Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Triumeq contains dolutegravir, abacavir and lamivudine, therefore any interactions identified for these individually are relevant to Triumeq. No clinically significant drug interactions are expected between dolutegravir, abacavir and lamivudine.

Effect of other medicinal products on the pharmacokinetics of dolutegravir, abacavir and lamivudine 
Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT) 1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Co-administration of Triumeq and other medicinal products that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may therefore increase dolutegravir plasma concentration. Medicinal products that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 1).

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

Abacavir is metabolised by UGT (UGT2B7) and alcohol dehydrogenase; co-administration of inducers (e.g. rifampicin, carbamazepine and phenytoin) or inhibitors (e.g. valproic acid) of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure.

Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through the OCT2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however the resulting increase was not clinically significant (see Table 1). Dolutegravir is an OCT2 and MATE1 inhibitor; however, lamivudine concentrations were similar with or without co-administration of dolutegravir based on a cross study analysis, indicating that dolutegravir has no effect on lamivudine exposure in vivo. Lamivudine is also substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.

Although abacavir and lamivudine are substrates of BCRP and P-gp in vitro, given the high absolute bioavailability of abacavir and lamivudine, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on abacavir or lamivudine concentrations.

Effect of dolutegravir, abacavir and lamivudine on the pharmacokinetics of other medicinal products 
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 transporters OCT2 and 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).

In vitro, dolutegravir inhibited the renal uptake 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.

In vitro, abacavir demonstrated the potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Abacavir was an inhibitor of MATE1; the clinical consequences are not known.

In vitro, lamivudine was an inhibitor of OCT1 and OCT2; the clinical consequences are not known.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 1.

Interaction table

Interactions between dolutegravir, abacavir, lamivudine and co-administered medical 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”, concentration at end of dosing interval as “Cτ”). The table should not be considered exhaustive but is representative of the classes studied.

Table 1:      Drug interactions

Medicinal products by             Interaction geometric          Recommendations concerning co- therapeutic areas                 mean change (%)                administration Antiretroviral medicinal products
Non-nucleoside reverse transcriptase inhibitors
Etravirine without boosted        Dolutegravir                  Etravirine without boosted protease protease inhibitors /               AUC  71%                    inhibitors decreased plasma dolutegravir Dolutegravir                        Cmax  52%                   concentration. The recommended dose C  88%                     of dolutegravir is 50 mg twice daily for patients taking etravirine without
Etravirine                  boosted protease inhibitors. As Triumeq (induction of UGT1A1         is a fixed dose tablet, an additional and CYP3A enzymes)           50 mg tablet of dolutegravir should be administered, approximately 12 hours after Triumeq for the duration of the etravirine without boosted protease inhibitor co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section
4.2).
Lopinavir+ritonavir+etravirine/     Dolutegravir                No dose adjustment is necessary.
Dolutegravir                         AUC  11%

Cmax  7%
C  28%

Lopinavir 
Ritonavir 
Etravirine 
Darunavir+ritonavir+etravirine/   Dolutegravir                No dose adjustment is necessary.
Dolutegravir                        AUC  25%
Cmax  12%
C  36%
Darunavir 
Ritonavir 
Etravirine 
Efavirenz/Dolutegravir            Dolutegravir                The recommended dose of dolutegravir AUC  57%                  is 50 mg twice daily when co-
Cmax  39%                 administered with efavirenz. As Triumeq
C  75%                   is a fixed dose tablet, an additional
50 mg tablet of dolutegravir should be
Efavirenz  (historical      administered, approximately 12 hours controls)                    after Triumeq for the duration of the
(induction of UGT1A1         efavirenz co-administration (a separate and CYP3A enzymes)           preparation of dolutegravir is available for this dose adjustment, see section
4.2).
Nevirapine/Dolutegravir           Dolutegravir                Co-administration with nevirapine may (Not studied, a similar      decrease dolutegravir plasma reduction in exposure as     concentration due to enzyme induction observed with efavirenz is   and has not been studied. Effect of expected, due to             nevirapine on dolutegravir exposure is induction)                   likely similar to or less than that of efavirenz. The recommended dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine. As
Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir should be administered, approximately
12 hours after Triumeq for the duration of the nevirapine co-administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).
Rilpivirine                        Dolutegravir               No dose adjustment is necessary.
AUC  12%
Cmax  13%
Cτ  22%
Rilpivirine 
Nucleoside reverse transcriptase inhibitors (NRTIs)
Tenofovir                          Dolutegravir               No dose adjustment is necessary when AUC  1%                   Triumeq is combined with nucleoside
Cmax  3%                  reverse transcript inhibitors.
Cτ  8%
Tenofovir 

Interaction not studied
Emtricitabine, didanosine,                              Triumeq is not recommended for use in stavudine, zidovudine.                                  combination with emtricitabine containing products, since both lamivudine (in Triumeq) and emtricitabine are cytidine analogues (i.e.
risk for intracellular interactions, (see section 4.4))
Protease inhibitors
Atazanavir/Dolutegravir      Dolutegravir              No dose adjustment is necessary.
AUC  91%
Cmax  50%
C  180%

Atazanavir  (historical controls)
(inhibition of UGT1A1 and CYP3A enzymes)
Atazanavir+ ritonavir/       Dolutegravir              No dose adjustment is necessary.
Dolutegravir                   AUC  62%
Cmax  34%
C  121%

Atazanavir 
Ritonavir 
Tipranavir+ritonavir/        Dolutegravir              The recommended dose of dolutegravir Dolutegravir                  AUC  59%                 is 50 mg twice daily when co- Cmax  47%                administered with tipranavir/ritonavir.
C  76%                  As Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir
Tipranavir                should be administered, approximately
Ritonavir                 12 hours after Triumeq for the duration
(induction of UGT1A1       of the tipranavir/ritonavir co- and CYP3A enzymes)         administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).
Fosamprenavir+ritonavir/     Dolutegravir              Fosamprenavir/ritonavir decreases Dolutegravir                  AUC  35%                 dolutegravir concentrations, but based Cmax  24%                on limited data, did not result in
C  49%                  decreased efficacy in Phase III studies.
No dose adjustment is necessary.
Fosamprenavir
Ritonavir 
(induction of UGT1A1 and CYP3A enzymes)
Lopinavir+ritonavir/         Dolutegravir              No dose adjustment is necessary.
Dolutegravir                   AUC  4%
Cmax  0%
C24  6%

Lopinavir 
Ritonavir 

Lopinavir+ritonavir/         Abacavir
Abacavir                     AUC 32%
Darunavir+ritonavir/            Dolutegravir                 No dose adjustment is necessary.
Dolutegravir                     AUC  22%
Cmax  11%
C  38%

Darunavir 
Ritonavir 
(induction of UGT1A1 and CYP3A enzymes)
Other antiviral agents
Daclatasvir/Dolutegravir        Dolutegravir                 Daclatasvir did not change dolutegravir AUC  33%                    plasma concentration to a clinically
Cmax  29%                   relevant extent. Dolutegravir did not
C  45%                     change daclatasvir plasma concentration.
Daclatasvir                  No dose adjustment is necessary.
Anti-infective products
Trimethoprim/sulfamethoxazole   Interaction not studied       No Triumeq dose adjustment necessary, (Co-trimoxazole)/Abacavir                                     unless patient has renal impairment (See Section 4.2).
Trimethoprim/sulfamethoxazole   Lamivudine:
(Co-trimoxazole)/Lamivudine      AUC 43%
(160mg/800mg once daily for 5    Cmax 7% days/300mg single dose)
Trimethoprim:
AUC 

Sulfamethoxazole:
AUC 

(organic cation transporter inhibition)
Antimycobacterials
Rifampicin/Dolutegravir         Dolutegravir                 The dose of dolutegravir is 50 mg twice AUC  54%                   daily when co-administered with
Cmax  43%                  rifampicin. As Triumeq is a fixed dose
C  72%                    tablet, an additional 50 mg tablet of (induction of UGT1A1          dolutegravir should be administered,
and CYP3A enzymes)            approximately 12 hours after Triumeq for the duration of the rifampicin co- administration (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).
Rifabutin                       Dolutegravir                 No dose adjustment is necessary.
AUC  5%
Cmax  16%
Cτ  30%
(induction of UGT1A1 and CYP3A enzymes)
Anticonvulsants
Carbamazepine/Dolutegravir      Dolutegravir                 The recommended dose of dolutegravir AUC  49%                    is 50 mg twice daily when co-
Cmax  33%                   administered with carbamazepine. As
C  73%                     Triumeq is a fixed dose tablet, an additional 50 mg tablet of dolutegravir

should be administered, approximately
12 hours after Triumeq for the duration of the carbamazepine co-administration
(a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).
Phenobarbital/Dolutegravir       Dolutegravir                  The recommended dose of dolutegravir Phenytoin/Dolutegravir           (Not studied, decrease         is 50 mg twice daily when co- Oxcarbazepine/Dolutegravir       expected due to induction      administered with these metabolic of UGT1A1 and CYP3A            inducers. As Triumeq is a fixed dose enzymes, a similar             tablet, an additional 50 mg tablet of reduction in exposure as       dolutegravir should be administered,
observed with                  approximately 12 hours after Triumeq carbamazepine is               for the duration of the co-administration expected)                      with these metabolic inducers (a separate preparation of dolutegravir is available for this dose adjustment, see section
4.2).
Antihistamines (histamine H2 receptor antagonists)
Ranitidine                     Interaction not studied.         No dose adjustment necessary.

Clinically significant interaction unlikely.
Cimetidine                       Interaction not studied.       No dose adjustment necessary.

Clinically significant interaction unlikely.
Cytotoxics
Cladribine/Lamivudine            Interaction not studied.       Concomitant use of Triumeq with cladribine is not recommended (see
In vitro lamivudine            section 4.4).
inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine
Opioids
Methadone/Abacavir               Abacavir:                      Methadone dose adjustment likely not (40 to 90mg once daily for 14     AUC                          needed in majority of patients; days/600mg single dose, then      Cmax 35%                     occasionally methadone re-titration may 600mg twice daily for 14 days)                                  be required.
Methadone:
CL/F 22%
Retinoids


Retinoid compounds                  Interaction not studied      Insufficient data to recommend dose (e.g. Isotretinoin)                                              adjustment.
Possible interaction given common pathway of elimination via alcohol dehydrogenase (abacavir- component).
Miscellaneous
Alcohol
Ethanol/Dolutegravir                Interaction not studied      No dose adjustment necessary.
Ethanol/Lamivudine                  (Inhibition of alcohol dehydrogenase)

Ethanol/Abacavir                    Abacavir:
(0.7 g/kg single dose/600mg           AUC  41% single dose)                        Ethanol:
AUC 

Sorbitol
Sorbitol solution (3.2 g, 10.2 g,   Single dose lamivudine       When possible, avoid chronic 13.4 g)/Lamivudine                  oral solution 300 mg         coadministration of Triumeq with medicinal products containing sorbitol
Lamivudine: or other osmotic acting poly-alcohols or
AUC  14%; 32%; 36%          monosaccharide alcohols (eg: xylitol,
mannitol, lactitol, maltitol). Consider
Cmax  28%; 52%, 55%.
more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.
Potassium channel blockers
Fampridine (also known as           Fampridine                  Co-administration of dolutegravir has dalfampridine)/Dolutegravir                                      the potential to cause seizures due to increased fampridine plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Fampridine co- administration with Triumeq is contraindicated (see section 4.3).
Antacids and supplements
Magnesium/                          Dolutegravir                Magnesium/ aluminium-containing aluminium-containing                AUC  74%                    antacids should be taken well separated antacids/Dolutegravir               Cmax  72%                   in time from the administration of Triumeq (minimum 2 hours after or 6
(Complex binding to          hours before the intake of Triumeq).
polyvalent ions)
Calcium                             Dolutegravir                - When taken with food, Triumeq and supplements/Dolutegravir              AUC  39%                  supplements or multivitamins containing Cmax  37%                 calcium, iron or magnesium can be taken
C24  39%                  at the same time.
(Complex binding to          - If Triumeq is taken in a fasted state, polyvalent ions)             such supplements should be taken a
Iron supplements/Dolutegravir       Dolutegravir                minimum 2 hours after or 6 hours before AUC  54%                  the intake of Triumeq.
Cmax  57%
C24  56%

(Complex binding to         The stated reductions in dolutegravir polyvalent ions)            exposure were observed with the intake
Multivitamins (containing      Dolutegravir               of dolutegravir and these supplements calcium, iron and magnesium)     AUC  33%                 during fasted conditions. In fed state, the /Dolutegravir                    Cmax  35%                changes in exposure following intake C24  32%                 together with calcium or iron supplements were modified by the food effect, resulting in an exposure similar to that obtained with dolutegravir administered in the fasted state.
Corticosteroids
Prednisone                     Dolutegravir               No dose adjustment is necessary.
AUC  11%
Cmax  6%
Cτ  17%
Antidiabetics
Metformin/Dolutegravir         Metformin                  A dose adjustment of metformin should Dolutegravir               be considered when starting and
When co-administered        stopping coadministration of with dolutegravir 50mg      dolutegravir with metformin, to maintain
QD:                         glycaemic control. In patients with
Metformin                   moderate renal impairment a dose
AUC  79%                  adjustment of metformin should be
Cmax  66%                 considered when coadministered with
When co-administered        dolutegravir, because of the increased with dolutegravir 50mg      risk for lactic acidosis in patients with BID:                        moderate renal impairment due to
Metformin                  increased metformin concentration
AUC  145 %                (section 4.4).
Cmax  111%
Herbal products
St. John’s wort/Dolutegravir   Dolutegravir               The recommended dose of dolutegravir (Not studied, decrease      is 50 mg twice daily when co- expected due to induction   administered with St. John’s wort. As of UGT1A1 and CYP3A         Triumeq is a fixed dose tablet, an enzymes, a similar          additional 50 mg tablet of dolutegravir reduction in exposure as    should be administered, approximately observed with               12 hours after Triumeq for the duration carbamazepine is            of the St John’s wort co-administration expected)                   (a separate preparation of dolutegravir is available for this dose adjustment, see section 4.2).
Oral contraceptives
Ethinyl estradiol (EE) and     Effect of dolutegravir:     Dolutegravir had no Pharmacodynamic Norgestromin                   EE                         effect on Luteinizing Hormone (LH), (NGMN)/Dolutegravir             AUC  3%                   Follicle Stimulating Hormone (FSH) and Cmax  1%                  progesterone. No dose adjustment of oral contraceptives is necessary when
Effect of dolutegravir:     co-administered with Triumeq.
NGMN 
AUC  2%
Cmax  11%
Antihypertensive


Riociguat/Abacavir                  Riociguat                    Riociguat dose may need to be reduced, consult the riociguat prescribing
In vitro, abacavir inhibits information for dosing
CYP1A1. Concomitant recommendations.
administration of a single dose of riociguat (0.5 mg) to HIV patients receiving
Triumeq led to an approximately three-fold higher riociguat AUC(0-∞) when compared to historical riociguat
AUC(0-∞) reported in healthy subjects.

Paediatric population

Interaction studies have only been performed in adults.