Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

As Stribild contains elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil, any interactions that have been identified with these active substances individually may occur with Stribild. Stribild is indicated for use as a complete regimen for the treatment of HIV-1 infection and must not be administered with other antiretroviral products. Therefore, information regarding drug-drug interactions with other antiretroviral products (including protease inhibitors and non-nucleoside reverse transcriptase inhibitors) is not provided (see section 4.4). Interaction studies have only been performed in adults.

Cobicistat is a strong mechanism-based CYP3A inhibitor and a CYP3A substrate. Cobicistat is also a weak CYP2D6 inhibitor and is metabolised, to a minor extent, by CYP2D6. The transporters that cobicistat inhibits include P-gp, BCRP, OATP1B1 and OATP1B3.

Co-administration of Stribild with medicinal products that are primarily metabolised by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of those products, which could increase or prolong their therapeutic effect and adverse reactions (see Concomitant use contraindicated and section 4.3). Co-administration of Stribild with medicinal products that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s).

Co-administration of Stribild with medicinal products that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased cobicistat plasma concentrations.

Elvitegravir is a modest inducer and may have the potential to induce CYP2C9 and/or inducible UGT enzymes; as such it may decrease the plasma concentration of substrates of these enzymes.
Elvitegravir is metabolised by CYP3A and, to a minor extent, by UGT1A1. Medicinal products that induce CYP3A activity are expected to increase the clearance of elvitegravir, resulting in decreased plasma concentration of elvitegravir which may lead to loss of therapeutic effect of Stribild and development of resistance (see Concomitant use contraindicated and section 4.3).

Concomitant use contraindicated

Co-administration of Stribild 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 and/or life-threatening 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 Stribild and other medicinal products primarily metabolised by CYP3A such as amiodarone, quinidine, cisapride, pimozide, lurasidone, alfuzosin and sildenafil for pulmonary arterial hypertension is contraindicated (see section 4.3).

Co-administration of Stribild 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).

Concomitant use not recommended

Renally eliminated medicinal products
Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Stribild with medicinal products that reduce renal function or compete for active tubular secretion (e.g.
cidofovir) may increase serum concentrations of emtricitabine, tenofovir and/or the co-administered medicinal products.

Use of Stribild should be avoided with concurrent or recent use of nephrotoxic medicinal products.
Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (also called aldesleukin).

Other interactions

Interactions between the components of Stribild 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 the components of Stribild as individual agents and/or in combination, or are potential drug interactions that may occur with Stribild.

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

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


Medicinal product by therapeutic             Effects on drug levels                Recommendation concerning areas                     Mean percent change in AUC, Cmax,          co-administration with Stribild Cmin1
Antimycobacterials
Rifabutin (150 mg every other         Co-administration of rifabutin, potent     Co-administration of Stribild and day)/Elvitegravir (150 mg once        CYP3A inducer, may significantly           rifabutin is not recommended. If the daily)/Cobicistat (150 mg once        decrease cobicistat and elvitegravir       combination is needed, the daily)                                plasma concentrations, which may           recommended dose of rifabutin is result in 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: ↔

Hepatitis C virus (HCV) antiviral agents
Ledipasvir/Sofosbuvir               Interaction not studied with Stribild.       Increased plasma concentrations of tenofovir resulting from
Co-administration with Stribild may        co-administration of Stribild and lead to increased tenofovir exposure.      ledipasvir/sofosbuvir may increase Ledipasvir/Sofosbuvir                 Observed:                                  adverse reactions related to (90 mg/400 mg once daily) +                                                      tenofovir disoproxil, including renal Elvitegravir/Cobicistat               Ledipasvir:                                disorders. The safety of tenofovir (150 mg/150 mg once daily)            AUC: ↑ 78%                                 disoproxil when used with Cmin: ↑ 91%                                ledipasvir/sofosbuvir and a Cmax: ↑ 63%                                pharmacokinetic enhancer (e.g.
cobicistat) has not been established.
Sofosbuvir:
AUC: ↑ 36%                                 The combination should be used Cmin: N/A                                  with caution with frequent renal Cmax: ↑ 33%                                monitoring, if other alternatives are not available (see section 4.4).
GS-3310075:
AUC: ↑ 44%
Cmin: ↑ 53%
Cmax: ↑ 33%

Elvitegravir:
AUC: ↔
Cmin: ↑ 36%
Cmax: ↔

Cobicistat:
AUC: ↑ 59%
Cmin: ↑ 325%
Cmax: ↔


Medicinal product by therapeutic             Effects on drug levels         Recommendation concerning areas                    Mean percent change in AUC, Cmax,    co-administration with Stribild Cmin1
Sofosbuvir/Velpatasvir               Sofosbuvir:                          Increased plasma concentrations of (400 mg/100 mg once daily) +         AUC: ↔                               tenofovir resulting from Elvitegravir/Cobicistat/             Cmax: ↔                              co-administration of Stribild and Emtricitabine/Tenofovir Disoproxil                                        sofosbuvir/velpatasvir may increase (150 mg/150 mg/200 mg/245 mg         GS-3310075:                          adverse reactions related to once daily)                          AUC: ↔                               tenofovir disoproxil, including renal Cmax: ↔                              disorders. The safety of tenofovir Cmin: ↑ 45%                          disoproxil when used with sofosbuvir/velpatasvir and a
Velpatasvir:                         pharmacokinetic enhancer (e.g.
AUC: ↔                               cobicistat) has not been established.
Cmax: ↔
Cmin: ↑ 37%                          The combination should be used with caution with frequent renal
Elvitegravir:                        monitoring (see section 4.4).
AUC: ↔
Cmax: ↔
Cmin: ↔

Cobicistat:
AUC: ↔
Cmax: ↔
Cmin: ↑ 71%

Emtricitabine:
AUC: ↔
Cmax: ↔
Cmin: ↔
Tenofovir:
AUC: ↔
Cmax: ↑ 36%
Cmin: ↑ 45%


Medicinal product by therapeutic              Effects on drug levels           Recommendation concerning areas                    Mean percent change in AUC, Cmax,       co-administration with Stribild Cmin1
Sofosbuvir/Velpatasvir/              Co-administration with Stribild may     Increased plasma concentrations of Voxilaprevir (400 mg/100 mg/         lead to increased tenofovir exposure.   tenofovir resulting from 100 mg+100 mg once daily)6 +                                                 co-administration of Stribild and Emtricitabine/Tenofovir disoproxil   Emtricitabine:                          sofosbuvir/velpatasvir/voxilaprevir (200 mg/245 mg once daily)7          AUC: ↔                                  may increase adverse reactions Cmax: ↔                                 related to tenofovir disoproxil, Cmin: ↔                                 including renal disorders. The safety of tenofovir disoproxil when
Tenofovir:                              used with
AUC: ↑ 39%                              sofosbuvir/velpatasvir/voxilaprevir Cmax: ↑ 48%                             and a pharmacokinetic enhancer Cmin: ↑ 47%                             (e.g. cobicistat) has not been Sofosbuvir/Velpatasvir/              Sofosbuvir:                             established.
Voxilaprevir (400 mg/100 mg/         AUC: ↔
100 mg+100 mg once daily)6 +         Cmax: ↑ 27%                             The combination should be used Elvitegravir/Cobicistat              Cmin: N/A                               with caution with frequent renal (150 mg/150 mg once daily)8                                                  monitoring (see section 4.4).
GS-3310075:
AUC: ↑ 43%
Cmax:↔
Cmin: N/A

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

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

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


Medicinal product by                   Effects on drug levels             Recommendation concerning therapeutic areas             Mean percent change in AUC, Cmax,         co-administration with Stribild Cmin1
Nucleoside reverse transcriptase inhibitors (NRTIs)
Didanosine                          Co-administration of tenofovir            Co-administration of Stribild and disoproxil and didanosine results in a    didanosine is not recommended.
40-60% increase in systemic exposure to didanosine.                            Increased systemic exposure to didanosine may increase didanosine related adverse reactions. Rarely,
pancreatitis and lactic acidosis,
sometimes fatal, have been reported. Co-administration of tenofovir disoproxil and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count,
possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of
250 mg didanosine co-administered with tenofovir disoproxil therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of
HIV-1 infection.

However, in case of initiation of
Stribild in patients previously taking didanosine or discontinuation of Stribild and change to a regimen including didanosine there could be a short period when measurable plasma levels of didanosine and tenofovir occur.
Macrolide antibiotics
Clarithromycin                      Interaction not studied with any of the   No dose adjustment of components of Stribild.                   clarithromycin is required for patients with normal renal function
Concentrations of clarithromycin          or mild renal impairment (ClCr and/or cobicistat may be altered with     60-90 mL/min). Clinical monitoring co-administration of Stribild.            is recommended for patients with ClCr < 90 mL/min. For patients with ClCr < 60 mL/min, alternative antibacterials should be considered.
Telithromycin                       Interaction not studied with any of the   Clinical monitoring is components of Stribild.                   recommended upon co-administration of Stribild.
Concentrations of telithromycin and/or cobicistat may be altered with co-administration of Stribild.


GLUCOCORTICOIDS
Corticosteroids
Corticosteroids primarily           Interaction not studied with any of the     Concomitant use of Stribild and metabolised by CYP3A (including     components of Stribild.                     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 increased         corticosteroids) may increase the when co-administered with Stribild,         risk of development of systemic resulting in reduced serum cortisol         corticosteroid effects, including 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 after ± It is recommended to separate antacid suspension (20 mL single 2 hours):                                Stribild 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.
Calcium or iron supplements         Interaction not studied with any of the (including multivitamins)           components of Stribild.
Other cation-containing antacids
Cation-containing laxatives         Elvitegravir plasma concentrations are Sucralfate                          expected to be lower with antacids, Buffered medicinal products         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 the   Careful patient monitoring and dose components of Stribild.                   adjustment of metformin is recommended in patients who are
Cobicistat reversibly inhibits MATE1,     taking Stribild.
and concentrations of metformin may be increased when co-administered with Stribild.
NARCOTIC ANALGESICS
Methadone/Elvitegravir/Cobicistat   Methadone:                                No dose adjustment of methadone AUC: ↔                                    is required.
Cmin: ↔
Cmax: ↔

Cobicistat:
AUC: ↔
Cmin: ↔
Cmax: ↔

Elvitegravir:
AUC: ↔
Cmin: ↔
Cmax: ↔
Methadone/Tenofovir disoproxil      Methadone:
AUC: ↔
Cmin: ↔
Cmax: ↔
Tenofovir:
AUC: ↔
Cmin: ↔
Cmax: ↔
Buprenorphine/Naloxone/             Buprenorphine:                            No dose adjustment of Elvitegravir/Cobicistat             AUC: ↑ 35%                                buprenorphine/naloxone is Cmin: ↑ 66%                               required.
Cmax: ↔

Naloxone:
AUC: ↓ 28%
Cmax: ↓ 28%

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


ORAL CONTRACEPTIVES
Drospirenone/Ethinyloestradiol       Interaction not studied with Stribild.    Plasma concentrations of (3 mg/0.02 mg single                                                           drospirenone may be increased dose)/Cobicistat (150 mg once        Expected                                  when co-administered with daily)                               Drospirenone:                             cobicistat-containing products.
AUC: ↑                                    Clinical monitoring is recommended due to the potential for hyperkalemia.

Norgestimate (0.180/0.215 mg once    Norgestimate:                             Caution should be exercised when daily)/Ethinyloestradiol (0.025 mg   AUC: ↑ 126%                               co-administering Stribild and a once daily)/                         Cmin: ↑ 167%                              hormonal contraceptive. The Elvitegravir (150 mg once            Cmax: ↑ 108%                              hormonal contraceptive should daily)/Cobicistat (150 mg once                                                 contain at least 30 µg daily)4                              Ethinyloestradiol:                        ethinyloestradiol and contain AUC: ↓ 25%                                drospirenone or norgestimate as the Cmin: ↓ 44%                               progestogen or patients should use Cmax: ↔                                   an alternative reliable method of contraception (see sections 4.4 and
Elvitegravir:                             4.6).
AUC: ↔
Cmin: ↔                                   The long-term effects of substantial Cmax: ↔                                   increases in progestogen exposure are unknown.
ANTIARRHYTHMICS
Digoxin (0.5 mg single               Digoxin:                                  It is recommended that digoxin dose)/Cobicistat (150 mg multiple    AUC: ↔                                    levels be monitored when digoxin doses)                               Cmax: ↑ 41%                               is combined with Stribild.
Disopyramide                         Interaction not studied with any of the   Caution is warranted and clinical Flecainide                           components of Stribild.                   monitoring is recommended upon Systemic lidocaine                                                             co-administration with Stribild.
Mexiletine                           Concentrations of these antiarrhythmic Propafenone                          drugs may be increased when co-administered with cobicistat.
ANTI-HYPERTENSIVES
Metoprolol                           Interaction not studied with any of the   Clinical monitoring is Timolol                              components of Stribild.                   recommended and a dose decrease may be necessary when these
Concentrations of beta-blockers may be    agents are co-administered with increased when co-administered with       Stribild.
cobicistat.
Amlodipine                           Interaction not studied with any of the   Clinical monitoring of therapeutic Diltiazem                            components of Stribild.                   and adverse effects is recommended Felodipine                                                                     when these medicinal products are Nicardipine              Concentrations of calcium channel                     concomitantly administered with Nifedipine               blockers may be increased when                        Stribild.
Verapamil                co-administered with cobicistat.
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan                 Interaction not studied with any of the               Alternative endothelin receptor components of Stribild.                               antagonists may be considered.

Co-administration with Stribild 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 the   Co-administration of Stribild with components of Stribild.                   dabigatran is contraindicated.

Co-administration with Stribild may increase dabigatran plasma concentrations with similar effects as seen with other strong P-gp inhibitors.
Apixaban         Interaction not studied with any of the   Co-administration of apixaban, Rivaroxaban      components of Stribild.                   rivaroxaban or edoxaban is not Edoxaban                                                   recommended with Stribild.
Co-administration with Stribild may result in increased plasma concentrations of the DOAC, which may lead to an increased bleeding risk.
Warfarin         Interaction not studied with any of the   It is recommended that the components of Stribild.                   international normalised ratio (INR) be monitored upon
Concentrations of warfarin may be         co-administration of Stribild. INR affected upon co-administration with      should continue to be monitored Stribild.                                 during the first weeks following ceasing treatment with Stribild.
ANTIPLATELETS
Clopidogrel      Interaction not studied with any of the   Co-administration of clopidogrel components of Stribild.                   with Stribild 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 the   No dose adjustment of prasugrel is components of Stribild.                   required.

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


ANTICONVULSANTS
Carbamazepine (200 mg twice          Co-administration of carbamazepine, a     Co-administration of Stribild with daily)/Elvitegravir (150 mg once     potent CYP3A inducer, may                 carbamazepine, phenobarbital, or daily)/Cobicistat (150 mg once       significantly decrease cobicistat and     phenytoin is contraindicated (see daily)                               elvitegravir plasma concentrations,       section 4.3).
which may result in loss of therapeutic effect and development of resistance.

Carbamazepine:
AUC: ↑ 43%
Cmin: ↑ 51%
Cmax: ↑ 40%

Elvitegravir:
AUC: ↓ 69%
Cmin: ↓ 97%
Cmax: ↓ 45%
Cobicistat:
AUC: ↓ 84%
Cmin: ↓ 90%
Cmax: ↓ 72%

Carbamazepine-10,11-epoxide:
AUC: ↓ 35%
Cmin: ↓ 41%
Cmax: ↓ 27%
INHALED BETA AGONIST
Salmeterol                           Interaction not studied with any of the   Concurrent administration of components of Stribild.                   salmeterol and Stribild is not recommended.
Co-administration with Stribild may result in increased plasma concentrations of salmeterol, which is associated with the potential for serious and/or life-threatening reactions.
HMG CO-A REDUCTASE INHIBITORS
Rosuvastatin (10 mg single        Elvitegravir:                                Concentrations of rosuvastatin are dose)/Elvitegravir (150 mg single AUC: ↔                                       transiently increased when dose)/Cobicistat (150 mg single   Cmin: ↔                                      administered with elvitegravir and dose)                             Cmax: ↔                                      cobicistat. Dose modifications are not necessary when rosuvastatin is
Rosuvastatin:                             administered in combination with AUC: ↑ 38%                                Stribild.
Cmin: N/A
Cmax: ↑ 89%
Atorvastatin (10 mg single dose)/    Atorvastatin:                             Concentrations of atorvastatin are Elvitegravir (150 mg once daily)/    AUC: ↑160%                                increased when co-administered Cobicistat (150 mg once daily)/      Cmin: NC                                  with elvitegravir and cobicistat.
Emtricitabine (200 mg once daily)/   Cmax: ↑132%                               Start with the lowest possible dose Tenofovir alafenamide (10 mg once                                              of atorvastatin with careful daily)                               Elvitegravir:                             monitoring upon co-administration AUC: ↔                                    with Stribild.
Cmin: ↔
Cmax: ↔
Pitavastatin                         Interaction not studied with any of the   Caution should be exercised when components of Stribild.                   co-administering Stribild with pitavastatin.
Concentrations of pitavastatin may be increased when administered with elvitegravir and cobicistat.


Pravastatin                      Interaction not studied with any of the     Dose modifications are not Fluvastatin                      components of Stribild.                     necessary when administered in combination with Stribild.
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 the     Co-administration of Stribild and Simvastatin                      components of Stribild.                     lovastatin and simvastatin is contraindicated (see section 4.3).
PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS
Sildenafil                 Interaction not studied with any of the           Co-administration of Stribild and Tadalafil                  components of Stribild.                           sildenafil for the treatment of Vardenafil                                                                   pulmonary arterial hypertension is PDE-5 inhibitors are primarily                    contraindicated.
metabolised by CYP3A.
Co-administration with Stribild may               Caution should be exercised, result in increased plasma                        including consideration of dose concentrations of sildenafil and                  reduction, when co-administering tadalafil, which may result in PDE-5              Stribild with tadalafil for the inhibitor-associated adverse reactions.           treatment of pulmonary arterial 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
Stribild.
ANTIDEPRESSANTS
Escitalopram                     Interaction not studied with any of the     Careful dose titration of the Trazodone                        components of Stribild.                     antidepressant and monitoring for antidepressant response is
Concentrations of trazodone may             recommended.
increase upon co-administration with cobicistat.
IMMUNOSUPPRESSANTS
Ciclosporin                      Interaction not studied with any of the     Therapeutic monitoring is Sirolimus                        components of Stribild.                     recommended upon Tacrolimus                                                                   co-administration with Stribild.
Concentrations of these immunosuppressant agents may be increased when administered with cobicistat.
SEDATIVES/HYPNOTICS
Buspirone                        Interaction not studied with any of the     Co-administration of Stribild and Clorazepate                      components of Stribild.                     orally administered midazolam and Diazepam                                                                     triazolam is contraindicated (see Estazolam                        Midazolam and triazolam are primarily       section 4.3). With other Flurazepam                       metabolised by CYP3A.                       sedatives/hypnotics, dose reduction Orally administered midazolam    Co-administration with Stribild may         may be necessary and concentration Triazolam                        result in increased plasma                  monitoring is recommended.
Zolpidem                         concentrations of these drugs, which is associated with the potential for serious and/or life-threatening reactions.


ANTI-GOUT
Colchicine                               Interaction not studied with any of the       Dose reductions of colchicine may components of Stribild.                       be required. Stribild should not be co-administered with colchicine to
Co-administration with Stribild may           patients with renal or hepatic result in increased plasma                    impairment.
concentrations of this drug.
N/A = not applicable
NC = not calculated
DOAC = direct oral anticoagulant
1  When data available from drug interaction studies.
2  Studies performed with ritonavir boosted elvitegravir.
3  These are drugs within class where similar interactions could be predicted.
4  Study conducted using Stribild.
5  The predominant circulating metabolite of sofosbuvir.
6  Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
7  Study conducted with emtricitabine/tenofovir disoproxil + darunavir (800 mg) + ritonavir (100 mg).
8  Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed dose combination tablet.

Studies conducted with other medicinal products

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