular adverse event with salmeterol, including QT prolongation,
palpitations and sinus tachycardia.

NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE

Methadone                 R(-) methadone AUC ↓ 16%                      No adjustment of methadone dosage is individual dose ranging   R(-) methadone Cmin ↓ 15%                     required when initiating co-administration from 55 mg to 150 mg      R(-) methadone Cmax ↓ 24%%                    with boosted Darunavir Teva. However, once daily                                                              increased methadone dose may be necessary when concomitantly administered for a longer period of time due to induction of metabolism by ritonavir. Therefore, clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.



Buprenorphine/          buprenorphine AUC ↓ 11%                          The clinical relevance of the increase in naloxone                buprenorphine Cmin ↔                             norbuprenorphine pharmacokinetic 8/2 mg-16/4 mg once     buprenorphine Cmax ↓ 8%                          parameters has not been established. Dose daily                   norbuprenorphine AUC ↑ 46%                       adjustment for buprenorphine may not be necessary when co-administered with norbuprenorphine Cmin ↑ 71% boosted Darunavir Teva but a careful clinical norbuprenorphine Cmax ↑ 36%                      monitoring for signs of opiate toxicity is naloxone AUC ↔                                   recommended.
naloxone Cmin ND naloxone Cmax ↔
Fentanyl                Based on theoretical considerations boosted      Clinical monitoring is recommended when Oxycodone               Darunavir Teva may increase plasma               co-administering boosted Darunavir Teva Tramadol                concentrations of these analgesics.              with these analgesics.
(CYP2D6 and/or CYP3A inhibition)

OESTROGEN-BASED CONTRACEPTIVES
Drospirenone            drospirenone AUC ↑ 58%€                          When Darunavir Teva is co-administered Ethinylestradiol        drospirenone Cmin ND€                            with a drospirenone-containing product, (3 mg/0.02 mg once      drospirenone Cmax ↑ 15%€                         clinical monitoring is recommended due to ethinylestradiol AUC ↓ 30%€                      the potential for hyperkalaemia.
daily) ethinylestradiol Cmin ND€ ethinylestradiol Cmax ↓ 14%€
€ with darunavir/cobicistat

Ethinylestradiol        ethinylestradiol AUC ↓ 44%β                      Alternative or additional contraceptive Norethindrone           ethinylestradiol Cmin ↓ 62%β                     measures are recommended when oestrogen- 35 µg/l mg once daily   ethinylestradiol Cmax ↓ 32%β                     based contraceptives are co-administered with boosted Darunavir Teva. Patients using norethindrone AUC ↓ 14%β oestrogens as hormone replacement therapy norethindrone Cmin ↓ 30%β                        should be clinically monitored for signs of norethindrone Cmax ↔β                            oestrogen deficiency.
β with darunavir/ritonavir

OPIOID ANTAGONIST
Naloxegol               Not studied.                                     Co-administration of boosted Darunavir Teva and naloxegol is contraindicated.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

For the treatment of    In an interaction study #, a comparable          The combination of avanafil and boosted erectile dysfunction    systemic exposure to sildenafil was observed     Darunavir Teva is contraindicated (see Avanafil                for a single intake of 100 mg sildenafil alone   section 4.3). Concomitant use of other PDE- Sildenafil              and a single intake of 25 mg sildenafil co-      5 inhibitors for the treatment of erectile Tadalafil               administered with Darunavir Teva and low         dysfunction with boosted Darunavir Teva dose ritonavir.                                  should be done with caution. If concomitant Vardenafil use of boosted Darunavir Teva with sildenafil, vardenafil or tadalafil is indicated,
sildenafil at a single dose not exceeding
25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours or tadalafil at a single dose not exceeding
10 mg in 72 hours is recommended.



For the treatment of              Not studied. Concomitant use of sildenafil or             A safe and effective dose of sildenafil for the pulmonary arterial                tadalafil for the treatment of pulmonary                  treatment of pulmonary arterial hypertension hypertension                      arterial hypertension and boosted Darunavir               co-administered with boosted Darunavir Sildenafil                        Teva may increase plasma concentrations of                Teva has not been established. There is an Tadalafil                         sildenafil or tadalafil.                                  increased potential for sildenafil-associated (CYP3A inhibition)                                        adverse events (including visual disturbances, hypotension, prolonged erection and syncope). Therefore, co- administration of boosted Darunavir Teva and sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated (see section 4.3).
Co-administration of tadalafil for the treatment of pulmonary arterial hypertension with boosted Darunavir Teva is not recommended.

PROTON PUMP INHIBITORS

Omeprazole                        #                                                         Boosted Darunavir Teva can be co- darunavir AUC ↔
20 mg once daily                  # darunavir Cmin ↔                                        administered with proton pump inhibitors #                                                         without dose adjustments.
darunavir Cmax ↔
SEDATIVES/HYPNOTICS

Buspirone                         Not studied. Sedative/hypnotics are                       Clinical monitoring is recommended when Clorazepate                       extensively metabolised by CYP3A. Co-                     co-administering boosted Darunavir Teva Diazepam                          administration with boosted Darunavir Teva                with these sedatives/hypnotics and a lower may cause a large increase in the concentration           dose of the sedatives/hypnotics should be Estazolam of these medicines.                                       considered.
Flurazepam
Midazolam (parenteral)            If parenteral midazolam is co-administered                If parenteral midazolam is co-administered Zoldipem                          with boosted Darunavir Teva it may cause a                with boosted Darunavir Teva it should be large increase in the concentration of this               done in an intensive care unit (ICU) or benzodiazepine. Data from concomitant use of              similar setting, which ensures close clinical parenteral midazolam with other protease                  monitoring and appropriate medical inhibitors suggest a possible 3-4 fold increase           management in case of respiratory in midazolam plasma levels.                               depression and/or prolonged sedation. Dose adjustment for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Midazolam (oral)                                                                            Boosted Darunavir Teva with triazolam or Triazolam                                                                                   oral midazolam is contraindicated (see section 4.3)
TREATMENT FOR PREMATURE EJACULATION
Dapoxetine                        Not studied.                                              Co-administration of boosted Darunavir Teva with dapoxetine is contraindicated.
UROLOGICAL DRUGS

Fesoterodine                      Not studied.                                              Use with caution. Monitor for fesoterodine Solifenacin                                                                                 or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.
#
Studies have been performed at lower than recommended doses of darunavir or with a different dosing regimen (see section 4.2 Posology).
†
The efficacy and safety of the use of Darunavir Teva with 100 mg ritonavir and any other HIV PI (e.g. (fos) amprenavir, nelfinavir and tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.
‡
Study was conducted with tenofovir disoproxil fumarate 300 mg once daily.