Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Gendevra should not be co-administered with other antiretroviral medicinal products. Therefore, information regarding drug-drug interactions with other antiretroviral products (including protease inhibitors [PIs] and non-nucleoside reverse transcriptase inhibitors [NNRTIs]) is not provided (see section 4.4). Interaction studies have only been performed in adults.

Gendevra should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of HBV infection.


Elvitegravir
Elvitegravir is primarily metabolised by CYP3A, and medicinal products that induce or inhibit CYP3A may affect the exposure of elvitegravir. Co-administration of Gendevra with medicinal products that induce CYP3A may result in decreased plasma concentrations of elvitegravir and reduced therapeutic effect of Gendevra (see “Concomitant use contraindicated” and section 4.3).
Elvitegravir may have the potential to induce CYP2C9 and/or inducible uridine diphosphate glucuronosyltransferase (UGT) enzymes; as such it may decrease the plasma concentration of substrates of these enzymes.

Cobicistat

Cobicistat is a strong mechanism-based inhibitor of CYP3A and is also a CYP3A substrate. Cobicistat is also a weak CYP2D6 inhibitor and is metabolised, to a minor extent, by CYP2D6. Medicinal products that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased plasma concentrations of cobicistat. Medicinal products that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s).

Medicinal products that are highly dependent on CYP3A metabolism and have high first pass metabolism are the most susceptible to large increases in exposure when co-administered with cobicistat (see “Concomitant use contraindicated” and section 4.3).

Cobicistat is an inhibitor of the following transporters: P-gp, breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration with medicinal products that are substrates of P-gp, BCRP, OATP1B1 and OATP1B3 may result in increased plasma concentrations of these products.

Emtricitabine

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low.
Co-administration of emtricitabine with medicinal products that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product.
Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-gp and BCRP. Medicinal products that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption. However, upon co-administration with cobicistat in Gendevra, near maximal inhibition of P-gp by cobicistat is achieved leading to increased availability of tenofovir alafenamide with resulting exposures comparable to tenofovir alafenamide 25 mg administered alone. As such, tenofovir alafenamide exposures following administration of Gendevra are not expected to be further increased when used in combination with another P-gp and/or BCRP inhibitor (e.g., ketoconazole). Based on data from an in vitro study, co-administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo. In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving tenofovir alafenamide with other medicinal products is low. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is a substrate of OATP in vitro. Inhibitors of OATP and BCRP include ciclosporin.

Concomitant use contraindicated

Co-administration of Gendevra and some medicinal products that are primarily metabolised by CYP3A may result in increased plasma concentrations of these products, which are associated with the potential for serious or life-threatening adverse reactions such as peripheral vasospasm or ischaemia 
(e.g., dihydroergotamine, ergotamine, ergometrine), or myopathy, including rhabdomyolysis (e.g., simvastatin, lovastatin), or prolonged or increased sedation or respiratory depression (e.g., orally administered midazolam or triazolam). Co-administration of Gendevra and other medicinal products primarily metabolised by CYP3A such as amiodarone, lomitapide, quinidine, cisapride, pimozide, lurasidone, alfuzosin and sildenafil for pulmonary arterial hypertension is contraindicated (see section 4.3).

Co-administration of Gendevra and some medicinal products that induce CYP3A such as St. John’s wort (Hypericum perforatum), rifampicin, carbamazepine, phenobarbital, and phenytoin may result in significantly decreased cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance (see section 4.3).

Other interactions

Cobicistat and tenofovir alafenamide are not inhibitors of human UGT1A1 in vitro. It is not known whether cobicistat, emtricitabine, or tenofovir alafenamide are inhibitors of other UGT enzymes.

Interactions between the components of Gendevra and potential co-administered medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). The interactions described are based on studies conducted with Gendevra, or the components of Gendevra (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide), as individual agents and/or in combination, or are potential drug-drug interactions that may occur with Gendevra.

Table 1: Interactions between the individual components of Gendevra and other medicinal products

Medicinal product by           Effects on medicinal product           Recommendation concerning therapeutic areas                        levels.                   co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
ANTI-INFECTIVES
Antifungals
Ketoconazole (200 mg twice          Elvitegravir:                         When administering with Gendevra, daily)/ Elvitegravir (150 mg once   AUC: ↑ 48%                            the maximum daily dose of daily)2                             Cmin: ↑ 67%                           ketoconazole should not exceed Cmax: ↔                               200 mg per day. Caution is warranted and clinical monitoring is
Concentrations of ketoconazole        recommended during the and/or cobicistat may increase with   co-administration.
co-administration of Gendevra.
Itraconazole3                       Interaction not studied with any of   Clinical monitoring should be made Voriconazole3                       the components of Gendevra.           upon co-administration with Posaconazole3                                                             Gendevra. When administering Fluconazole                         Concentrations of itraconazole,       with Gendevra, the maximum daily fluconazole and posaconazole may      dose of itraconazole should not be increased when co-administered     exceed 200 mg per day.
with cobicistat.
An assessment of benefit/risk ratio
Concentrations of voriconazole        is recommended to justify use of may increase or decrease when         voriconazole with Gendevra.
co-administered with Gendevra.



Medicinal product by         Effects on medicinal product           Recommendation concerning therapeutic areas                      levels.                   co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
Antimycobacterials
Rifabutin (150 mg every other     Co-administration of rifabutin, a     Co-administration of Gendevra and day)/ Elvitegravir (150 mg once   potent CYP3A inducer, may             rifabutin is not recommended.
daily)/ Cobicistat (150 mg once   significantly decrease cobicistat daily)                            and elvitegravir plasma               If the combination is needed, the concentrations, which may result in   recommended dose of rifabutin is loss of therapeutic effect and        150 mg 3 times per week on set development of resistance.            days (for example Monday-
Wednesday-Friday).
Rifabutin:                            Increased monitoring for
AUC: ↔                                rifabutin-associated adverse
Cmin: ↔                               reactions including neutropenia and Cmax: ↔                               uveitis is warranted due to an expected increase in exposure to
25-O-desacetyl-rifabutin              desacetyl-rifabutin. Further dose AUC: ↑ 525%                           reduction of rifabutin has not been Cmin: ↑ 394%                          studied. It should be kept in mind Cmax: ↑ 384%                          that a twice weekly dose of 150 mg may not provide an optimal
Elvitegravir:                         exposure to rifabutin thus leading to AUC: ↓ 21%                            a risk of rifamycin resistance and a Cmin: ↓ 67%                           treatment failure.
Cmax: ↔

Cobicistat:
AUC: ↔
Cmin: ↓ 66%
Cmax: ↔



Medicinal product by             Effects on medicinal product      Recommendation concerning therapeutic areas                          levels.              co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
Anti-hepatitis C virus medicinal products
Ledipasvir (90 mg once daily)/      Ledipasvir:                       No dose adjustment of Sofosbuvir (400 mg once daily)/     AUC: ↑ 79%                        ledipasvir/sofosbuvir and Gendevra Elvitegravir (150 mg once daily)/   Cmin: ↑ 93%                       is warranted upon co-administration.
Cobicistat (150 mg once daily)/     Cmax: ↑ 65%
Emtricitabine (200 mg once daily)/
Tenofovir alafenamide (10 mg        Sofosbuvir: once daily)5                        AUC: ↑ 47%
Cmin: N/A
Cmax: ↑ 28%

Sofosbuvir metabolite GS-566500:
AUC: ↔
Cmin: ↔
Cmax: ↔

Sofosbuvir metabolite GS-331007:
AUC: ↑ 48%
Cmin: ↑ 66%
Cmax: ↔
Elvitegravir:
AUC: ↔
Cmin: ↑ 46%
Cmax: ↔

Cobicistat:
AUC: ↑ 53%
Cmin: ↑ 225%
Cmax: ↔

Emtricitabine:
AUC: ↔
Cmin: ↔
Cmax: ↔
Tenofovir alafenamide:
AUC: ↔
Cmin: N/A
Cmax: ↔



Medicinal product by             Effects on medicinal product       Recommendation concerning therapeutic areas                          levels.               co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
Sofosbuvir (400 mg once daily)/      Sofosbuvir:                        No dose adjustment of Velpatasvir (100 mg once daily)/     AUC: ↑ 37%                         sofosbuvir/velpatasvir and Gendevra Elvitegravir (150 mg once daily)/    Cmin: N/A                          is warranted upon co-administration.
Cobicistat (150 mg once daily)/      Cmax: ↔
Emtricitabine (200 mg once daily)/
Tenofovir alafenamide (10 mg         Sofosbuvir metabolite GS-331007: once daily)5                         AUC: ↑ 48%
Cmin: ↑ 58%
Cmax: ↔

Velpatasvir:
AUC: ↑ 50%
Cmin: ↑ 60%
Cmax: ↑ 30%

Elvitegravir:
AUC: ↔
Cmin: ↔
Cmax: ↔
Cobicistat:
AUC: ↔
Cmin: ↑ 103%
Cmax: ↔

Emtricitabine:
AUC: ↔
Cmin: ↔
Cmax: ↔

Tenofovir alafenamide:
AUC: ↔
Cmin: N/A
Cmax: ↓ 20%


Medicinal product by             Effects on medicinal product          Recommendation concerning therapeutic areas                          levels.                  co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
Sofosbuvir/Velpatasvir/              Sofosbuvir:                           No dose adjustment of Voxilaprevir                         AUC: ↔                                sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg+100 mg         Cmin: N/A                             and Gendevra is warranted upon once daily)7/                        Cmax: ↑ 27%                           co-administration.
Elvitegravir (150 mg once daily)/
Cobicistat (150 mg once daily)/      Sofosbuvir metabolite GS-331007: Emtricitabine (200 mg once daily)/   AUC: ↑ 43%
Tenofovir alafenamide (10 mg         Cmin: N/A once daily)5                         Cmax: ↔

Velpatasvir:
AUC: ↔
Cmin: ↑ 46%
Cmax: ↔

Voxilaprevir:
AUC: ↑ 171%
Cmin: ↑ 350%
Cmax: ↑ 92%
Elvitegravir:
AUC: ↔
Cmin: ↑ 32%
Cmax: ↔

Cobicistat:
AUC: ↑ 50%
Cmin: ↑ 250%
Cmax: ↔

Emtricitabine:
AUC: ↔
Cmin: ↔
Cmax: ↔
Tenofovir alafenamide:
AUC: ↔
Cmin: N/A
Cmax: ↓ 21%
Macrolide antibiotics
Clarithromycin                       Interaction not studied with any of   Clarithromycin dosing should be the components of Gendevra.           based on the patient’s CrCl, taking into consideration the effect of
Concentrations of clarithromycin      cobicistat on CrCl and serum and/or cobicistat may be altered      creatinine (see section 4.8).
with co-administration of
Gendevra.                             Patients with CrCl greater than or equal to 60 mL/min:
No dose adjustment of clarithromycin is required.

Patients with CrCl between
30 mL/min and 60 mL/min:
The dose of clarithromycin should be reduced by 50%.



Medicinal product by             Effects on medicinal product         Recommendation concerning therapeutic areas                           levels.                co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
Telithromycin                       Interaction not studied with any of   Clinical monitoring is recommended the components of Gendevra.           upon co-administration of
Gendevra.
Concentrations of telithromycin and/or cobicistat may be altered with co-administration of
Gendevra.
ANTICONVULSANTS
Carbamazepine (200 mg twice         Co-administration of                  Carbamazepine decreases plasma daily)/ Elvitegravir (150 mg once   carbamazepine, a potent CYP3A         concentrations of elvitegravir and daily)/ Cobicistat (150 mg once     inducer, may significantly decrease   cobicistat, which may result in loss daily)                              cobicistat plasma concentrations.     of therapeutic effect and development of resistance.
Elvitegravir:                         Co-administration of Gendevra with AUC: ↓ 69%                            carbamazepine is contraindicated Cmin: ↓ 97%                           (see section 4.3).
Cmax: ↓ 45%

Cobicistat:
AUC: ↓ 84%
Cmin: ↓ 90%
Cmax: ↓ 72%

Carbamazepine:
AUC: ↑ 43%
Cmin: ↑ 51%
Cmax: ↑ 40%
Carbamazepine-10,11-epoxide:
AUC: ↓ 35%
Cmin: ↓ 41%
Cmax: ↓ 27%



Medicinal product by            Effects on medicinal product           Recommendation concerning therapeutic areas                         levels.                   co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
GLUCOCORTICOIDS
Corticosteroids
Corticosteroids primarily          Interaction not studied with any of    Concomitant use of Gendevra and metabolised by CYP3A (including    the components of Gendevra.            corticosteroids that are metabolised betamethasone, budesonide,                                                by CYP3A (e.g. fluticasone fluticasone, mometasone,           Plasma concentrations of these         propionate or other inhaled or nasal prednisone, triamcinolone).        medicinal products may be              corticosteroids) may increase the increased when co-administered         risk of development of systemic with Gendevra, resulting in reduced    corticosteroid effects, including serum cortisol concentrations.         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 for intranasal or inhalational use should be considered, particularly for long-term use.

For coadministration of cutaneously-administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for conditions or uses that augment its systemic absorption.
MEDICINAL PRODUCTS or ORAL SUPPLEMENTS CONTAINING POLYVALENT CATIONS (e.g. Mg, Al, Ca, Fe, Zn)
Magnesium/aluminium-containing    Elvitegravir (antacid suspension It is recommended to separate antacid suspension (20 mL single  after ± 2 hours):                Gendevra and administration of dose)/ Elvitegravir (50 mg single AUC: ↔                           antacids, medicinal products or oral dose)/ Ritonavir (100 mg single   Cmin: ↔                          supplements containing polyvalent dose)                             Cmax: ↔                          cations by at least 4 hours.

Elvitegravir (simultaneous             For information on other acid administration):                       reducing agents (e.g., H2-receptor AUC: ↓ 45%                             antagonists and proton pump
Cmin: ↓ 41%                            inhibitors), see “Studies conducted Cmax: ↓ 47%                            with other medicinal products”.

Elvitegravir plasma concentrations are lower with antacids due to local complexation in the gastrointestinal tract and not to changes in gastric pH.



Medicinal product by             Effects on medicinal product           Recommendation concerning therapeutic areas                           levels.                  co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
Calcium or iron supplements         Interaction not studied with any of (including multivitamins)           the components of Gendevra.
Other cation-containing antacids
Cation-containing laxatives         Elvitegravir plasma concentrations Sucralfate                          are expected to be lower with
Buffered medicinal products         antacids, medicinal products or oral supplements containing polyvalent cations, due to local complexation in the gastrointestinal tract and not to changes in gastric pH.
ORAL ANTI-DIABETICS
Metformin                           Interaction not studied with any of     Careful patient monitoring and dose the components of Gendevra.             adjustment of metformin is recommended in patients who are
Cobicistat reversibly inhibits          taking Gendevra.
MATE1, and concentrations of metformin may be increased when co-administered with Gendevra.
NARCOTIC ANALGESICS
Methadone (80-120 mg)/              Methadone:                              No dose adjustment of methadone is Elvitegravir (150 mg once daily)/   AUC: ↔                                  required.
Cobicistat (150 mg once daily)      Cmin: ↔
Cmax: ↔

Cobicistat:
AUC: ↔
Cmin: ↔
Cmax: ↔

Elvitegravir:
AUC: ↔
Cmin: ↔
Cmax: ↔
Buprenorphine/Naloxone (16/4 to     Buprenorphine:                          No dose adjustment of 24/6 mg)/ Elvitegravir (150 mg      AUC: ↑ 35%                              buprenorphine/naloxone is required.
once daily)/ Cobicistat (150 mg     Cmin: ↑ 66% once daily)                         Cmax: ↔

Naloxone:
AUC: ↓ 28%
Cmax: ↓ 28%

Cobicistat:
AUC: ↔
Cmin: ↔
Cmax: ↔
Elvitegravir:
AUC: ↔
Cmin: ↔
Cmax: ↔



Medicinal product by             Effects on medicinal product           Recommendation concerning therapeutic areas                          levels.                   co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
ORAL CONTRACEPTIVES
Drospirenone/Ethinyloestradiol        Interaction not studied with          Plasma concentrations of (3 mg/0.02 mg single dose)/           Gendevra.                             drospirenone may be increased Cobicistat (150 mg once daily)                                              when co-administered with Expected                              cobicistat-containing products.
Drospirenone:                         Clinical monitoring is recommended AUC: ↑                                due to the potential for hyperkalaemia.
Norgestimate                          Norelgestromin:
(0.180/0.215/0.250 mg once daily)/    AUC: ↔                                Caution should be exercised when Ethinyloestradiol (0.025 mg once      Cmin: ↔                               co-administering Gendevra and a daily)/ Emtricitabine/Tenofovir       Cmax: ↔                               hormonal contraceptive. The alafenamide (200/25 mg once                                                 hormonal contraceptive should daily)6                               Norgestrel:                           contain at least 30 µg AUC: ↔                                ethinyloestradiol and contain Cmin: ↔                               drospirenone or norgestimate as the Cmax: ↔                               progestogen or patients should use an alternative reliable method of
Ethinyloestradiol:                    contraception (see sections 4.4 and AUC: ↔                                4.6).
Cmin: ↔
Cmax: ↔                               The long-term effects of substantial increases in progestogen exposure are unknown.
Norgestimate (0.180/0.215 mg          Norgestimate: once daily)/ Ethinyloestradiol        AUC: ↑ 126%
(0.025 mg once daily)/ Elvitegravir   Cmin: ↑ 167%
(150 mg once daily)/ Cobicistat       Cmax: ↑ 108%
(150 mg once daily)4
Ethinyloestradiol:
AUC: ↓ 25%
Cmin: ↓ 44%
Cmax: ↔

Elvitegravir:
AUC: ↔
Cmin: ↔
Cmax: ↔
ANTIARRHYTHMICS
Digoxin (0.5 mg single dose)/         Digoxin:                              It is recommended that digoxin Cobicistat (150 mg multiple doses)    AUC: ↔                                levels be monitored when digoxin is Cmax: ↑ 41%                           combined with Gendevra.
Disopyramide                          Interaction not studied with any of   Caution is warranted and clinical Flecainide                            the components of Gendevra.           monitoring is recommended upon Systemic lidocaine                                                          co-administration with Gendevra.
Mexiletine                            Concentrations of these
Propafenone                           antiarrhythmic drugs may be increased when co-administered with cobicistat.
ANTI-HYPERTENSIVES
Metoprolol                            Interaction not studied with any of   Clinical monitoring is recommended Timolol                               the components of Gendevra.           and a dose decrease may be necessary when these agents are
Concentrations of beta-blockers       co-administered with Gendevra.
may be increased when co-administered with cobicistat.



Medicinal product by       Effects on medicinal product          Recommendation concerning therapeutic areas                     levels.                 co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
Amlodipine                    Interaction not studied with any of    Clinical monitoring of therapeutic Diltiazem                     the components of Gendevra.            effects and adverse reactions is Felodipine                                                           recommended when these medicinal Nicardipine             Concentrations of calcium channel            products are concomitantly Nifedipine              blockers may be increased when               administered with Gendevra.
Verapamil               co-administered with cobicistat.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan                Interaction not studied with any of          Alternative endothelin receptor the components of Gendevra.                  antagonists may be considered.

Co-administration with Gendevra may lead to decreased elvitegravir and/or cobicistat exposures and loss of therapeutic effect and development of resistance.
ANTICOAGULANTS
Dabigatran                    Interaction not studied with any of    Co-administration of Gendevra with the components of Gendevra.            dabigatran is contraindicated.

Co-administration with Gendevra may increase dabigatran plasma concentrations with similar effects as seen with other strong P-gp inhibitors.
Apixaban                      Interaction not studied with any of    Co-administration of apixaban, Rivaroxaban                   the components of Gendevra.            rivaroxaban or edoxaban is not Edoxaban                                                             recommended with Gendevra.
Co-administration with Gendevra may result in increased plasma concentrations of the DOAC,
which may lead to an increased bleeding risk.
Warfarin                      Interaction not studied with any of    It is recommended that the the components of Gendevra.            international normalised ratio (INR) be monitored upon
Concentrations of warfarin may be      co-administration of Gendevra. INR affected upon co-administration        should continue to be monitored with Gendevra.                         during the first weeks following ceasing treatment with Gendevra.
ANTIPLATELETS
Clopidogrel                   Interaction not studied with any of    Co-administration of Gendevra with the components of Gendevra.            clopidogrel is not recommended.

Co-administration of clopidogrel with cobicistat is expected to decrease clopidogrel active metabolite plasma concentrations,
which may reduce the antiplatelet activity of clopidogrel.
Prasugrel                     Interaction not studied with any of    No dose adjustment of prasugrel is the components of Gendevra.            required.

Gendevra is not expected to have a clinically relevant effect on plasma concentrations of the active metabolite of prasugrel.



Medicinal product by            Effects on medicinal product           Recommendation concerning therapeutic areas                         levels.                   co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
INHALED BETA AGONIST
Salmeterol                          Interaction not studied with any of    Concurrent administration of the components of Gendevra.            salmeterol and Gendevra is not recommended.
Co-administration with Gendevra may result in increased plasma concentrations of salmeterol, which is associated with the potential for serious or life-threatening adverse reactions.
HMG CO-A REDUCTASE INHIBITORS
Rosuvastatin (10 mg single dose)/ Elvitegravir:                            Concentrations of rosuvastatin are Elvitegravir (150 mg once daily)/ AUC: ↔                                   transiently increased when Cobicistat (150 mg once daily)    Cmin: ↔                                  administered with elvitegravir and Cmax: ↔                                  cobicistat. Dose modifications are not necessary when rosuvastatin is
Rosuvastatin:                          administered in combination with AUC: ↑ 38%                             Gendevra.
Cmin: N/A
Cmax: ↑ 89%
Atorvastatin (10 mg single          Atorvastatin:                          Concentrations of atorvastatin are dose)/Elvitegravir (150 mg once     AUC: ↑ 160%                            increased when co-administered daily)/Cobicistat (150 mg once      Cmin: N/A                              with elvitegravir and cobicistat.
daily)/Emtricitabine (200 mg once   Cmax: ↑ 132%                           Start with the lowest possible dose daily)/Tenofovir alafenamide                                               of atorvastatin with careful (10 mg once daily)                  Elvitegravir:                          monitoring upon co-administration AUC: ↔                                 with Gendevra.
Cmin: ↔
Cmax: ↔
Pitavastatin                        Interaction not studied with any of    Caution should be exercised when the components of Gendevra.            co-administering Gendevra with pitavastatin.
Concentrations of pitavastatin may be increased when administered with elvitegravir and cobicistat.
Pravastatin                         Interaction not studied with any of    Dose modifications are not Fluvastatin                         the components of Gendevra.            necessary when administered in combination with Gendevra.
Concentrations of these
HMG Co-A reductase inhibitors are expected to transiently increase when administered with elvitegravir and cobicistat.
Lovastatin                          Interaction not studied with any of    Co-administration of Gendevra and Simvastatin                         the components of Gendevra.            lovastatin and simvastatin is contraindicated (see section 4.3).
LIPID-MODIFYING AGENTS



Medicinal product by            Effects on medicinal product           Recommendation concerning therapeutic areas                         levels.                   co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
Lomitapide                           Interaction not studied with any      Coadministration with of the components of Gendevra.        lomitapide is contraindicated
(see section 4.3).
Lomitapide is highly dependent on CYP3A for its metabolism and co-administration with
Gendevra may result in increased concentrations of lomitapide and potential for markedly increased transaminases.
PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS
Sildenafil                   Interaction not studied with any of           Co-administration of Gendevra and Tadalafil                         the components of Gendevra.              sildenafil for the treatment of Vardenafil                                                                 pulmonary arterial hypertension is PDE-5 inhibitors are primarily                  contraindicated.
metabolised by CYP3A.
Co-administration with Gendevra                 Caution should be exercised, may result in increased plasma                  including consideration of dose concentrations of sildenafil and                reduction, when co-administering tadalafil, which may result in                  Gendevra with tadalafil for the PDE-5 inhibitor-associated adverse              treatment of pulmonary arterial reactions.                                      hypertension.

For the treatment of erectile dysfunction, it is recommended that a single dose of sildenafil no more than 25 mg in 48 hours, vardenafil no more than 2.5 mg in 72 hours, or tadalafil no more than 10 mg in
72 hours be co-administered with
Gendevra.
ANTIDEPRESSANTS
Sertraline (50 mg single dose)/      Elvitegravir:                         Concentrations of sertraline are not Elvitegravir (150 mg once daily)/    AUC: ↔                                affected upon co-administration Cobicistat (150 mg once daily)/      Cmin: ↔                               with Gendevra. No dose adjustment Emtricitabine (200 mg once daily)/   Cmax: ↔                               is required upon co-administration.
Tenofovir alafenamide (10 mg once daily)5                         Tenofovir alafenamide:
AUC: ↔
Cmin: ↔
Cmax: ↔

Sertraline:
AUC: ↔
Cmin: ↔
Cmax: ↔
Tricyclic antidepressants (TCAs)     Interaction not studied with any of   Careful dose titration of the Trazodone                            the components of Gendevra.           antidepressant and monitoring for Selective serotonin reuptake                                               antidepressant response is inhibitors (SSRIs)                   Concentrations of antidepressant      recommended.
Escitalopram                         agents may be increased when co-administered with cobicistat.



Medicinal product by         Effects on medicinal product           Recommendation concerning therapeutic areas                      levels.                   co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
IMMUNOSUPPRESSANTS
Ciclosporin                       Interaction not studied with any of   Therapeutic monitoring is Sirolimus                         the components of Gendevra.           recommended upon Tacrolimus                                                              co-administration with Gendevra.
Concentrations of these immunosuppressant agents may be increased when administered with cobicistat.
SEDATIVES/HYPNOTICS
Buspirone                         Interaction not studied with any of   Co-administration of Gendevra and Clorazepate                       the components of Gendevra.           triazolam is contraindicated (see Diazepam                                                                section 4.3). With other Estazolam                         Triazolam is primarily metabolised    sedatives/hypnotics, dose reduction Flurazepam                        by CYP3A. Co-administration           may be necessary and concentration Lorazepam                         with Gendevra may result in           monitoring is recommended.
Triazolam                         increased plasma concentrations of
Zolpidem                          this medicinal product, which is associated with the potential for serious or life-threatening adverse reactions.

Concentrations of other benzodiazepines, including diazepam, may be increased when administered with Gendevra.

Based on non-CYP-mediated elimination pathways for lorazepam, no effect on plasma concentrations is expected upon co-administration with Gendevra.
Orally administered midazolam     Midazolam:                            Co-administration of Gendevra and (2.5 mg single dose)/ Tenofovir   AUC: ↔                                orally administered midazolam is alafenamide (25 mg once daily)    Cmax: ↔                               contraindicated (see section 4.3).

Intravenously administered        Midazolam is primarily midazolam (1 mg single dose)/     metabolised by CYP3A. Due to
Tenofovir alafenamide (25 mg      the presence of cobicistat,
once daily)                       co-administration with Gendevra may result in increased plasma concentrations of this medicinal product, which is associated with the potential for serious or life-threatening adverse reactions.



Medicinal product by                Effects on medicinal product             Recommendation concerning therapeutic areas                             levels.                     co-administration with Gendevra Mean percent change in AUC,
Cmax, Cmin1
ANTI-GOUT
Colchicine                               Interaction not studied with any of      Dose reductions of colchicine may the components of Gendevra.              be required. Gendevra should not be co-administered with colchicine
Co-administration with Gendevra          to patients with renal or hepatic may result in increased plasma           impairment.
concentrations of this medicinal product.
N/A = not applicable
DOAC = direct oral anticoagulant
1  When data available from drug-drug interaction studies.
2  These studies were performed with ritonavir boosted elvitegravir.
3  These are medicinal products within class where similar interactions could be predicted.
4  This study was conducted using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil.
5  This study was conducted using Gendevra.
6  This study was conducted using emtricitabine/tenofovir alafenamide.
7  This study was conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV- infected patients.

Studies conducted with other medicinal products

Based on drug-drug interaction studies conducted with Gendevra or the components of Gendevra, no clinically significant drug-drug interactions have been either observed or are expected between the components of Gendevra and the following medicinal products: entecavir, famciclovir, ribavirin, famotidine, and omeprazole.