Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Juluca is intended for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medicinal products for the treatment of HIV. Therefore, information regarding drug-drug interactions with other antiretroviral medicinal products is not provided. Juluca contains dolutegravir and rilpivirine, therefore any interactions identified with these active substances are relevant to Juluca. Interaction studies have only been performed in adults.

Effect of other medicinal products on the pharmacokinetics of dolutegravir and rilpivirine 
Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT)1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, cytochrome P450 (CYP)3A4, P- glycoprotein (P-gp), and breast cancer resistance protein (BCRP); therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 1). Co-administration of dolutegravir/rilpivirine and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 1).

The absorption of dolutegravir is reduced by certain anti-acid medicinal products (see Table 1).

Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration of dolutegravir/rilpivirine with medicinal products that induce CYP3A may result in decreased plasma concentrations of rilpivirine, which could reduce the therapeutic effect of dolutegravir/rilpivirine (see Table 1). Co-administration of dolutegravir/rilpivirine with medicinal products that inhibit CYP3A may result in increased plasma concentrations of rilpivirine (see Table 1). In patients with severe renal impairment or end stage renal disease, the combination of dolutegravir/rilpivirine with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk (see section 4.2).

Co-administration of dolutegravir/rilpivirine with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of dolutegravir/rilpivirine.

Effect of dolutegravir and rilpivirine on the pharmacokinetics of other medicinal products 
Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2).

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1). In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 1 and sections 4.3 and 4.4).

In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT)1 and OAT3.
Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3.

Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolised by CYP enzymes.

Rilpivirine inhibits P-gp in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increase the exposure to other medicinal products transported by P-gp that are more sensitive to intestinal P-gp inhibition, e.g. dabigatran etexilate.

Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinical implications of this finding are currently unknown.

Interaction table

Selected established and theoretical interactions between dolutegravir, rilpivirine and co-administered medicinal products are listed in Table 1.
(increase is indicated as “↑”, decrease as “ ”, no change as “ ”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, minimum observed concentration as “Cmin”concentration at end of dosing interval as “Cτ”).

Table 1:            Drug Interactions

Medicinal products      Interaction                          Recommendations concerning by therapeutic areas    Geometric mean change                co-administration (%)
Antiviral active substances
Tenofovir disoproxil / Dolutegravir                         No dose adjustment is required.
Dolutegravir1             AUC  1%

Cmax  3%
Cτ  8%

Tenofovir 
Tenofovir disoproxil /
Rilpivirine1,2           Rilpivirine
AUC
Cmin
Cmax

Tenofovir
AUC ↑ 23%
Cmin ↑ 24%
Cmax ↑ 19%
Tenofovir alafenamide    Dolutegravir        No dose adjustment is required.
/ Dolutegravir           (Not studied)

Tenofovir alafenamide
/ Rilpivirine1           Rilpivirine 
Lamivudine/              Dolutegravir        No dose adjustment is required.
Dolutegravir

Lamivudine/              Rilpivirine 
Rilpivirine              (Not studied)
Entecavir/               Dolutegravir        No dose adjustment is required.
Dolutegravir             (Not studied)

Entecavir/ Rilpivirine   Rilpivirine 
(Not studied)
Daclatasvir/             Dolutegravir        No dose adjustment is required.
Dolutegravir1              AUC  33%
Cmax  29%
C  45%
Daclatasvir 

Daclatasvir/             Rilpivirine 
Rilpivirine
Simeprevir/              Dolutegravir        No dose adjustment is required.
Dolutegravir

Simeprevir/              Rilpivirine 
Rilpivirine                AUC 
Cmin  25%
Cmax 
Simeprevir 
AUC 
Cmin 
Cmax  10%
Sofosbuvir /             Dolutegravir        No dose adjustment is required.
Dolutegravir1            (Not studied)


Sofosbuvir /             Rilpivirine 
Rilpivirine                AUC 
Cmin 
Cmax 
Sofosbuvir 
AUC 
Cmax  21%
Sofosbuvir metabolite GS-
331007 
AUC 
Cmax 
Ledipasvir/Sofosbuvir    Dolutegravir                   No dose adjustment is required.
/ Dolutegravir1          (Not studied)

Ledipasvir/Sofosbuvir    Rilpivirine 
/ Rilpivirine              AUC  5%
Cmin  7%
Cmax  3%
Ledipasvir 
AUC  2%
Cmin  2%
Cmax  1%
Sofosbuvir 
AUC  5%
Cmax  4%
Sofosbuvir metabolite GS-
331007 
AUC  8%
Cmin  10%
Cmax  8%
Sofosbuvir/              Dolutegravir                   No dose adjustment is required.
Velpatasvir/             (Not studied)
Dolutegravir1

Sofosbuvir/              Rilpivirine 
Velpatasvir/               AUC 
Rilpivirine                Cmin 
Cmax 
Sofosbuvir 
AUC 
Cmax 
Sofosbuvir metabolite GS-
331007 
AUC 
Cmin 
Cmax 
Velpatasvir 
AUC 
Cmin 
Cmax 
Ribavirin/               Dolutegravir                   No dose adjustment is required.
Dolutegravir             (Not studied)
Ribavirin/ Rilpivirine   Rilpivirine 
(Not studied)

Other active substances
Antiarrhythmics
Digoxin/ Dolutegravir Dolutegravir                     No dose adjustment is required.
(Not studied)

Digoxin/ Rilpivirine1   Rilpivirine 
Digoxin
AUC
Cmin NA
Cmax
Anticonvulsants
Carbamazepine/          Dolutegravir                   Metabolic inducers may significantly decrease Dolutegravir1            AUC  49%                      dolutegravir/rilpivirine plasma concentrations, Cmax  33%                     resulting in loss of therapeutic effect.
C  73%                       Co-administration of dolutegravir/rilpivirine with these metabolic inducers is contraindicated (see
Carbamazepine/          Rilpivirine                    section 4.3).
Rilpivirine             Not studied. Significant decreases in rilpivirine plasma concentrations are expected (induction of
CYP3A enzymes).
Oxcarbazepine           Dolutegravir                   Metabolic inducers may significantly decrease Phenytoin               Not studied. Decrease           dolutegravir/rilpivirine plasma concentrations, Phenobarbital/          expected due to induction of    resulting in loss of therapeutic effect.
Dolutegravir            UGT1A1 and CYP3A                Co-administration of dolutegravir/rilpivirine with enzymes, a similar reduction    these metabolic inducers is contraindicated (see in exposure as observed         section 4.3).
with carbamazepine is expected.
Oxcarbazepine
Phenytoin               Rilpivirine 
Phenobarbital/          Not studied. Significant
Rilpivirine             decreases in rilpivirine plasma concentrations are expected
(induction of CYP3A enzymes).
Azole anti-fungals
Ketoconazole/           Dolutegravir                   No dose adjustment is required.
Dolutegravir            (Not studied)

Ketoconazole/           Rilpivirine
Rilpivirine1,2            AUC ↑ 49%
Cmin ↑ 76%
Cmax ↑ 30%
(inhibition of CYP3A enzymes).

Ketoconazole
AUC 24%
Cmin 66%
Cmax

(induction of CYP3A due to high rilpivirine dose in the study).
Fluconazole            Dolutegravir                   No dose adjustment is required.
Itraconazole           (Not studied)
Isavuconazole
Posaconazole
Voriconazole/
Dolutegravir

Fluconazole            Rilpivirine ↑
Itraconazole           Not studied. May cause an
Isavuconazole          increase in the
Posaconazole           plasma concentrations of
Voriconazole/          rilpivirine
Rilpivirine            (inhibition of CYP3A enzymes).
Herbal products
St. John’s wort/       Dolutegravir                   Co-administration may cause significant decreases Dolutegravir           Not studied. Decrease           in rilpivirine plasma concentrations. This may expected due to induction of    result in loss of therapeutic effect of UGT1A1 and CYP3A                dolutegravir/rilpivirine. Co-administration of enzymes, a similar reduction    dolutegravir/rilpivirine with St. John’s wort is in exposure as observed         contraindicated (see section 4.3).
with carbamazepine is expected.
St. John’s wort/
Rilpivirine            Rilpivirine 
Not studied. Significant decreases in rilpivirine plasma concentrations are expected
(induction of CYP3A enzymes).
Potassium channel blockers
Fampridine (also       Fampridine                     Co-administration of dolutegravir has the potential known as                                               to cause seizures due to increased fampridine dalfampridine)/                                        plasma concentration via inhibition of OCT2 Dolutegravir                                           transporter; co-administration has not been studied.
Fampridine co-administration with dolutegravir/rilpivirine is contraindicated (see section 4.3).
Proton pump inhibitors
Omeprazole             Dolutegravir                   Co-administration may significantly decrease Lansoprazole           (Not studied)                   rilpivirine plasma concentration. This may result in Rabeprazole                                            loss of therapeutic effect of Pantoprazole                                           dolutegravir/rilpivirine. Co-administration of Esomeprazole/                                          dolutegravir/rilpivirine with proton pump Dolutegravir                                           inhibitors is contraindicated (see section 4.3).

Omeprazole/            Rilpivirine
Rilpivirine1,2          AUC 40%
Cmin 33%
Cmax 40%

(reduced absorption due to gastric pH increase).
Omeprazole
AUC 14%
Cmin NA
Cmax 14%


Lansoprazole            Rilpivirine 
Rabeprazole             Not studied. Significant
Pantoprazole            decreases in rilpivirine
Esomeprazole/           plasma concentrations are
Rilpivirine             expected
(reduced absorption due to gastric pH increase).
H2-recepter antagonists
Famotidine              Dolutegravir                 The combination of dolutegravir/rilpivirine and Cimetidine              (Not studied)                 H2-receptor antagonists should be used with Nizatidine                                            particular caution. Only H2-receptor antagonists Ranitidine/                                           that can be dosed once daily should be used.
Dolutegravir
H2-receptor antagonists should be taken well
Famotidine/             Rilpivirine                   separated in time from the administration of Rilpivirine1,2           AUC 9%                       dolutegravir/rilpivirine (minimum 4 hours after or 40 mg single dose        Cmin NA                      12 hours before) taken 12 hours before    Cmax rilpivirine

Famotidine/             Rilpivirine
Rilpivirine1,2            AUC 76%
40 mg single dose         Cmin NA taken 2 hours before      Cmax 85% rilpivirine             (reduced absorption due to gastric pH increase).

Famotidine/             Rilpivirine
Rilpivirine1,2           AUC ↑ 13%
40 mg single dose        Cmin NA taken 4 hours after      Cmax ↑ 21% rilpivirine
Cimetidine             Rilpivirine 
Nizatidine             Not studied. Significant
Ranitidine/            decreases in rilpivirine
Rilpivirine            plasma concentrations are expected (reduced absorption due to gastric pH increase).
Antacids and supplements
Antacids (e.g.,        Dolutegravir                  The combination of dolutegravir/rilpivirine and aluminium                AUC  74%                    antacids should be used with particular caution.
magnesium hydroxide,     Cmax  72%                   Antacids should be taken well separated in time and/or calcium           C24  74%                    from the administration of dolutegravir/rilpivirine (minimum 6 hours before or 4 hours after).

carbonate)/               (Complex binding to
Dolutegravir1             polyvalent ions).

Antacids (e.g.,           Rilpivirine  aluminium                 Not studied. Significant magnesium hydroxide,      decreases in rilpivirine and/or calcium            plasma concentrations are carbonate)/ Rilpivirine   expected
(reduced absorption due to gastric pH increase).
Calcium supplements/      Dolutegravir                 The combination of dolutegravir/rilpivirine and Dolutegravir1               AUC  39%                   supplements should be used with particular Cmax  37%                  caution. Calcium supplements, iron supplements or C24  39%                   multivitamins should be co-administered at the (Complex binding to           same time as dolutegravir/rilpivirine with a meal.
polyvalent ions).
Iron supplements/         Dolutegravir                 If calcium supplements, iron supplements or Dolutegravir1               AUC  54%                   multivitamins cannot be taken at the same time as Cmax  57%                  dolutegravir/rilpivirine, these supplements should C24  56%                   be taken well separated in time from the (Complex binding to           administration of dolutegravir/rilpivirine polyvalent ions).             (minimum 6 hours before or 4 hours after).
Multivitamin/             Dolutegravir 
Dolutegravir1               AUC  33%
Cmax  35%
C24  32%
(Complex binding to polyvalent ions).
Corticosteroids
Prednisone/               Dolutegravir                 No dose adjustment is required.
Dolutegravir1              AUC  11%
Cmax  6%
Cτ  17%

Prednisone/               Rilpivirine 
Rilpivirine               (Not studied)
Dexamethasone/            Dolutegravir               Co-administration may cause significant decreases Dolutegravir              (Not studied)               in rilpivirine plasma concentrations. This may result in loss of therapeutic effect of
Dexamethasone/            Rilpivirine                dolutegravir/rilpivirine. Co-administration of Rilpivirine               Not studied. Dose dependent dolutegravir/rilpivirine with systemic (systemic, except for     decreases in rilpivirine    dexamethasone is contraindicated (except as a single dose use)          plasma concentrations are   single dose) see section 4.3. Alternatives should be expected                    considered, particularly for long-term use.
(induction of CYP3A enzymes).
Antidiabetics
Metformin/                Metformin                    A dose adjustment of metformin should be Dolutegravir1              AUC  79%                    considered when starting and stopping co- Cmin NA                      administration of dolutegravir/rilpivirine with Cmax  66%                   metformin, to maintain glycaemic control. In patients with moderate renal impairment a dose
Metformin/                Metformin                     adjustment of metformin should be considered Rilpivirine1               AUC                          when co-administered with dolutegravir, because Cmin NA                      of the increased risk for lactic acidosis in patients 
Cmax                           with moderate renal impairment due to increased metformin concentration (section 4.4).
Antimycobacterials
Rifampicin/               Dolutegravir                   Co-administration may cause significant decreases Dolutegravir1               AUC  54%                     in rilpivirine plasma concentrations. This may Cmax  43%                    result in loss of therapeutic effect of Cτ 72%                       dolutegravir/rilpivirine. Co-administration of (induction of UGT1A1 and        dolutegravir/rilpivirine with rifampicin is CYP3A enzymes).                 contraindicated (see section 4.3).

Rifampicin/               Rilpivirine
Rilpivirine1,2              AUC 80%
Cmin 89%
Cmax 69%
(induction of CYP3A enzymes).

Rifampicin
AUC
Cmin NA
Cmax
25-desacetyl-rifampicin
AUC 9%
Cmin NA
Cmax
Rifabutin/                Dolutegravir                   Co-administration is likely to cause significant Dolutegravir1               AUC  5%                      decreases in rilpivirine plasma concentrations Cmax  16%                    (induction of CYP3A enzymes). When Juluca is Cτ  30%                      co-administered with rifabutin, an additional 25 (induction of UGT1A1 and        mg tablet of rilpivirine per day should be taken at CYP3A enzymes).                 the same time with Juluca, for the duration of the rifabutin co-administration (a separate formulation
Rifabutin/ Rilpivirine1   Rifabutin                       of rilpivirine is available for this dose adjustment, 300 mg once daily2          AUC                           see section 4.2).
Cmin
Cmax
25-O-desacetyl-rifabutin
AUC
Cmin
Cmax

300 mg once daily         Rilpivirine
(+ 25 mg once daily        AUC 42% rilpivirine)               Cmin 48%
Cmax 31%

300 mg once daily         Rilpivirine
(+ 50 mg once daily        AUC ↑ 16%* rilpivirine)               Cmin *
Cmax ↑ 43%*
* compared to 25 mg once daily rilpivirine alone



(induction of CYP3A enzymes).
Rifapentine/              Dolutegravir                      Co-administration may cause significant decreases Dolutegravir              (Not studied)                     in rilpivirine plasma concentrations. This may result in loss of therapeutic effect of
Rifapentine/              Rilpivirine                       dolutegravir/rilpivirine (induction of CYP3A Rilpivirine               Not studied. Significant          enzymes). Co-administration of decreases in rilpivirine          dolutegravir/rilpivirine with rifapentine is plasma concentrations are         contraindicated (see section 4.3).
expected.
Antimalarials
Artemether/               Dolutegravir                     The combination of dolutegravir/rilpivirine and Lumefantrine/             (Not studied)                     artemether/lumefantrine should be used with Dolutegravir                                                caution.

Artemether/               Rilpivirine
Lumefantrine/             Not studied. Decreased
Rilpivirine               exposure of rilpivirine is expected
(induction of CYP3A enzymes).
Atovaquone/               Dolutegravir                     No dose adjustment is required.
Proguanil/                (Not studied)
Dolutegravir

Atovaquone/               Rilpivirine
Proguanil/                (Not studied).
Rilpivirine
Macrolide antibiotics
Clarithromycin            Dolutegravir                     Where possible, alternatives such as azithromycin Erythromycin              (Not studied)                     should be considered.
/Dolutegravir

Clarithromycin            Rilpivirine 
Erythromycin              Not studied. Increased
/Rilpivirine              exposure of rilpivirine is expected
(inhibition of CYP3A enzymes).
Oral contraceptives
Ethinyl estradiol (EE)1   Dolutegravir                     Dolutegravir or rilpivirine did not change ethinyl and Norelgestromin        EE                               estradiol and norelgestromin (dolutegravir) or (NGMN)1 /                  AUC  3%                         norethindrone (rilpivirine) plasma concentrations Dolutegravir               Cmax  1%                        to a clinically relevant extent. No dose adjustment of oral contraceptives is required when
NGMN                             co-administered with Juluca.
AUC  2%
Cmax  11%


Ethinyl estradiol (EE)1   Rilpivirine * and Norethindrone1/       EE 
Rilpivirine                AUC 
Cmin 
Cmax  17%
Norethindrone 
AUC 
Cmin 
Cmax 

*based on historic controls.
Analgesics
Methadone/              Dolutegravir                    No dose adjustments are required when initiating Dolutegravir1           Methadone                       co-administration of methadone with AUC  2%                        dolutegravir/rilpivirine. However, clinical Cmax  0%                       monitoring is recommended as methadone C  1%                         maintenance therapy may need to be adjusted in some patients.
Methadone /             Rilpivirine:
Rilpivirine1             AUC: *
Cmin: *
Cmax: *

R(-) methadone:
AUC: 16%
Cmin: 22%
Cmax: 14%

*based on historic controls.
Paracetamol/            Dolutegravir                    No dose adjustment is required.
Dolutegravir            (Not studied)
Paracetamol /           Rilpivirine
Rilpivirine1,2           AUC
Cmin ↑ 26%
Cmax

Paracetamol
AUC
Cmin NA
Cmax
Anticoagulants
Dabigatran etexilate/   Dolutegravir                    The combination of dolutegravir/rilpivirine and Dolutegravir            (Not studied)                    dabigatran etexilate should be used with caution.

Dabigatran etexilate/Rilpivirine 
Rilpivirine          Not studied. Dabigatran etexilate 
A risk for increases in dabigatran plasma concentrations cannot be excluded
(inhibition of intestinal P- gp).
HMG CO-A reductase inhibitors
Atorvastatin/        Dolutegravir                        No dose adjustment is required.
Dolutegravir         (Not studied)

Rilpivirine
Atorvastatin/              AUC
Rilpivirine1,2             Cmin
Cmax 9%

Atorvastatin
AUC
Cmin 15%
Cmax ↑ 35%
Phosphodiesterase type 5 (PDE-5) inhibitors
Sildenafil /            Dolutegravir                     No dose adjustment is required.
Dolutegravir

Sildenafil/              Rilpivirine
Rilpivirine1,2            AUC
Cmin
Cmax
Sildenafil
AUC
Cmin NA
Cmax
Vardenafil               Dolutegravir                    No dose adjustment is required.
Tadalafil/               (Not studied)
Dolutegravir

Vardenafil                Rilpivirine
Tadalafil/                (Not studied)
Rilpivirine
1
The interaction between dolutegravir and/or rilpivirine and the medicinal product was evaluated in a clinical study. All other drug-drug interactions shown are predicted.
2
This interaction study has been performed with a dose higher than the recommended dose for rilpivirine assessing the maximal effect on the co-administered medicinal product.
NA = Not applicable

QT prolonging medicinal products

There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and medicinal products that prolong the QTc interval of the ECG. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the ECG (see section 5.1). Dolutegravir/rilpivirine should be used with caution when co- administered with a medicinal product with a known risk of Torsade de Pointes.