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.


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).
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).

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



Didanosine              didanosine AUC ↓ 9%            Boosted PREZISTA and      400 mg once daily       didanosine Cmin ND             didanosine can be used didanosine Cmax ↓ 16%          without dose adjustments.
darunavir AUC ↔                Didanosine is to be darunavir Cmin ↔               administered on an empty darunavir Cmax ↔               stomach, thus it should be administered 1 hour before or 2 hours after boosted PREZISTA given with food.
Tenofovir disoproxil    tenofovir AUC ↑ 22%            Monitoring of renal      245 mg once daily‡      tenofovir Cmin ↑ 37%           function may be indicated tenofovir Cmax ↑ 24%           when boosted PREZISTA
#darunavir AUC ↑ 21%           is given in combination min ↑ 24%
#darunavir C                   with tenofovir disoproxil,
max ↑ 16%
#darunavir C                   particularly in patients with
(↑ tenofovir from effect on    underlying systemic or
MDR-1 transport in the renal   renal disease, or in tubules)                       patients taking nephrotoxic agents.

PREZISTA co-administered with cobicistat lowers the creatinine clearance.
Refer to section 4.4 if creatinine clearance is used for dose adjustment of tenofovir disoproxil.
Emtricitabine/tenofo    Tenofovir alafenamide ↔        The recommended dose vir alafenamide                                        of emtricitabine/tenofovir Tenofovir ↑                    alafenamide is 200/10 mg once daily when used with boosted PREZISTA.
Abacavir             Not studied. Based on the         Boosted PREZISTA can Emtricitabine        different elimination pathways    be used with these NRTIs Lamivudine           of the other NRTIs zidovudine,    without dose adjustment.
Stavudine            emtricitabine, stavudine,
Zidovudine           lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and boosted PREZISTA.
Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)



Efavirenz               efavirenz AUC ↑ 21%               Clinical monitoring for 600 mg once daily       efavirenz Cmin ↑ 17%              central nervous system efavirenz Cmax ↑ 15%              toxicity associated with
#darunavir AUC ↓ 13%              increased exposure to min ↓ 31%
#darunavir C                      efavirenz may be max ↓ 15%
#darunavir C                      indicated when
(↑ efavirenz from CYP3A           PREZISTA inhibition)                       co-administered with low
(↓ darunavir from CYP3A           dose ritonavir is given in induction)                        combination with efavirenz.

Efavirenz in combination with PREZISTA/ritonavir
800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with
PREZISTA/ritonavir, the
PREZISTA/ritonavir
600/100 mg twice daily regimen should be used
(see section 4.4).
Co-administration with
PREZISTA co-administered with cobicistat is not recommended (see section 4.4).
Etravirine              etravirine AUC ↓ 37%              PREZISTA
100 mg twice daily      etravirine Cmin ↓ 49%             co-administered with low etravirine Cmax ↓ 32%             dose ritonavir and darunavir AUC ↑ 15%               etravirine 200 mg twice darunavir Cmin ↔                  daily can be used without darunavir Cmax ↔                  dose adjustments.

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


HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir†
Atazanavir           atazanavir AUC ↔                  PREZISTA
300 mg once daily    atazanavir Cmin ↑ 52%             co-administered with low atazanavir Cmax ↓ 11%             dose ritonavir and
#darunavir AUC ↔                  atazanavir can be used min ↔
#darunavir C                      without dose adjustments.
max ↔
#darunavir C


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 800 mg twice daily      indinavir Cmin ↑ 125%             with PREZISTA indinavir Cmax ↔                  co-administered with low
#darunavir AUC ↑ 24%              dose ritonavir, dose min ↑ 44%
#darunavir C                      adjustment of indinavir max ↑ 11%
#darunavir C                      from 800 mg twice daily to
600 mg twice daily may be
Indinavir: comparison of          warranted in case of indinavir/ritonavir 800/100 mg    intolerance.
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              #darunavir AUC ↓ 26%         It is not recommended to 1,000 mg twice daily    #darunavir Cmin ↓ 42%        combine PREZISTA max ↓ 17%
#darunavir C                 co-administered with low saquinavir AUC ↓ 6%          dose ritonavir with saquinavir Cmin ↓ 18%        saquinavir.
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      400/100 mg twice     lopinavir Cmin ↑ 23%             exposure (AUC) of daily                lopinavir Cmax ↓ 2%              darunavir by 40%, darunavir AUC ↓ 38%‡             appropriate doses of the darunavir Cmin ↓ 51%  ‡          combination have not darunavir Cmax ↓ 21%‡            been established. Hence,
lopinavir AUC ↔                  concomitant use of
Lopinavir/ritonavir  lopinavir Cmin ↑ 13%             boosted PREZISTA and 533/133.3 mg twice lopinavir Cmax ↑ 11%               the combination product daily                darunavir AUC ↓ 41%              lopinavir/ritonavir is darunavir Cmin ↓ 55%             contraindicated (see darunavir Cmax ↓ 21%             section 4.3).
‡ based upon non dose
 normalised values
CCR5 ANTAGONIST
Maraviroc            maraviroc AUC ↑ 305%             The maraviroc dose 150 mg twice daily   maraviroc Cmin ND                should be 150 mg twice maraviroc Cmax ↑ 129%            daily when darunavir, ritonavir             co-administered with concentrations were consistent boosted PREZISTA.
with historical data
α1-ADRENORECEPTOR ANTAGONIST
Alfuzosin            Based on theoretical             Co-administration of considerations PREZISTA is       boosted PREZISTA and expected to increase alfuzosin alfuzosin is plasma concentrations.           contraindicated (see
(CYP3A inhibition)               section 4.3).
ANAESTHETIC



Alfentanil              Not studied. The metabolism of   The concomitant use with alfentanil is mediated via       boosted PREZISTA may
CYP3A, and may as such be        require to lower the dose inhibited by boosted             of alfentanil and requires
PREZISTA.                        monitoring for risks of prolonged or delayed respiratory depression.
ANTIANGINA/ANTIARRHYTHMIC
Disopyramide         Not studied. Boosted                Caution is warranted and Flecainide           PREZISTA is expected to             therapeutic concentration Lidocaine (systemic) increase these antiarrhythmic       monitoring, if available, is Mexiletine           plasma concentrations.              recommended for these Propafenone          (CYP3A and/or CYP2D6                antiarrhythmics when inhibition)                         co-administered with boosted PREZISTA.

Co-administration of
Amiodarone                                               boosted PREZISTA and Bepridil                                                 amiodarone, bepridil, Dronedarone                                              dronedarone, ivabradine, Ivabradine                                               quinidine, or ranolazine is contraindicated (see
Quinidine                                                section 4.3).
Ranolazine
Digoxin                 digoxin AUC ↑ 61%                Given that digoxin has a 0.4 mg single dose      digoxin Cmin ND                  narrow therapeutic index, digoxin Cmax ↑ 29%               it is recommended that the
(↑ digoxin from probable         lowest possible dose of inhibition of P-gp)              digoxin should initially be prescribed in case digoxin is given to patients on boosted PREZISTA 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 clarithromycin Cmin ↑ 174%
500 mg twice daily                                exercised when clarithromycin Cmax ↑ 26%         clarithromycin is combined
#darunavir AUC ↓ 13%              with boosted PREZISTA.
min ↑ 1%
#darunavir C
 max ↓ 17%
#darunavir C                      For patients with renal
14-OH-clarithromycin              impairment the Summary concentrations were not           of Product Characteristics detectable when combined with for clarithromycin should
PREZISTA/ritonavir.               be consulted for the
(↑ clarithromycin from CYP3A      recommended dose.
inhibition and possible P-gp inhibition)
ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban        Not studied. Co-administration The use of boosted
Edoxaban        of boosted PREZISTA with          PREZISTA and these
Rivaroxaban     these anticoagulants may          anticoagulants is not increase concentrations of the    recommended.
anticoagulant, which may lead to an increased bleeding risk
(CYP3A and/or P-gp inhibition)
Dabigatran     Not studied. Co-administration Concomitant with boosted PREZISTA may         administration of boosted
Ticagrelor      lead to a substantial increase in PREZISTA with exposure to dabigatran or dabigatran or ticagrelor is ticagrelor.
contraindicated (see
Clopidogrel                                       section 4.3).
Not studied. Co-administration of clopidogrel with boosted       Co-administration of
PREZISTA is expected to           clopidogrel with boosted decrease clopidogrel active       PREZISTA is not 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             It is recommended that concentrations may be affected the international when co-administered with         normalised ratio (INR) be boosted PREZISTA.                 monitored when warfarin is combined with boosted
PREZISTA.
ANTICONVULSANTS



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



Paroxetine              paroxetine AUC ↓ 39%              If antidepressants are      20 mg once daily        paroxetine Cmin ↓ 37%             co-administered with paroxetine Cmax ↓ 36%             boosted PREZISTA, the
#darunavir AUC ↔                  recommended approach min ↔
#darunavir C                      is a dose titration of the max ↔
#darunavir C                      antidepressant based on a
Sertraline              sertraline AUC ↓ 49%              clinical assessment of 50 mg once daily        sertraline Cmin ↓ 49%             antidepressant response.
sertraline Cmax ↓ 44%             In addition, patients on a
#darunavir AUC ↔                  stable dose of these min ↓ 6%
#darunavir C                      antidepressants who start max ↔
#darunavir C                      treatment with boosted
PREZISTA should be monitored for antidepressant response.

Amitriptyline           Concomitant use of boosted
Desipramine             PREZISTA and these                Clinical monitoring is Imipramine              antidepressants may increase      recommended when Nortriptyline           concentrations of the             co-administering boosted Trazodone               antidepressant.                   PREZISTA with these (CYP2D6 and/or CYP3A              antidepressants and a inhibition)                       dose adjustment of the antidepressant may be needed.
ANTI-DIABETICS
Metformin               Not studied. Based on             Careful patient monitoring theoretical considerations        and dose adjustment of
PREZISTA co-administered          metformin is with cobicistat is expected to    recommended in patients increase metformin plasma         who are taking PREZISTA concentrations.                   co-administered with cobicistat.
(MATE1 inhibition)
(not applicable for
PREZISTA co-administered with ritonavir)
ANTIEMETICS
Domperidone             Not studied.                      Co-administration of domperidone with boosted
PREZISTA is contraindicated
ANTIFUNGALS
Voriconazole            Not studied. Ritonavir may        Voriconazole should not decrease plasma                   be combined with boosted concentrations of voriconazole.   PREZISTA unless an
(induction of CYP450              assessment of the enzymes)                          benefit/risk ratio justifies the use of voriconazole.


Fluconazole             Not studied. Boosted             Caution is warranted and Isavuconazole          PREZISTA may increase            clinical monitoring is Itraconazole           antifungal plasma                recommended.
Posaconazole            concentrations and               When co-administration is posaconazole, isavuconazole,     required the daily dose of itraconazole or fluconazole      itraconazole should not
Clotrimazole            may increase darunavir           exceed 200 mg concentrations.
(CYP3A and/or P-gp inhibition)

Not studied. Concomitant systemic use of clotrimazole and boosted PREZISTA may increase plasma concentrations of darunavir and/or clotrimazole.
darunavir AUC24h ↑ 33%
(based on population pharmacokinetic model)

ANTIGOUT MEDICINES
Colchicine       Not studied. Concomitant use            A reduction in colchicine of colchicine and boosted               dosage or an interruption
PREZISTA may increase the               of colchicine treatment is exposure to colchicine.                 recommended in patients
(CYP3A and/ or P-gp inhibition)         with normal renal or hepatic function if treatment with boosted
PREZISTA is required.
For patients with renal or hepatic impairment colchicine with boosted
PREZISTA is contraindicated (see sections 4.3 and 4.4).
ANTIMALARIALS artemether AUC ↓ 16%
Artemether/Lumefan                                       The combination of trine           artemether Cmin ↔                        boosted PREZISTA and artemether Cmax ↓ 18%
80/480 mg, 6 doses                                       artemether/lumefantrine dihydroartemisinin AUC ↓ 18% at 0, 8, 24, 36, 48,                                     can be used without dose and 60 hours    dihydroartemisinin Cmin ↔                adjustments; however, dihydroartemisinin Cmax ↓ 18%            due to the increase in lumefantrine AUC ↑ 175%                  lumefantrine exposure,
lumefantrine Cmin ↑ 126%                 the combination should be lumefantrine Cmax ↑ 65%                  used with caution.
darunavir AUC ↔ darunavir Cmin ↓ 13% darunavir Cmax ↔
ANTIMYCOBACTERIALS



Rifampicin              Not studied. Rifapentine and        The combination of Rifapentine             rifampicin are strong CYP3A         rifapentine and boosted inducers and have been shown        PREZISTA is not to cause profound decreases in      recommended.
concentrations of other protease inhibitors, which can      The combination of result in virological failure and   rifampicin and boosted resistance development              PREZISTA is
(CYP450 enzyme induction).          contraindicated (see
During attempts to overcome         section 4.3).
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 150 mg once every       rifabutin Cmin** ↑ ND            rifabutin by 75% of the other day               rifabutin Cmax** ↔               usual dose of 300 mg/day darunavir AUC ↑ 53%              (i.e. rifabutin 150 mg once darunavir Cmin ↑ 68%             every other day) and darunavir Cmax ↑ 39%             increased monitoring for
** sum of active moieties of     rifabutin related adverse rifabutin (parent drug           events is warranted in
+ 25-O-desacetyl metabolite)     patients receiving the combination with
The interaction trial showed a   PREZISTA comparable daily systemic        co-administered with exposure for rifabutin between ritonavir. In case of safety treatment at 300 mg once daily issues, a further increase alone and 150 mg once every      of the dosing interval for other day in combination with    rifabutin and/or monitoring
PREZISTA/ritonavir               of rifabutin levels should
(600/100 mg twice daily) with    be considered.
an about 10-fold increase in the Consideration should be daily exposure to the active     given to official guidance metabolite                       on the appropriate
25-O-desacetylrifabutin.         treatment of tuberculosis
Furthermore, AUC of the sum      in HIV infected patients.
of active moieties of rifabutin  Based upon the safety
(parent drug + 25-O-desacetyl    profile of metabolite) was increased        PREZISTA/ritonavir, the
1.6-fold, while Cmax remained    increase in darunavir comparable.                      exposure in the presence
Data on comparison with a        of rifabutin does not
150 mg once daily reference      warrant a dose adjustment dose is lacking.                 for PREZISTA/ritonavir.
Based on pharmacokinetic
(Rifabutin is an inducer and     modeling, this dosage substrate of CYP3A.) An          reduction of 75% is also increase of systemic exposure applicable if patients to darunavir was observed        receive rifabutin at doses when PREZISTA                    other than 300 mg/day.
co-administered with 100 mg ritonavir was co-administered with rifabutin (150 mg once every other day).
ANTINEOPLASTICS



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

Concomitant use of everolimus or irinotecan and boosted PREZISTA is not recommended.
ANTIPSYCHOTICS/NEUROLEPTICS
Quetiapine       Not studied. Boosted                   Concomitant
PREZISTA is expected to                administration of boosted increase these antipsychotic           PREZISTA and quetiapine plasma concentrations.                 is contraindicated as it
(CYP3A inhibition)                     may increase quetiapine-related toxicity.
Increased concentrations of quetiapine may lead to coma (see section 4.3).
Perphenazine            Not studied. Boosted            A dose decrease may be Risperidone             PREZISTA is expected to         needed for these drugs Thioridazine            increase these antipsychotic    when co-administered plasma concentrations.          with boosted PREZISTA.
Lurasidone              (CYP3A, CYP2D6 and/or P-gp
Pimozide                inhibition)                     Concomitant
Sertindole                                              administration of boosted PREZISTA and lurasidone, pimozide or sertindole is contraindicated (see section 4.3).
β-BLOCKERS
Carvedilol              Not studied. Boosted            Clinical monitoring is Metoprolol              PREZISTA is expected to         recommended when Timolol                 increase these β-blocker        co-administering boosted plasma concentrations.          PREZISTA with
(CYP2D6 inhibition)             β-blockers. A lower dose of the β-blocker should be considered.
CALCIUM CHANNEL BLOCKERS


Amlodipine              Not studied. Boosted               Clinical monitoring of Diltiazem               PREZISTA can be expected to        therapeutic and adverse Felodipine              increase the plasma                effects is recommended Nicardipine             concentrations of calcium          when these medicines are Nifedipine              channel blockers.                  concomitantly Verapamil               (CYP3A and/or CYP2D6               administered with boosted inhibition)                        PREZISTA.
CORTICOSTEROIDS
Corticosteroids         Fluticasone: in a clinical study   Concomitant use of primarily               where ritonavir 100 mg             boosted PREZISTA and metabolised by          capsules twice daily were          corticosteroids (all routes CYP3A (including        co-administered with 50 µg         of administration) that are betamethasone,          intranasal fluticasone             metabolised by CYP3A budesonide,             propionate (4 times daily) for     may increase the risk of fluticasone,            7 days in healthy subjects,        development of systemic mometasone,             fluticasone propionate plasma      corticosteroid effects, prednisone,             concentrations increased           including Cushing’s triamcinolone)          significantly, whereas the         syndrome and adrenal intrinsic cortisol levels          suppression.
decreased by approximately         Co-administration with
86% (90% CI 82-89%). Greater       CYP3A-metabolised effects may be expected when       corticosteroids is not fluticasone is inhaled. Systemic   recommended unless the corticosteroid effects including   potential benefit to the
Cushing’s syndrome and             patient outweighs the risk,
adrenal suppression have been      in which case patients reported in patients receiving     should be monitored for ritonavir and inhaled or           systemic corticosteroid intranasally administered          effects.
fluticasone. The effects of high   Alternative corticosteroids fluticasone systemic exposure      which are less dependent on ritonavir plasma levels are     on CYP3A metabolism unknown.                           e.g. beclomethasone should be considered,
Other corticosteroids:                     particularly for long term interaction not studied. Plasma            use.
concentrations of these medicinal products may be increased when co- administered with boosted
PREZISTA, resulting in reduced serum cortisol concentrations.
Dexamethasone   Not studied. Dexamethasone                 Systemic dexamethasone (systemic)      may decrease plasma                        should be used with concentrations of darunavir.               caution when combined
(CYP3A induction)                          with boosted PREZISTA.
ENDOTHELIN RECEPTOR ANTAGONISTS



Bosentan             Not studied. Concomitant use When administered of bosentan and boosted      concomitantly with
PREZISTA may increase        PREZISTA and low dose plasma concentrations of     ritonavir, the patient’s bosentan.                    tolerability of bosentan
Bosentan is expected to      should be monitored.
decrease plasma concentrations of darunavir and/or its pharmacoenhancer.
(CYP3A induction)
HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A protease inhibitors
Elbasvir/grazoprevir Boosted PREZISTA may         Concomitant use of increase the exposure to     boosted PREZISTA and grazoprevir.                 elbasvir/grazoprevir is
(CYP3A and OATP1B            contraindicated (see inhibition)                  section 4.3).

Glecaprevir/pibrent   Based on theoretical          It is not recommended to asvir                 considerations boosted        co-administer boosted PREZISTA may increase the     PREZISTA with exposure to glecaprevir and   glecaprevir/pibrentasvir.
pibrentasvir.

(P-gp, BCRP and/or
OATP1B1/3 inhibition)

HERBAL PRODUCTS
St John's Wort  Not studied. St John’s Wort is        Boosted PREZISTA must (Hypericum      expected to decrease the              not be used concomitantly perforatum)     plasma concentrations of              with products containing darunavir or its                      St John’s Wort pharmacoenhancers.                    (Hypericum perforatum)
(CYP450 induction)                    (see 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        Increased plasma Simvastatin             simvastatin are expected to        concentrations of have markedly increased            lovastatin or simvastatin plasma concentrations when         may cause myopathy,
co-administered with boosted       including rhabdomyolysis.
PREZISTA.                          Concomitant use of
(CYP3A inhibition)                 boosted PREZISTA with lovastatin and simvastatin is therefore contraindicated (see section 4.3).
Atorvastatin            atorvastatin AUC ↑ 3-4 fold        When administration of 10 mg once daily        atorvastatin Cmin ↑ ≈5.5-10 fold   atorvastatin and boosted atorvastatin Cmax ↑ ≈2 fold        PREZISTA is desired, it is
#darunavir/ritonavir               recommended to start with an atorvastatin dose of atorvastatin AUC ↑ 290% Ω          10 mg once daily. A atorvastatin Cmax ↑ 319% Ω         gradual dose increase of atorvastatin Cmin ND Ω             atorvastatin may be
Ω with darunavir/cobicistat        tailored to the clinical
800/150 mg                         response.

Pravastatin             pravastatin AUC ↑ 81%¶             When administration of      40 mg single dose       pravastatin Cmin ND                pravastatin and boosted pravastatin Cmax ↑ 63%             PREZISTA is required, it
¶ an up to five-fold increase      is recommended to start was seen in a limited subset of    with the lowest possible subjects                           dose of pravastatin and titrate up to the desired clinical effect while monitoring for safety.
Rosuvastatin            rosuvastatin AUC ↑ 48%║            When administration of 10 mg once daily        rosuvastatin Cmax ↑ 144%║          rosuvastatin and boosted ║ based on published data with     PREZISTA is required, it darunavir/ritonavir                is recommended to start with the lowest possible dose of rosuvastatin and rosuvastatin AUC ↑ 93%§                  titrate up to the desired rosuvastatin Cmax ↑ 277%§                clinical effect while rosuvastatin Cmin ND§                    monitoring for safety.
§ with darunavir/cobicistat

800/150 mg
OTHER LIPID MODIFYING AGENTS
Lomitapide        Based on theoretical                     Co-administration is considerations boosted                   contraindicated (see
PREZISTA is expected to                  section 4.3) increase the exposure of lomitapide when co- administered.

(CYP3A inhibition)

H2-RECEPTOR ANTAGONISTS
Ranitidine         #darunavir AUC ↔              Boosted PREZISTA can min ↔
150 mg twice daily #darunavir C                  be co-administered with max ↔
#darunavir C                  H2-receptor antagonists without dose adjustments.
IMMUNOSUPPRESSANTS
Ciclosporin    Not studied. Exposure to these    Therapeutic drug
Sirolimus      immunosuppressants will be        monitoring of the
Tacrolimus     increased when                    immunosuppressive agent co-administered with boosted      must be done when
PREZISTA.                         co-administration occurs.
Everolimus     (CYP3A inhibition)
Concomitant use of everolimus and boosted
PREZISTA is not recommended.
INHALED BETA AGONISTS
Salmeterol      Not studied. Concomitant use   Concomitant use of of salmeterol and boosted      salmeterol and boosted darunavir may increase plasma  PREZISTA is not concentrations of salmeterol.  recommended. The 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 individual dose      R(-) methadone Cmin ↓ 15% methadone dosage is ranging from 55 mg R(-) methadone Cmax ↓ 24%   required when initiating to 150 mg once daily                           co-administration with boosted PREZISTA.
However, adjustment of the methadone dose may be necessary when concomitantly administered for a longer period of time. Therefore,
clinical monitoring is recommended, as maintenance therapy may need to be adjusted in some patients.



Buprenorphine/nalox     buprenorphine AUC ↓ 11%         The clinical relevance of one                     buprenorphine Cmin ↔            the increase in 8/2 mg–16/4 mg          buprenorphine Cmax ↓ 8%         norbuprenorphine once daily              norbuprenorphine AUC ↑ 46%      pharmacokinetic norbuprenorphine Cmin ↑ 71%     parameters has not been norbuprenorphine Cmax ↑ 36%     established. Dose naloxone AUC ↔                  adjustment for naloxone Cmin ND                buprenorphine may not be naloxone Cmax ↔                 necessary when co-administered with boosted PREZISTA but a careful clinical monitoring for signs of opiate toxicity is recommended.
Fentanyl          Based on theoretical                  Clinical monitoring is Oxycodone         considerations boosted                recommended when Tramadol          PREZISTA may increase                 co-administering boosted plasma concentrations of these        PREZISTA with these analgesics.                           analgesics.
(CYP2D6 and/or CYP3A inhibition)
OESTROGEN-BASED CONTRACEPTIVES
Drospirenone     drospirenone AUC ↑ 58%€               When PREZISTA is Ethinylestradiol drospirenone Cmin ND€                 coadministered with a (3 mg/0.02 mg    drospirenone Cmax ↑ 15%€              drospirenone-containing once daily)      ethinylestradiol AUC ↓ 30%€           product, clinical ethinylestradiol Cmin ND€             monitoring is ethinylestradiol Cmax ↓ 14%€          recommended due to the
€ with darunavir/cobicistat           potential for hyperkalaemia.
Ethinylestradiol        ethinylestradiol AUC ↓ 44% β
Norethindrone           ethinylestradiol Cmin ↓ 62% β
35 µg/1 mg once         ethinylestradiol Cmax ↓ 32% β daily                   norethindrone AUC ↓ 14% β norethindrone Cmin ↓ 30% β      Alternative or additional norethindrone Cmax ↔ β          contraceptive measures
β with darunavir/ritonavir      are recommended when oestrogen-based contraceptives are co-administered with boosted PREZISTA.
Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
OPIOID ANTAGONIST



Naloxegol             Not studied.                  Co-administration of boosted PREZISTA and naloxegol is contraindicated.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of In an interaction study #, a     The combination of erectile dysfunction comparable systemic exposure avanafil and boosted Avanafil             to sildenafil was observed for a PREZISTA is
Sildenafil           single intake of 100 mg          contraindicated (see Tadalafil            sildenafil alone and a single    section 4.3).
Vardenafil           intake of 25 mg sildenafil       Concomitant use of other co-administered with             PDE-5 inhibitors for the
PREZISTA and low dose            treatment of erectile ritonavir.                       dysfunction with boosted
PREZISTA should be done with caution. If concomitant use of boosted PREZISTA 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         A safe and effective dose pulmonary arterial      of sildenafil or tadalafil for the   of sildenafil for the hypertension            treatment of pulmonary arterial      treatment of pulmonary Sildenafil              hypertension and boosted             arterial hypertension Tadalafil               PREZISTA may increase                co-administered with plasma concentrations of             boosted PREZISTA has sildenafil or tadalafil.             not been established.
(CYP3A inhibition)                   There is an increased potential for sildenafil-associated adverse events (including visual disturbances,
hypotension, prolonged erection and syncope).
Therefore,
co-administration of boosted PREZISTA 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
PREZISTA is not recommended.
PROTON PUMP INHIBITORS
Omeprazole       #darunavir AUC ↔                            Boosted PREZISTA can min ↔
20 mg once daily #darunavir C                                be co-administered with max ↔
#darunavir C                                proton pump inhibitors without dose adjustments.
SEDATIVES/HYPNOTICS



Buspirone               Not studied. Sedative/hypnotics   Clinical monitoring is Clorazepate             are extensively metabolised by    recommended when Diazepam                CYP3A. Co-administration with     co-administering boosted Estazolam               boosted PREZISTA may cause        PREZISTA with these Flurazepam              a large increase in the           sedatives/hypnotics and a Midazolam               concentration of these            lower dose of the (parenteral)            medicines.                        sedatives/hypnotics Zoldipem                                                  should be considered.

If parenteral midazolam is
If parenteral midazolam is        co-administered with co-administered with boosted      boosted PREZISTA, it
PREZISTA it may cause a           should be done in an large increase in the             intensive care unit (ICU) concentration of this             or similar setting, which benzodiazepine. Data from         ensures close clinical concomitant use of parenteral     monitoring and midazolam with other protease     appropriate medical inhibitors suggest a possible     management in case of
3-4 fold increase in midazolam    respiratory depression plasma levels.                    and/or prolonged sedation. Dose
Midazolam (oral)                                          adjustment for midazolam Triazolam                                                 should be considered, especially if more than a single dose of midazolam is administered.

Boosted PREZISTA with triazolam or oral midazolam is contraindicated (see section 4.3)
TREATMENT FOR PREMATURE EJACULATION

Dapoxetime              Not studied.                      Co-administration of boosted PREZISTA with dapoxetine is contraindicated.
UROLOGICAL DRUGS

Fesoterodine            Not studied.                      Use with caution. Monitor Solifenacin                                               for fesoterodine 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 PREZISTA with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir 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.