Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Effect of other agents on the pharmacokinetics of dolutegravir

All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance.

Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3).
Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 3).

The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 3).

Effect of dolutegravir on the pharmacokinetics of other agents
In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. 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 (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE-1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 3).

In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) 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.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 3.

Interaction table
Interactions between dolutegravir and co-administered medicinal products are listed in Table 3 (increase is indicated as “↑”, decrease as “ ”, no change as “ ”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”).

Table 3: Drug Interactions
Medicinal products     Interaction                        Recommendations concerning by therapeutic areas Geometric mean change                co-administration (%)
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors
Etravirine without     Dolutegravir                      Etravirine without boosted protease inhibitors boosted protease          AUC  71%                       decreased plasma dolutegravir concentration. The inhibitors                Cmax  52%                      recommended adult dose of dolutegravir should be Cτ  88%                        given twice daily when co-administered with etravirine without boosted protease inhibitors. In
Etravirine                     paediatric patients the weight-based once daily (induction of UGT1A1 and        dose should be administered twice daily.
CYP3A enzymes)                  Dolutegravir should not be used with etravirine without co-administration of atazanavir/ritonavir,
darunavir/ritonavir or lopinavir/ritonavir in INI- resistant patients (see further below in table).
Lopinavir/ritonavir +     Dolutegravir                   No dose adjustment is necessary.
etravirine                 AUC  11%
Cmax  7%
Cτ  28%
LPV 
RTV 
Darunavir/ritonavir +     Dolutegravir                   No dose adjustment is necessary.
etravirine                 AUC  25%
Cmax  12%
Cτ  36%
DRV 
RTV 
Efavirenz                 Dolutegravir                   The recommended adult dose of dolutegravir AUC  57%                      should be given twice daily when co-administered Cmax  39%                     with efavirenz. In paediatric patients the weight- Cτ  75%                       based once daily dose should be administered twice daily.
Efavirenz  (historical         In the presence of integrase class resistance controls)                       alternative combinations that do not include (induction of UGT1A1 and        efavirenz should be considered (see section 4.4).
CYP3A enzymes)
Nevirapine                Dolutegravir                   The recommended adult dose of dolutegravir (Not studied, a similar         should be given twice daily when co-administered reduction in exposure as        with nevirapine. In paediatric patients the weight- observed with efavirenz is      based once daily dose should be administered expected, due to induction)     twice daily.


In the presence of integrase class resistance alternative combinations that do not include nevirapine should be considered (see section 4.4).
Rilpivirine            Dolutegravir                No dose adjustment is necessary.
AUC  12%
Cmax  13%
Cτ  22%
Rilpivirine 
Nucleoside Reverse Transcriptase Inhibitors
Tenofovir              Dolutegravir                No dose adjustment is necessary.
AUC  1%
Cmax  3%
Cτ  8%
Tenofovir 
Protease Inhibitors
Atazanavir             Dolutegravir                No dose adjustment is necessary.
AUC  91%
Cmax  50%                 Tivicay should not be dosed higher than 30 mg Cτ  180%                  twice daily in combination with atazanavir (see section 5.2) due to lack of data.
Atazanavir  (historical controls)
(inhibition of UGT1A1 and
CYP3A enzymes)
Atazanavir/ritonavir    Dolutegravir               No dose adjustment is necessary.
AUC  62%
Cmax  34%                Tivicay should not be dosed higher than 30 mg Cτ  121%                 twice daily in combination with atazanavir (see section 5.2) due to lack of data.
Atazanavir 
Ritonavir 
(inhibition of UGT1A1 and
CYP3A enzymes)
Tipranavir/ritonavir    Dolutegravir               The recommended adult dose of dolutegravir (TPV+RTV)                 AUC  59%                 should be given twice daily when co-administered Cmax  47%                with tipranavir/ritonavir. In paediatric patients the Cτ  76%                  weight-based once daily dose should be
(induction of UGT1A1 and    administered twice daily.
CYP3A enzymes)              In the presence of integrase class resistance this combination should be avoided (see section 4.4).
Fosamprenavir/          Dolutegravir               No dose adjustment is necessary in the absence of ritonavir (FPV+RTV)       AUC  35%                 integrase class resistance.
Cmax  24%                In the presence of integrase class resistance Cτ  49%                  alternative combinations that do not include (induction of UGT1A1 and    fosamprenavir/ritonavir should be considered.
CYP3A enzymes)
Darunavir/ritonavir     Dolutegravir               No dose adjustment is necessary.
AUC  22%
Cmax  11%
C24  38%
(induction of UGT1A1 and
CYP3A enzymes)
Lopinavir/ritonavir     Dolutegravir               No dose adjustment is necessary.
AUC  4%
Cmax  0%

C24  6%
Other Antiviral agents
Daclatasvir            Dolutegravir                    Daclatasvir did not change dolutegravir plasma AUC  33%                     concentration to a clinically relevant extent.
Cmax  29%                    Dolutegravir did not change daclatasvir plasma C  45%                      concentration. No dose adjustment is necessary.
Daclatasvir 
Other agents
Potassium channel blocker
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 transporter; co-administration has not been studied.
Fampridine co-administration with dolutegravir is contraindicated.
Anticonvulsants
Carbamazepine           Dolutegravir                   The recommended adult dose of dolutegravir AUC  49%                      should be given twice daily when co-administered Cmax  33%                     with carbamazepine. In paediatric patients the C  73%                       weight-based once daily dose should be administered twice daily. Alternatives to carbamazepine should be used where possible for
INI resistant patients.
Oxcarbazepine           Dolutegravir                   The recommended adult dose of dolutegravir Phenytoin               (Not studied, decrease          should be given twice daily when co-administered Phenobarbital           expected due to induction of    with these metabolic inducers. In paediatric UGT1A1 and CYP3A                patients the weight-based once daily dose should enzymes, a similar reduction    be administered twice daily. Alternative in exposure as observed         combinations that do not include these metabolic with carbamazepine is           inducers should be used where possible in INI- expected)                       resistant patients.
Azole anti-fungal agents
Ketoconazole             Dolutegravir                  No dose adjustment is necessary. Based on data Fluconazole              (Not studied)                  from other CYP3A4 inhibitors, a marked increase Itraconazole                                            is not expected.
Posaconazole
Voriconazole
Herbal products
St. John’s wort          Dolutegravir                  The recommended adult dose of dolutegravir (Not studied, decrease         should be given twice daily when co-administered expected due to induction of   with St. John’s wort. In paediatric patients the UGT1A1 and CYP3A               weight-based once daily dose should be enzymes, a similar reduction   administered twice daily. Alternative combinations in exposure as observed        that do not include St. John’s wort should be used with carbamazepine is          where possible in INI-resistant patients.
expected)
Antacids and supplements
Magnesium/               Dolutegravir                  Magnesium/ aluminium-containing antacid should aluminium-containing       AUC  74%                    be taken well separated in time from the antacid                    Cmax  72%                   administration of dolutegravir (minimum 2 hours (Complex binding to            after or 6 hours before).
polyvalent ions)
Calcium supplements      Dolutegravir                  Calcium supplements, iron supplements or AUC  39%                    multivitamins should be taken well separated in 

Cmax  37%                  time from the administration of dolutegravir C24  39%                   (minimum 2 hours after or 6 hours before).
(Complex binding to polyvalent ions)
Iron supplements         Dolutegravir 
AUC  54%
Cmax  57%
C24  56%
(Complex binding to polyvalent ions)
Multivitamin             Dolutegravir 
AUC  33%
Cmax  35%
C24  32%
(Complex binding to polyvalent ions)
Corticosteroids
Prednisone               Dolutegravir                 No dose adjustment is necessary.
AUC  11%
Cmax  6%
Cτ  17%
Antidiabetics
Metformin                Metformin                    A dose adjustment of metformin should be When co-administered with     considered when starting and stopping dolutegravir 50mg film-       coadministration of dolutegravir with metformin, coated tablets once daily:    to maintain glycaemic control. In patients with Metformin                     moderate renal impairment a dose adjustment of AUC  79%                   metformin should be considered when
Cmax  66%                  coadministered with dolutegravir, because of the When co-administered with     increased risk for lactic acidosis in patients with dolutegravir 50mg film-       moderate renal impairment due to increased coated tablets twice daily:   metformin concentration (section 4.4).
Metformin
AUC  145 %
Cmax  111%
Antimycobacterials
Rifampicin               Dolutegravir                 The recommended adult dose of dolutegravir AUC  54%                   should be given twice daily when co-administered Cmax  43%                  with rifampicin in the absence of integrase class Cτ 72%                     resistance. In paediatric patients the weight-based (induction of UGT1A1 and      once daily dose should be administered twice CYP3A enzymes)                daily.
In the presence of integrase class resistance this combination should be avoided (see section 4.4).
Rifabutin                Dolutegravir                 No dose adjustment is necessary.
AUC  5%
Cmax  16%
Cτ  30%
(induction of UGT1A1 and
CYP3A enzymes)
Oral contraceptives
Ethinyl estradiol (EE)   Dolutegravir                 Dolutegravir had no pharmacodynamic effect on and Norelgestromin       EE                           Luteinizing Hormone (LH), Follicle Stimulating (NGMN)                    AUC  3%                     Hormone (FSH) and progesterone. No dose 

Cmax  1%                     adjustment of oral contraceptives is necessary when co-administered with dolutegravir.
NGMN 
AUC  2%
Cmax  11%
Analgesics
Methadone                 Dolutegravir                   No dose adjustment is necessary of either agent.
Methadone 
AUC  2%
Cmax  0%
C  1%

Paediatric population

Interaction studies have only been performed in adults.