Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.


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

Bictegravir

Bictegravir is a substrate of CYP3A and UGT1A1. Co-administration of bictegravir and medicinal products that potently induce both CYP3A and UGT1A1, such as rifampicin or St. John’s wort, may significantly decrease plasma concentrations of bictegravir, which may result in a loss of therapeutic effect of Biktarvy and development of resistance, therefore co-administration is contraindicated (see section 4.3). Co-administration of bictegravir with medicinal products that potently inhibit both CYP3A and UGT1A1, such as atazanavir, may significantly increase plasma concentrations of bictegravir, therefore co-administration is not recommended.

Bictegravir is both a P-gp and a BCRP substrate. The clinical relevance of this feature is not established. Therefore, caution is recommended when bictegravir is combined with medicinal products known to inhibit P-gp and/or BCRP (e.g. macrolides, ciclosporin, verapamil, dronedarone, glecaprevir/pibrentasvir) (see also table below).

Bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro. Co-administration of Biktarvy with the OCT2 and MATE1 substrate metformin did not result in a clinically significant increase in metformin exposure. Biktarvy may be co-administered with substrates of OCT2 and MATE1.

Bictegravir is not an inhibitor or inducer of CYP in vivo.

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-glycoprotein (P–gp) and breast cancer resistance protein (BCRP). Co-administration of Biktarvy with medicinal products that strongly affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption. Medicinal products that induce P-gp activity (e.g. rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Biktarvy and development of resistance. Co-administration of Biktarvy with other medicinal products that inhibit P-gp and BCRP may increase the absorption and plasma concentration of tenofovir alafenamide.

Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo.

Other interactions
Interactions between Biktarvy or its individual component(s) and co-administered medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓” and no change as “↔”; all No Effect Boundaries are 70%-143%).



Table 1: Interactions between Biktarvy or its individual component(s) and other medicinal products

Medicinal product by          Effects on medicinal product          Recommendation concerning therapeutic areas/possible                 levels.                      co-administration with mechanism of interaction        Mean percent change in AUC,                   Biktarvy Cmax, Cmin
HERBAL PRODUCTS
St. John’s wort (Hypericum        Interaction not studied with any of   Co-administration with St. John's perforatum)                       the components of Biktarvy.           wort is contraindicated, due to the Co-administration may decrease        effect of St. John’s wort on the (Induction of CYP3A, UGT1A1,      bictegravir and tenofovir             bictegravir component of and P-gp)                         alafenamide plasma                    Biktarvy.
concentrations.
ANTI-INFECTIVES
Antimycobacterials
Rifampicin (600 mg once daily),   Bictegravir:                          Co-administration is Bictegravir1                      AUC: ↓ 75%                            contraindicated due to the effect Cmax: ↓ 28%                           of rifampicin on the bictegravir (Induction of CYP3A, UGT1A1,                                            component of Biktarvy.
and P-gp)                         Interaction not studied with tenofovir alafenamide.
Co-administration of rifampicin may decrease tenofovir alafenamide plasma concentrations.
Rifabutin (300 mg once daily),    Bictegravir:                          Co-administration is not Bictegravir1                      AUC: ↓ 38%                            recommended due to the expected Cmin: ↓ 56%                           decrease of tenofovir
(Induction of CYP3A and P-gp)     Cmax: ↓ 20%                           alafenamide.

Interaction not studied with tenofovir alafenamide.
Co-administration of rifabutin may decrease tenofovir alafenamide plasma concentrations.
Rifapentine                       Interaction not studied with any of   Co-administration is not the components of Biktarvy.           recommended.
(Induction of CYP3A and P-gp)     Co-administration of rifapentine may decrease bictegravir and tenofovir alafenamide plasma concentrations.



Medicinal product by             Effects on medicinal product       Recommendation concerning therapeutic areas/possible                    levels.                   co-administration with mechanism of interaction           Mean percent change in AUC,                Biktarvy Cmax, Cmin
HIV-1 antiviral agents
Atazanavir (300 mg once daily),      Bictegravir:                       Co-administration is not Cobicistat (150 mg once daily),      AUC: ↑ 306%                        recommended.
Bictegravir1                         Cmax: ↔

(Inhibition of CYP3A, UGT1A1,
and P-gp/BCRP)
Atazanavir (400 mg once daily),      Bictegravir:
Bictegravir1                         AUC: ↑ 315%
Cmax: ↔
(Inhibition of CYP3A and
UGT1A1)
Hepatitis C virus antiviral agents
Ledipasvir/Sofosbuvir                Bictegravir:                       No dose adjustment is required (90 mg/400 mg once daily),           AUC: ↔                             upon co-administration.
Bictegravir/Emtricitabine/           Cmin: ↔
Tenofovir alafenamide2               Cmax: ↔

Emtricitabine:
AUC: ↔
Cmin: ↔
Cmax: ↔

Tenofovir alafenamide:
AUC: ↔
Cmax: ↔
Ledipasvir:
AUC: ↔
Cmin: ↔
Cmax: ↔

Sofosbuvir:
AUC: ↔
Cmax: ↔

Sofosbuvir metabolite GS-331007:
AUC: ↔
Cmin: ↔
Cmax: ↔


Medicinal product by              Effects on medicinal product         Recommendation concerning therapeutic areas/possible                      levels.                    co-administration with mechanism of interaction           Mean percent change in AUC,                   Biktarvy Cmax, Cmin
Sofosbuvir/Velpatasvir/              Bictegravir:                          No dose adjustment is required Voxilaprevir                         AUC: ↔                                upon co-administration.
(400/100/100 + 100 mg3 once          Cmin: ↔ daily), Bictegravir/Emtricitabine/   Cmax: ↔
Tenofovir alafenamide
Emtricitabine:
(Inhibition of P-gp/BCRP)            AUC: ↔
Cmin: ↔
Cmax: ↔

Tenofovir alafenamide:
AUC: ↑ 57%
Cmax: ↑ 28%

Sofosbuvir:
AUC: ↔
Cmax: ↔
Sofosbuvir metabolite GS-331007:
AUC: ↔
Cmin: ↔
Cmax: ↔

Velpatasvir:
AUC: ↔
Cmin: ↔
Cmax: ↔

Voxilaprevir:
AUC: ↔
Cmin: ↔
Cmax: ↔
Antifungals
Voriconazole (300 mg twice           Bictegravir:                          No dose adjustment is required daily), Bictegravir1                 AUC: ↑ 61%                            upon co-administration.
Cmax: ↔
(Inhibition of CYP3A)
Itraconazole                         Interaction not studied with any of Posaconazole                         the components of Biktarvy.
Co-administration of itraconazole
(Inhibition of P-gp/BCRP)            or posaconazole may increase bictegravir plasma concentrations.
Macrolides
Azithromycin                         Interaction not studied.              Caution is recommended due to Clarithromycin                       Co-administration of azithromycin     the potential effect of these or clarithromycin may increase        medicinal products on the
(Inhibition of P-gp)                 bictegravir plasma concentrations.    bictegravir component of Biktarvy.



Medicinal product by           Effects on medicinal product        Recommendation concerning therapeutic areas/possible                  levels.                    co-administration with mechanism of interaction         Mean percent change in AUC,                 Biktarvy Cmax, Cmin
ANTICONVULSANTS
Carbamazepine (titrated from      Tenofovir alafenamide:               Co-administration is not 100 mg to 300 mg twice a day),    AUC: ↓ 54%                           recommended.
Emtricitabine/Tenofovir           Cmax: ↓ 57% alafenamide4
Interaction not studied with
(Induction of CYP3A, UGT1A1,     bictegravir.
and P-gp)                        Co-administration of carbamazepine may decrease bictegravir plasma concentrations.
Oxcarbazepine                    Interaction not studied with any of   Co-administration is not Phenobarbital                    the components of Biktarvy.           recommended.
Phenytoin                        Co-administration of oxcarbazepine, phenobarbital, or
(Induction of CYP3A, UGT1A1,     phenytoin may decrease bictegravir and P-gp)                        and tenofovir alafenamide plasma concentrations.
ANTACIDS, SUPPLEMENTS AND BUFFERED MEDICINES
Magnesium/aluminium-containing Bictegravir (antacid suspension         Biktarvy should not be taken antacid suspension (20 mL single 2 hours prior, fasted):               simultaneously with supplements dose5), Bictegravir              AUC: ↓ 52%                            containing magnesium and/or Cmax: ↓ 58%                           aluminium due to the expected (Chelation with polyvalent                                             substantial decrease of bictegravir cations)                         Bictegravir (antacid suspension       exposure (see section 4.4).
after 2 hours, fasted):
AUC: ↔                                Biktarvy should be administered Cmax: ↔                               at least 2 hours before, or with food 2 hours after antacids
Bictegravir (simultaneous            containing magnesium and/or administration, fasted):             aluminium.
AUC: ↓ 79%
Cmax: ↓ 80%

Bictegravir (simultaneous administration with food):
AUC: ↓ 47%
Cmax: ↓ 49%
Ferrous fumarate (324 mg single   Bictegravir (simultaneous            Biktarvy should be administered dose), Bictegravir                administration, fasted):             at least 2 hours before iron AUC: ↓ 63%                           supplements, or taken together (Chelation with polyvalent        Cmax: ↓ 71%                          with food.
cations)
Bictegravir (simultaneous administration with food):
AUC: ↔
Cmax: ↓ 25%



Medicinal product by           Effects on medicinal product         Recommendation concerning therapeutic areas/possible                    levels.                   co-administration with mechanism of interaction         Mean percent change in AUC,                  Biktarvy Cmax, Cmin
Calcium carbonate (1,200 mg       Bictegravir (simultaneous             Biktarvy and calcium-containing single dose), Bictegravir         administration, fasted):              supplements can be taken AUC: ↓ 33%                            together, without regard to food.
(Chelation with polyvalent        Cmax: ↓ 42% cations)
Bictegravir (simultaneous administration with food):
AUC: ↔
Cmax: ↔
Sucralfate                        Interaction not studied with any of   Co-administration not the components of Biktarvy.           recommended.
(Chelation with polyvalent        Co-administration may decrease cations)                          bictegravir plasma concentrations.
ANTIDEPRESSANTS
Sertraline (50 mg single dose),   Tenofovir alafenamide:                No dose adjustment is required Tenofovir alafenamide6            AUC: ↔                                upon co-administration.
Cmax: ↔

Sertraline:
AUC: ↔
Cmax: ↔

No interaction is expected with bictegravir and emtricitabine.
IMMUNOSUPPRESSANTS
Ciclosporin (IV or oral use)      Interaction not studied with any of   Co-administration of ciclosporin the components of Biktarvy.           (IV or oral use) is not
(P-gp inhibition)                 Co-administration of ciclosporin      recommended. If the combination (IV or oral use) is expected to       is needed, clinical and biological increase plasma concentrations of     monitoring, notably renal both bictegravir and tenofovir        function, is recommended.
alafenamide.
ORAL ANTI-DIABETICS
Metformin (500 mg twice daily),   Metformin:                            No dose adjustment is required Bictegravir/Emtricitabine/        AUC: ↑ 39%                            upon co-administration in patients Tenofovir alafenamide             Cmin: ↑ 36%                           with normal renal function.
Cmax: ↔
(Inhibition of OCT2/MATE1)                                              In patients with moderate renal impairment, close monitoring should be considered when starting co-administration of bictegravir with metformin, due to the increased risk for lactic acidosis in these patients. A dose adjustment of metformin should be considered if required.



Medicinal product by                 Effects on medicinal product             Recommendation concerning therapeutic areas/possible                        levels.                         co-administration with mechanism of interaction               Mean percent change in AUC,                      Biktarvy Cmax, Cmin
ORAL CONTRACEPTIVES
Norgestimate                            Norelgestromin:                          No dose adjustment is required (0.180/0.215/0.250 mg once              AUC: ↔                                   upon co-administration.
daily)/ Ethinylestradiol (0.025 mg      Cmin: ↔ once daily), Bictegravir1               Cmax: ↔
Norgestimate
(0.180/0.215/0.250 mg once              Norgestrel: daily), Ethinylestradiol (0.025 mg      AUC: ↔ once daily),                            Cmin: ↔
Emtricitabine/Tenofovir                 Cmax: ↔ alafenamide4
Ethinylestradiol:
AUC: ↔
Cmin: ↔
Cmax: ↔
SEDATIVES/HYPNOTICS
Midazolam (2 mg, oral syrup,            Midazolam:                               No dose adjustment is required single dose),                           AUC: ↔                                   upon co-administration.
Bictegravir/Emtricitabine/              Cmax: ↔
Tenofovir alafenamide
1     This study was conducted using bictegravir 75 mg single dose.
2     This study was conducted using bictegravir/emtricitabine/tenofovir alafenamide 75/200/25 mg once daily.
3     Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
4     This study was conducted using emtricitabine/tenofovir alafenamide 200/25 mg once daily.
5     Maximum strength antacid contained 80 mg aluminium hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone per mL.
6     This study was conducted using elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 150/150/200/10 mg once daily.

Based on drug interaction studies conducted with Biktarvy or the components of Biktarvy, no clinically significant drug interactions are expected with: amlodipine, atorvastatin, buprenorphine, drospirenone, famciclovir, famotidine, fluticasone, methadone, naloxone, norbuprenorphine, omeprazole or rosuvastatin.