Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
As REZOLSTA contains darunavir and cobicistat, interactions that have been identified with darunavir (in combination with cobicistat or with low dose ritonavir) or with cobicistat determine the interactions that may occur with REZOLSTA. Interaction trials with darunavir/cobicistat, darunavir/ritonavir and with cobicistat have only been performed in adults.

Medicinal products that may be affected by darunavir/cobicistat
Darunavir is an inhibitor of CYP3A, a weak inhibitor of CYP2D6 and an inhibitor of P-gp. Cobicistat is a mechanism based inhibitor of CYP3A, and a weak CYP2D6 inhibitor. Cobicistat inhibits the transporters p-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3.. Cobicistat is not expected to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9 or CYP2C19. Cobicistat is not expected to induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, UGT1A1, or P-gp (MDR1). Co-administration of darunavir/cobicistat and medicinal products primarily metabolised by CYP3A or transported by P-gp, BCRP, MATE1, OATP1B1 and OATP1B3 may result in increased systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse reactions (see section 4.3 or table below).

REZOLSTA 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).




Co-administration of REZOLSTA with medicinal products 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. These interactions are described in the interaction table below.

Medicinal products that affect darunavir/cobicistat exposure
Darunavir and cobicistat are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations of darunavir and cobicistat (e.g. efavirenz, carbamazepine, phenytoin, phenobarbital, rifampicin, rifapentine, rifabutin, St John’s Wort) (see section 4.3 and interaction table below).

Co-administration of REZOLSTA and other medicinal products that inhibit CYP3A may decrease the clearance of darunavir and cobicistat and may result in increased plasma concentrations of darunavir and cobicistat (e.g. azole antifungals such as clotrimazole). These interactions are described in the interaction table below.

REZOLSTA should not be used concurrently with products or regimens containing ritonavir or cobicistat. REZOLSTA should not be used in combination with the individual components of REZOLSTA (darunavir or cobicistat). REZOLSTA should not be used in combination with another antiretroviral that requires pharmacoenhancement since dosing recommendations for such combination have not been established.

Interaction table
Expected interactions between REZOLSTA and antiretroviral and non-antiretroviral medicinal products are listed in the table below and are based on the identified interactions with darunavir/ritonavir, darunavir/cobicistat and with cobicistat.

The interaction profile of darunavir depends on whether ritonavir or cobicistat is used as pharmacokinetic enhancer, therefore there may be different recommendations for the use of darunavir with concomitant medicine. In the table below it is specified when recommendations for REZOLSTA differ from those for darunavir boosted with low dose ritonavir. Refer to the Summary of Product Characteristics for PREZISTA for further information.

The below list of examples of drug drug interactions is not comprehensive and therefore the label of each drug that is co-administered with REZOLSTA 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 examples by Interaction       Recommendations concerning therapeutic area                                co-administration
HIV ANTIRETROVIRALS
Integrase strand transfer inhibitors
Dolutegravir                         Based on theoretical                 REZOLSTA and dolutegravir considerations dolutegravir is not   can be used without dose expected to affect the               adjustments.
pharmacokinetics of REZOLSTA.
Raltegravir                          Some clinical trials suggest         At present the effect of raltegravir may cause a modest       raltegravir on darunavir plasma decrease in darunavir plasma         concentrations does not appear concentrations.                      to be clinically relevant;
REZOLSTA and raltegravir can be used without dose adjustments.



HIV Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)
Didanosine                       No mechanistic interaction            REZOLSTA and didanosine can    400 mg once daily                expected based on theoretical         be used without dose consideration.                        adjustments.
When didanosine is co-administered with
REZOLSTA, didanosine should be administered on an empty stomach 1 hour before or 2 hours after REZOLSTA (which is administered with food).
Tenofovir disoproxil *           Based on theoretical                  REZOLSTA and tenofovir considerations REZOLSTA is            disoproxil can be used without
*study was done with tenofovir   expected to increase tenofovir        dose adjustments.
disoproxil fumarate              plasma concentrations.                Monitoring of renal function (P-glycoprotein inhibition)           may be indicated when
REZOLSTA is given in combination with tenofovir disoproxil, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
Emtricitabine/tenofovir            Tenofovir alafenamide ↔               The recommended dose of alafenamide                        Tenofovir ↑                           emtricitabine/tenofovir alafenamide is 200/10 mg once daily when used with
REZOLSTA.



Abacavir                         Based on the different elimination    REZOLSTA can be used with Emtricitabine                    pathways of the other NRTIs (i.e.     these NRTIs without dose Lamivudine                       emtricitabine, lamivudine,            adjustment.
Stavudine                        stavudine and zidovudine) that are
Zidovudine                       primarily renally excreted, and abacavir for which metabolism is not mediated by CYP, no interactions are expected for these medicinal compounds and
REZOLSTA.
HIV Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)
Efavirenz                        Based on theoretical                  Co-administration of considerations efavirenz is           REZOLSTA and efavirenz is not expected to decrease darunavir        recommended.
and/or cobicistat plasma concentrations.                       This recommendation is
(CYP3A induction)                     different from ritonavir-boosted darunavir. Consult the Summary of Product Characteristics for darunavir for further details.
Etravirine                       Based on theoretical                  Co-administration of considerations etravirine is          REZOLSTA and etravirine is expected to decrease darunavir        not recommended.
and/or cobicistat plasma concentrations.                       This recommendation is
(CYP3A induction)                     different from ritonavir-boosted darunavir. Consult the Summary of Product Characteristics for darunavir for further details.

Nevirapine                  Based on theoretical               Co-administration of considerations nevirapine is       REZOLSTA and nevirapine is expected to decrease darunavir     not recommended.
and/or cobicistat plasma concentrations, (CYP3A             This recommendation is induction). REZOLSTA is            different from ritonavir-boosted expected to increase nevirapine    darunavir. Consult the Summary plasma concentrations.             of Product Characteristics for
(CYP3A inhibition)                 darunavir for further details.
Rilpivirine                 Based on theoretical               Co-administration of considerations REZOLSTA is         REZOLSTA and rilpivirine can expected to increase rilpivirine   be used without dose plasma concentrations.             adjustments, as the expected
(CYP3A inhibition)                 increase in rilpivirine concentrations is not considered clinically relevant.
CCR5 ANTAGONIST
Maraviroc                    Based on theoretical               The recommended dose of 150 mg twice daily           considerations REZOLSTA is         maraviroc is 150 mg twice daily expected to increase maraviroc     when co-administered with plasma concentrations.             REZOLSTA. For further details,
(CYP3A inhibition)                 consult the maraviroc Summary of Product Characteristics.
α1-ADRENORECEPTOR ANTAGONIST
Alfuzosin            Based on theoretical                      Co-administration of considerations REZOLSTA is                REZOLSTA with alfuzosin is expected to increase alfuzosin            contraindicated (see section 4.3).
plasma concentrations.
(CYP3A inhibition)
ANAESTHETIC
Alfentanil           Based on theoretical                      The concomitant use with considerations REZOLSTA is                REZOLSTA may require to expected to increase alfentanil           lower the dose of alfentanil and plasma concentrations.                    requires monitoring for risks of prolonged or delayed respiratory depression.
ANTACIDS
Aluminium/magnesium   No mechanistic interaction                REZOLSTA and antacids can be hydroxide             expected based on theoretical             used concomitantly without dose Calcium carbonate     consideration.                            adjustment.
ANTIANGINA/ANTIARRHYTHMIC
Disopyramide          Based on theoretical                      Caution is warranted and Flecainide            considerations REZOLSTA is                therapeutic concentration Lidocaine (systemic)  expected to increase these                monitoring, if available, is Mexiletine            antiarrhythmic plasma                     recommended for these Propafenone           concentrations.                           antiarrhythmics when (CYP3A and/or CYP2D6                      co-administered with inhibition)                               REZOLSTA.

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



Digoxin                     Based on theoretical               It is recommended that the considerations REZOLSTA is         lowest possible dose of digoxin expected to increase digoxin       should initially be given to plasma concentrations.             patients on REZOLSTA. The
(P-glycoprotein inhibition)        digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.
ANTIBIOTIC
Clarithromycin         Based on theoretical                     Caution should be exercised considerations clarithromycin is         when clarithromycin is expected to increase darunavir           combined with REZOLSTA.
and/or cobicistat plasma concentrations.                          For patients with renal
(CYP3A inhibition)                       impairment the Summary of
Concentrations of clarithromycin         Product Characteristics for may be increased upon                    clarithromycin should be co-administration with                   consulted for the recommended REZOLSTA.                                dose.
(CYP3A inhibition)
ANTICOAGULANT/PLATELET AGGREGATION INHIBITOR
Apixaban               Based on theoretical                     Co-administration of Rivaroxaban            considerations co-administration         REZOLSTA. with a direct oral of REZOLSTA with these                   anticoagulant (DOAC) that is anticoagulants may increase              metabolised by CYP3A4 and concentrations of the                    transported by P-gp is not anticoagulant. (CYP3A and/or             recommended as this may lead P-glycoprotein inhibition)               to an increased bleeding risk.
Dabigatran etexilate   dabigatran etexilate (150 mg):           Clinical monitoring and dose Edoxaban               darunavir/cobicistat 800/150 mg          reduction is required when a single dose:                             DOAC transported by P-gp but dabigatran AUC ↑ 164%                    not metabolised by CYP3A4, dabigatran Cmax ↑ 164%                   including dabigatran etexilate and edoxaban, is darunavir/cobicistat 800/150 mg    co-administered with once daily:                        REZOLSTA.
dabigatran AUC ↑ 88% dabigatran Cmax ↑ 99%

Ticagrelor                  Based on theoretical               Concomitant administration of considerations co-administration   REZOLSTA with ticagrelor is of REZOLSTA with ticagrelor        contraindicated. (see may increase concentrations of     section 4.3).
ticagrelor.
(CYP3A and/or P-glycoprotein inhibition).

Based on theoretical               Co-administration of
Clopidogrel                 considerations co-administration   REZOLSTA with clopidogrel is of REZOLSTA with clopidogrel is    not recommended.
expected to decrease clopidogrel active metabolite plasma 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 (see section 4.3).



Warfarin                Based on theoretical                It is recommended that the considerations REZOLSTA may         international normalised ratio alter warfarin plasma               (INR) be monitored when concentrations.                     warfarin is co-administered with
REZOLSTA.
ANTICONVULSANTS
Carbamazepine            Based on theoretical                Co-administration of Phenobarbital            considerations these                REZOLSTA and these Phenytoin                anticonvulsants are expected to     anticonvulsants is decrease darunavir and/or           contraindicated (see section 4.3).
cobicistat plasma concentrations.
(CYP3A induction).
Clonazepam              Based on theoretical                Clinical monitoring is considerations REZOLSTA is          recommended when expected to increase                co-administering REZOLSTA concentrations of clonazepam.       with clonazepam.
(inhibition of CYP3A)
ANTI-DEPRESSANTS
Herbal supplements       Based on theoretical                Co-administration of St John’s Wort           considerations St John’s Wort is    St John’s Wort and REZOLSTA expected to decrease darunavir      is contraindicated (see and/or cobicistat plasma            section 4.3).
concentrations.
(CYP3A induction)
Paroxetine              Based on theoretical                If these anti-depressants are to Sertraline              considerations REZOLSTA is          be used with REZOLSTA expected to increase these          clinical monitoring is anti-depressant plasma              recommended and a dose concentrations.                     adjustment of the anti-depressant (CYP2D6 and/or CYP3A                may be needed.
inhibition)
Prior data with ritonavir-boosted darunavir however showed a decrease in these anti-depressant plasma concentrations (unknown mechanism); the latter may be specific to ritonavir.

Amitriptyline           Based on theoretical
Desipramine             considerations REZOLSTA is
Imipramine              expected to increase these
Nortriptyline           anti-depressant plasma
Trazodone               concentrations.
(CYP2D6 and/or CYP3A inhibition)
ANTI-DIABETICS
Metformin                Based on theoretical                Careful patient monitoring and considerations REZOLSTA is          dose adjustment of metformin is expected to increase metformin      recommended in patients who plasma concentrations.              are taking REZOLSTA.
(MATE1 inhibition)
ANTIEMETICS
Domperidone              Not studied.                        Co-administration of domperidone with REZOLSTA is contraindicated.



ANTIFUNGALS
Clotrimazole              Based on theoretical                Caution is warranted and clinical Fluconazole               considerations REZOLSTA is          monitoring is recommended.
Itraconazole              expected to increase these
Isavuconazole             antifungal plasma concentrations,   When co-administration is Posaconazole              and darunavir and/or cobicistat     required, the daily dose of plasma concentrations may be        itraconazole should not exceed increased by the antifungals.       200 mg.
(CYP3A inhibition and/or P-gp inhibition)
Voriconazole                                                 Voriconazole should not be Concentrations of voriconazole      combined with REZOLSTA may increase or decrease when       unless an assessment of the co-administered with                benefit/risk ratio justifies the use REZOLSTA.                           of voriconazole.
ANTIGOUT MEDICINES
Colchicine                Based on theoretical                A reduction in colchicine dosage considerations REZOLSTA is          or an interruption of colchicine expected to increase colchicine     treatment is recommended in plasma concentrations.              patients with normal renal or
(CYP3A and/or P-glycoprotein        hepatic function if treatment inhibition)                         with REZOLSTA is required.
The combination of colchicine and REZOLSTA is contraindicated in patients with renal or hepatic impairment (see section 4.3).
ANTIMALARIALS
Artemether/Lumefantrine   Based on theoretical                REZOLSTA and considerations REZOLSTA is          artemether/lumefantrine can be expected to increase lumefantrine   used without dose adjustments;
plasma concentrations.              however, due to the increase in
(CYP3A inhibition)                  lumefantrine exposure, the combination should be used with caution.
ANTIMYCOBACTERIALS
Rifampicin                Based on theoretical                The combination of rifampicin considerations rifampin is          and REZOLSTA is expected to decrease darunavir      contraindicated (see section 4.3).
and/or cobicistat plasma concentrations.
(CYP3A induction)



Rifabutin               Based on theoretical                 Co-administration of Rifapentine             considerations these                 REZOLSTA with rifabutin and antimycobacterials are expected to   rifapentine is not recommended.
decrease darunavir and/or            If the combination is needed, the cobicistat plasma concentrations.    recommended dose of rifabutin
(CYP3A induction)                    is 150 mg 3 times per week on set days (for example
Monday-Wednesday-Friday).
Increased monitoring for rifabutin associated adverse reactions including neutropenia and uveitis is warranted due to an expected increase in exposure to rifabutin. Further dosage reduction of rifabutin has not been studied. It should be kept in mind that the twice weekly dosage of 150 mg may not provide an optimal exposure to rifabutin thus leading to a risk of rifamycin resistance and a treatment failure. Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV infected patients.

This recommendation is different from ritonavir-boosted darunavir. Consult the Summary of Product Characteristics for darunavir for further details.
ANTI-NEOPLASTICS
Dasatinib                Based on theoretical                 Concentrations of these Nilotinib                considerations REZOLSTA is           medicinal products may be Vinblastine              expected to increase these           increased when co-administered Vincristine              anti-neoplastic plasma               with REZOLSTA resulting in concentrations.                      the potential for increased
(CYP3A inhibition)                   adverse events usually associated with these medicinal products.
Caution should be exercised when combining one of these anti-neoplastic agents with
REZOLSTA.

Everolimus                                                   Concomitant use of everolimus Irinotecan                                                   or irinotecan and REZOLSTA is not recommended.



ANTIPSYCHOTICS/NEUROLEPTICS
Perphenazine           Based on theoretical                      Clinical monitoring is Risperidone            considerations REZOLSTA is                recommended when Thioridazine           expected to increase these                co-administering REZOLSTA neuroleptic plasma concentrations.        perphenazine, risperidone or (CYP3A, CYP2D6 and/or P-gp                thioridazine. For these inhibition)                               neuroleptics, consider reducing the dose of the neuroleptic upon co-administration with
REZOLSTA.

Lurasidone                                                      The combination of lurasidone, Pimozide                                                        pimozide, quetiapine or Sertindole                                                      sertindole and REZOLSTA is Quetiapine                                                      contraindicated (see section 4.3).
β-BLOCKERS
Carvedilol                  Based on theoretical                Clinical monitoring is Metoprolol                  considerations REZOLSTA is          recommended when Timolol                     expected to increase these beta     co-administering REZOLSTA blocker plasma concentrations.      with beta-blockers and a lower
(CYP3A inhibition)                  dose of the beta-blocker should be considered.
CALCIUM CHANNEL BLOCKERS
Amlodipine            Based on theoretical                       Clinical monitoring of Diltiazem             considerations REZOLSTA is                 therapeutic and adverse effects is Felodipine            expected to increase these calcium         recommended when these Nicardipine           channel blocker plasma                     medicines are co-administered Nifedipine            concentrations.                            with REZOLSTA.
Verapamil             (CYP3A and/or CYP2D6 inhibition)
CORTICOSTEROIDS
Corticosteroids primarily    Based on theoretical               Concomitant use of REZOLSTA metabolised by CYP3A        considerations REZOLSTA is          and corticosteroids (all routes of (including betamethasone,   expected to increase these          administration) that are budesonide, fluticasone,    corticosteroid plasma               metabolised by CYP3A may mometasone, prednisone,     concentrations. (CYP3A              increase the risk of development triamcinolone).             inhibition)                         of systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression.

Co-administration with CYP3A- metabolised corticosteroids is not recommended unless the potential benefit to the patient outweighs the risk, in which case patients should be monitored for systemic corticosteroid effects.
Alternative corticosteroids which are less dependent on
CYP3A metabolism e.g.
beclomethasone should be considered, particularly for long term use.
Dexamethasone (systemic)    Based on theoretical                Systemic dexamethasone should considerations (systemic)           be used with caution when dexamethasone is expected to        combined with REZOLSTA.
decrease darunavir and/or cobicistat plasma concentrations.
(CYP3A induction)


 ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan                   Based on theoretical                    Co-administration of considerations bosentan is              REZOLSTA and bosentan is not expected to decrease darunavir          recommended.
and/or cobicistat plasma concentrations.
(CYP3A induction)
REZOLSTA is expected to increase bosentan plasma concentrations.
(CYP3A inhibition)
HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS
NS3-4A inhibitors
Elbasvir/grazoprevir    Based on theoretical                      Concomitant use of REZOLSTA considerations REZOLSTA may               with elbasvir/grazoprevir is increase the exposure to                  contraindicated (see section 4.3).
grazoprevir.
(OATP1B and CYP3A inhibition)
Glecaprevir/pibrentasvir Based on theoretical                      It is not recommended to considerations REZOLSTA may               co-administer REZOLSTA with increase the exposure to                  glecaprevir/pibrentasvir.
glecaprevir and pibrentasvir.
(P-gp, BCRP and/or OATP1B1/3 inhibition)
HMG CO-A REDUCTASE INHIBITORS
Atorvastatin               Atorvastatin (10 mg once daily):        Concomitant use of a HMG CoA Fluvastatin                atorvastatin AUC ↑ 290%                 reductase inhibitor and Pitavastatin               atorvastatin Cmax ↑ 319%                REZOLSTA may increase Pravastatin                atorvastatin Cmin ND                    plasma concentrations of the Rosuvastatin               Rosuvastatin (10 mg once                lipid lowering agent, which may daily):                                 lead to adverse events such as rosuvastatin AUC ↑ 93%                  myopathy.
rosuvastatin Cmax ↑ 277%                When administration of rosuvastatin Cmin ND                    HMG CoA reductase inhibitors
Based on theoretical                    and REZOLSTA is desired, it is considerations REZOLSTA is              recommended to start with the expected to increase the plasma         lowest dose and titrate up to the concentrations of                       desired clinical effect while fluvastatin, pitavastatin,              monitoring for safety.
pravastatin, lovastatin and
Lovastatin                 simvastatin.                            Concomitant use of REZOLSTA Simvastatin                (CYP3A inhibition and/or                with lovastatin and simvastatin transport)                              is contraindicated (see section 4.3).
OTHER LIPID MODIFYING AGENTS

Lomitapide                    Based on theoretical                Co-administration is considerations, REZOLSTA is         contraindicated (see section 4.3) expected to increase the exposure of lomitapide when co- administered.
(CYP3A inhibition)
H2-RECEPTOR ANTAGONISTS
Cimetidine             Based on theoretical                        REZOLSTA can be Famotidine             considerations, no mechanistic              co-administered with Nizatidine             interaction is expected.                    H2-receptor antagonists without Ranitidine                                                         dose adjustments.



IMMUNOSUPPRESSANTS
Ciclosporin                    Based on theoretical              Therapeutic drug monitoring of Sirolimus                      considerations REZOLSTA is        the immunosuppressive agent Tacrolimus                     expected to increase these        must be done when immunosuppressant plasma          co-administration occurs.
concentrations.
(CYP3A inhibition)
Everolimus                                                      Concomitant use of everolimus and REZOLSTA is not recommended.
INHALED BETA AGONISTS
Salmeterol                    Based on theoretical      Concomitant use of salmeterol considerations REZOLSTA isand REZOLSTA is not expected to increase salmeterol recommended. The combination plasma concentrations.    may result in increased risk of
(CYP3A inhibition)        cardiovascular adverse event with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NARCOTIC ANALGESICS/TREATMENT OF OPIOID DEPENDENCE
Buprenorphine/naloxone Based on theoretical              Dose adjustment for considerations REZOLSTA may       buprenorphine may not be increase buprenorphine and/or     necessary when co-administered norbuprenorphine plasma           with REZOLSTA but a careful concentrations.                   clinical monitoring for signs of opiate toxicity is recommended.
Methadone              Based on theoretical              No adjustment of methadone considerations REZOLSTA may       dosage is expected when increase methadone plasma         initiating co-administration with concentrations.                   REZOLSTA. Clinical monitoring is recommended, as
With ritonavir-boosted darunavir, maintenance therapy may need a small decrease in methadone     to be adjusted in some patients.
plasma concentrations was observed. Consult the Summary of
Product Characteristics for darunavir for further details.
Fentanyl               Based on theoretical              Clinical monitoring is Oxycodone              considerations REZOLSTA may       recommended when Tramadol               increase plasma concentrations of co-administering REZOLSTA these analgesics.                 with these analgesics.
(CYP2D6 and/or CYP3A inhibition)



OESTROGEN-BASED CONTRACEPTIVES
Drospirenone (3 mg once        drospirenone AUC ↑ 58% daily)                         drospirenone Cmax ↑ 15%          Alternative drospirenone Cmin ND             or additional contraceptive
Ethinylestradiol (0.02 mg once ethinylestradiol AUC ↓30%        measures are recommended daily)                         ethinylestradiol Cmax ↓14%       when oestrogen based ethinylestradiol Cmin ND         contraceptives are co
Norethindrone                  Based  on theoretical            administered with REZOLSTA.
considerations REZOLSTA may      Patients using oestrogens as alter norethindrone plasma       hormone replacement therapy concentrations.                  should be clinically monitored
(CYP3A inhibition, UGT/SULT      for signs of oestrogen induction)                       deficiency.
When REZOLSTA is co-administered with a drospirenone-containing product, clinical monitoring is recommended due to the potential for hyperkalaemia.

OPIOID ANTAGONIST
Naloxegol                       Not studied.                    Co-administration of REZOLSTA and naloxegol is contraindicated.
PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS
For the treatment of erectile Based on theoretical               Concomitant use of PDE-5 dysfunction                   considerations REZOLSTA is         inhibitors for the treatment of Sildenafil                  expected to increase these PDE-5   erectile dysfunction with Tadalafil                   inhibitor plasma concentrations.   REZOLSTA should be done Vardenafil                  (CYP3A inhibition)                 with caution. If concomitant use of REZOLSTA 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.

Avanafil                                                       The combination of avanafil and REZOLSTA is contraindicated
(see section 4.3).



For the treatment of pulmonary   Based on theoretical               A safe and effective dose of arterial hypertension            considerations REZOLSTA is         sildenafil for the treatment of Sildenafil                     expected to increase these PDE-5   pulmonary arterial hypertension Tadalafil                      inhibitor plasma concentrations.   co-administered with (CYP3A inhibition)                 REZOLSTA has not been established. There is an increased potential for sildenafil-associated adverse events (including visual disturbances, hypotension,
prolonged erection and syncope). Therefore,
co-administration of
REZOLSTA 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
REZOLSTA is not recommended.
PROTON PUMP INHIBITORS
Dexlansoprazole                 Based on theoretical               REZOLSTA can be Esomeprazole                    considerations, no mechanistic     co-administered with proton Lansoprazole                    interaction is expected.           pump inhibitors without dose Omeprazole                                                         adjustments.
Pantoprazole
Rabeprazole



SEDATIVES/HYPNOTICS
Buspirone                          Based on theoretical              Clinical monitoring is Clorazepate                        considerations REZOLSTA is        recommended when Diazepam                           expected to increase these        co-administering REZOLSTA Estazolam                          sedative/hypnotic plasma          with these sedatives/hypnotics Flurazepam                         concentrations.                   and a lower dose of the Midazolam (parenteral)             (CYP3A inhibition)                sedatives/hypnotics should be Zolpidem                                                             considered.

Caution should be used with co-administration of
REZOLSTA and parenteral midazolam.

If REZOLSTA is co-administered with parenteral midazolam, it should be done in an intensive care unit or similar setting, which ensures close clinical monitoring and appropriate medical management in case of respiratory 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)                                                 Co-administration of oral Triazolam                                                        midazolam or triazolam and REZOLSTA is contraindicated
(see section 4.3).
TREATMENT FOR PREMATURE EJACULATION
Dapoxetine            Not studied.                                   Co-administration of REZOLSTA with dapoxetine is contraindicated.
UROLOGICAL DRUGS
Fesoterodine                       Not studied.                      Use with caution. Monitor for Solifenacin                                                          fesoterodine or solifenacin adverse reactions, dose reduction of fesoterodine or solifenacin may be necessary.