Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
No drug interaction studies have been conducted using Dovato. Dovato contains dolutegravir and lamivudine, therefore any interactions identified for these individually are relevant to Dovato. No clinically significant drug interactions are expected between dolutegravir and lamivudine.

Effect of other medicinal products on the pharmacokinetics of dolutegravir 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 Dovato 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.

The absorption of dolutegravir is reduced by certain metal cation-containing anti-acid substances and supplements (see Table 1).

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 transporters) has been shown to increase lamivudine plasma concentrations, however the resulting Page 4 of 26
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 relevant 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 lamivudine is a substrate of BCRP and P-gp in vitro, given its high absolute bioavailability, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on lamivudine concentrations.

Effect of dolutegravir 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 and section 4.3).

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, 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, 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 Dovato
(induction of UGT1A1        is a fixed-dose tablet, an additional and CYP3A enzymes)          50 mg tablet of dolutegravir should be administered, approximately 12 hours
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after Dovato for the duration of the etravirine without boosted protease inhibitor co-administration (a separate formulation 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
Cmax  39%                 co-administered with efavirenz. As
C  75%                   Dovato is a fixed-dose tablet, an additional 50 mg tablet of dolutegravir
Efavirenz  (historical      should be administered, approximately controls)                    12 hours after Dovato for the duration of (induction of UGT1A1         the efavirenz co-administration (a and CYP3A enzymes)           separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).
Nevirapine/Dolutegravir           Dolutegravir                The recommended dose of dolutegravir (Not studied, a similar      is 50 mg twice daily when reduction in exposure as     co-administered with nevirapine. As observed with efavirenz is   Dovato is a fixed-dose tablet, an expected, due to             additional 50 mg tablet of dolutegravir induction)                   should be administered, approximately
12 hours after Dovato for the duration of the nevirapine co-administration (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).
Rilpivirine/Dolutegravir           Dolutegravir               No dose adjustment is necessary.
AUC  12%
Cmax  13%
Cτ  22%
Rilpivirine 
Nucleoside reverse transcriptase inhibitors (NRTIs)
Tenofovir disoproxil               Dolutegravir               No dose adjustment is necessary when AUC  1%                   Dovato is combined with tenofovir,
Cmax  3%                  didanosine, stavudine or zidovudine.
Cτ  8%
Tenofovir 
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Dovato is not recommended for use in combination with emtricitabine
Emtricitabine, didanosine,   Interaction not studied     containing products, since both stavudine, tenofovir                                     lamivudine (in Dovato) and alafenamide, zidovudine                                  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 Cmax  47%                 co administered with
C  76%                   tipranavir/ritonavir. As Dovato is a fixed-dose tablet, an additional 50 mg
Tipranavir                 tablet of dolutegravir should be
Ritonavir                  administered, approximately 12 hours
(induction of UGT1A1        after Dovato for the duration of the and CYP3A enzymes)          tipranavir/ritonavir co-administration (a separate formulation 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 
Darunavir+ritonavir/         Dolutegravir               No dose adjustment is necessary.
Dolutegravir                  AUC  22%

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Cmax  11%
C  38%
Darunavir 
Ritonavir 
(induction of UGT1A1 and CYP3A enzymes)
Other antiviral active substances
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.
Ledipasvir/Sofosbuvir/           Lamivudine                    No dosage adjustment necessary.
Lamivudine (with abacavir)       Ledipasvir 
Sofosbuvir 
Sofosbuvir/                      Dolutegravir                  No dosage adjustment necessary.
Velpatasvir/Dolutegravir         Sofosbuvir 
Velpatasvir
Ribavirin                        Interaction not studied.       No dosage adjustment necessary.

Clinically significant interaction unlikely.
Anti-infective products
Trimethoprim/sulfamethoxazole     Lamivudine:                   No dosage adjustment necessary.
(Co-trimoxazole)/Lamivudine        AUC  43%
(160 mg/800 mg once daily for      Cmax  7%
5 days/300 mg single dose)
Trimethoprim:
AUC 

Sulfamethoxazole:
AUC 
(organic cation transporter inhibition)
Antimycobacterials
Rifampicin/Dolutegravir           Dolutegravir                 The recommended dose of dolutegravir AUC  54%                   is 50 mg twice daily when
Cmax  43%                  co-administered with rifampicin. As
C  72%                    Dovato is a fixed-dose tablet, an
(induction of UGT1A1          additional 50 mg tablet of dolutegravir and CYP3A enzymes)            should be administered, approximately
12 hours after Dovato for the duration of the rifampicin co-administration (a separate formulation of dolutegravir is available for this dose adjustment, see section 4.2).
Rifabutin/Dolutegravir            Dolutegravir                 No dose adjustment is necessary.
AUC  5%
Cmax  16%
Cτ  30%
(induction of UGT1A1 and CYP3A enzymes)
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Anticonvulsants
Carbamazepine/Dolutegravir          Dolutegravir                  The recommended dose of dolutegravir AUC  49%                     is 50 mg twice daily when
Cmax  33%                    co-administered with these metabolic
C  73%                      inducers. As Dovato is a fixed-dose tablet, an additional 50 mg tablet of
Phenobarbital/Dolutegravir     Dolutegravir                       dolutegravir should be administered, Phenytoin/Dolutegravir         (Not studied, decrease              approximately 12 hours after Dovato for Oxcarbazepine/Dolutegravir     expected due to induction           the duration of the co-administration of UGT1A1 and CYP3A                 with these metabolic inducers (a separate enzymes, a similar                  formulation of dolutegravir is available reduction in exposure as            for this dose adjustment, see section observed with                       4.2).
carbamazepine is expected).
Antihistamines (histamine H2 receptor antagonists)
Ranitidine                     Interaction not studied.            No dosage adjustment necessary.

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

Clinically significant interaction unlikely.
Cytotoxics
Cladribine/Lamivudine               Interaction not studied.       Concomitant use of Dovato 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.
Miscellaneous
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 Dovato 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
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concentration via inhibition of OCT2 transporter; co-administration has not been studied. Fampridine co- administration with Dovato 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 Dovato (minimum 2 hours after or
(Complex binding to         6 hours before).
polyvalent ions)
Calcium                         Dolutegravir               - When taken with food, Dovato and supplements/Dolutegravir          AUC  39%                 supplements or multivitamins containing (fasted intake)                   Cmax  37%                calcium, iron or magnesium can be taken C24  39%                 at the same time.
(Complex binding to         - If Dovato 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 (fasted intake)                   AUC  54%                 the intake of Dovato.
Cmax  57%
C24  56%                 The stated reductions in dolutegravir
(Complex binding to         exposure were observed with the intake polyvalent ions)            of dolutegravir and these supplements
Multivitamins (containing       Dolutegravir               during fasted conditions. In fed state, the calcium, iron and magnesium)      AUC  33%                 changes in exposure following intake /Dolutegravir                     Cmax  35%                together with calcium or iron (fasted intake)                   C24  32%                 supplements were modified by the food (Complex binding to         effect, resulting in an exposure similar to polyvalent ions)            that obtained with dolutegravir administered in the fasted state.
Proton pump inhibitors
Omeprazole                      Dolutegravir               No dosage adjustment necessary.
Corticosteroids
Prednisone/Dolutegravir         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 Dovato with dolutegravir 50 mg     with metformin, to maintain glycaemic
QD:                         control. In patients with moderate renal
Metformin                   impairment a dose adjustment of
AUC  79%                  metformin should be considered when
Cmax  66%                 coadministered with Dovato, because of
When co-administered        the increased risk for lactic acidosis in with dolutegravir 50 mg     patients with moderate renal impairment
BID:                        due to increased metformin
Metformin                  concentration (section 4.4).
AUC  145 %
Cmax  111%
Herbal products

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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           Dovato 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 Dovato for the duration of carbamazepine is              the St. John’s wort co-administration (a expected).                    separate formulation 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 Dovato.
NGMN 
AUC  2%
Cmax  11%

Paediatric population

Interaction studies have only been performed in adults.