TRIUMEQ 50mg / 600mg / 300mg tablets medication leaflet

Triumeq 50 mg/600 mg/300 mg film-coated tablets

Each film-coated tablet contains 50 mg dolutegravir (as sodium), 600 mg of abacavir (as sulfate) and300 mg of lamivudine.

For the full list of excipients see section 6.1.

Film-coated tablet (tablet)

Purple, biconvex, film-coated oval tablets, approximately 22 x 11 mm, debossed with “572 Trı” onone side.

Triumeq is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infectedadults, adolescents and children weighing at least 25 kg (see sections 4.4 and 5.1).

Before initiating treatment with abacavir-containing products, screening for carriage of the HLA-

B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin (seesection 4.4). Abacavir should not be used in patients known to carry the HLA-B*5701 allele.

Therapy should be prescribed by a physician experienced in the management of HIV infection.

Adults, adolescents and children (weighing at least 25kg)

The recommended dose is one tablet once daily.

Triumeq film-coated tablets should not be administered to adults, adolescents or children who weighless than 25 kg because it is a fixed-dose tablet that cannot be dose reduced. Triumeq dispersibletablets should be administered to children of at least 3 months of age and weighing at least 6 kg to lessthan 25 kg.

Separate preparations of dolutegravir, abacavir or lamivudine are available in cases wherediscontinuation or dose adjustment of one of the active substances is indicated. In these cases thephysician should refer to the individual product information for these medicinal products.

A separate dose of dolutegravir (film-coated tablets or dispersible tablets) is applicable where a doseadjustment is indicated due to drug-drug interactions, e.g. rifampicin, carbamazepine, oxcarbazepine,phenytoin, phenobarbital, St. John’s wort, etravirine (without boosted protease inhibitors), efavirenz,nevirapine, or tipranavir/ritonavir (see sections 4.4 and 4.5).

Dispersible tablets

Triumeq is available as dispersible tablets for patients of at least 3 months of age and weighing at least6 kg to less than 25 kg. The bioavailability of dolutegravir from film-coated tablets and dispersibletablets is not comparable; therefore, they must not be used as direct replacements (see section 5.2).

If the patient misses a dose of Triumeq, the patient should take it as soon as possible, providing thenext dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not takethe missed dose and simply resume the usual dosing schedule.

There are limited data available on the use of dolutegravir, abacavir and lamivudine in patients aged65 years and over. There is no evidence that elderly patients require a different dose than youngeradult patients (see section 5.2). Special care is advised in this age group due to age associated changessuch as the decrease in renal function and alteration of haematological parameters.

Triumeq is not recommended for use in patients with a creatinine clearance < 30 mL/min (see section5.2). No dose adjustment is required in patients with mild or moderate renal impairment. However, thelamivudine exposure is significantly increased in patients with a creatinine clearance < 50 mL/min(see section 4.4).

Abacavir is primarily metabolised by the liver. No clinical data are available in patients with moderateor severe hepatic impairment, therefore the use of Triumeq is not recommended unless judgednecessary. In patients with mild hepatic impairment (Child-Pugh score 5-6) close monitoring isrequired, including monitoring of abacavir plasma levels if feasible (see sections 4.4 and 5.2).

The safety and efficacy of Triumeq in children less than 3 months of age or weighing less than 6 kghave not yet been established.

Currently available data are described in section 4.8, 5.1 and 5.2, but no recommendation on aposology can be made.

Oral use

Triumeq can be taken with or without food (see section 5.2).

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Co-administration with medicinal products with narrow therapeutic windows, that are substrates oforganic cation transporter (OCT) 2, including but not limited to fampridine (also known asdalfampridine; see section 4.5).

Hypersensitivity reactions (see section 4.8)

Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR) (seesection 4.8), and share some common features such as fever and/or rash with other symptomsindicating multi-organ involvement. Clinically it is not possible to determine whether a HSR with

Triumeq would be caused by abacavir or dolutegravir. Hypersensitivity reactions have beenobserved more commonly with abacavir, some of which have been life-threatening, and in rarecases fatal, when not managed appropriately. The risk for abacavir HSR to occur is high for patientswho test positive for the HLA-B*5701 allele. However, abacavir HSRs have been reported at a lowfrequency in patients who do not carry this allele.

Therefore, the following should always be adhered to:

- HLA-B*5701 status must always be documented prior to initiating therapy.

- Triumeq should never be initiated in patients with a positive HLA-B*5701 status, nor in patientswith a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-containing regimen.

- Triumeq must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an

HSR is suspected. Delay in stopping treatment with Triumeq after the onset of hypersensitivity mayresult in an immediate and life-threatening reaction. Clinical status including liveraminotransferases and bilirubin should be monitored.

- After stopping treatment with Triumeq for reasons of a suspected HSR, Triumeq or any othermedicinal product containing abacavir or dolutegravir must never be re-initiated.

- Restarting abacavir containing products following a suspected abacavir HSR can result in aprompt return of symptoms within hours. This recurrence is usually more severe than on initialpresentation, and may include life-threatening hypotension and death.

- In order to avoid restarting abacavir and dolutegravir, patients who have experienced a suspected

HSR should be instructed to dispose of their remaining Triumeq tablets.

Hypersensitivity reactions have been reported in <1% of patients treated with dolutegravir inclinical studies, and were characterized by rash, constitutional findings, and sometimes, organdysfunction, including severe liver reactions.

Abacavir HSR has been well characterised through clinical studies and during post marketingfollow-up. Symptoms usually appeared within the first six weeks (median time to onset 11 days) ofinitiation of treatment with abacavir, although these reactions may occur at any time duringtherapy.

Almost all HSR to abacavir will include fever and/or rash. Other signs and symptoms that havebeen observed as part of abacavir HSR are described in detail in section 4.8 (Description of selectedadverse reactions), including respiratory and gastrointestinal symptoms. Importantly, suchsymptoms may lead to misdiagnosis of HSR as respiratory disease (pneumonia, bronchitis,pharyngitis), or gastroenteritis. The symptoms related to this HSR worsen with continued therapyand can be life- threatening. These symptoms usually resolve upon discontinuation of abacavir.

Rarely, patients who have stopped abacavir for reasons other than symptoms of HSR have alsoexperienced life-threatening reactions within hours of re- initiating abacavir therapy (see Section 4.8

Description of selected adverse reactions). Restarting abacavir in such patients must be done in asetting where medical assistance is readily available.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and lifestyle. For lipids and weight,there is in some cases evidence for a treatment effect. For monitoring of blood lipids and glucosereference is made to established HIV treatment guidelines. Lipid disorders should be managed asclinically appropriate.

The safety and efficacy of Triumeq has not been established in patients with significant underlyingliver disorders. Triumeq is not recommended in patients with moderate to severe hepatic impairment(see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy, and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, interruption or discontinuation of treatment must be considered.

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at anincreased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviraltherapy for hepatitis B or C, please refer also to the relevant product information for these medicinalproducts.

Triumeq includes lamivudine, which is active against hepatitis B. Abacavir and dolutegravir lack suchactivity. Lamivudine monotherapy is generally not considered an adequate treatment for hepatitis B,since the risk for hepatitis B resistance development is high. If Triumeq is used in patients co-infectedwith hepatitis B an additional antiviral is, therefore, generally needed. Reference should be made totreatment guidelines.

If Triumeq is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of bothliver function tests and markers of HBV replication is recommended, as withdrawal of lamivudinemay result in an acute exacerbation of hepatitis.

In HIV-infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,such reactions have been observed within the first few weeks or months of initiation of CART.

Relevant examples are Cytomegalovirus retinitis, generalised and/or focal mycobacterial infections,and Pneumocystis jirovecii pneumonia (often referred to as PCP). Any inflammatory symptoms shouldbe evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ diseaseand autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation;however, the reported time to onset is more variable and these events can occur many months afterinitiation of treatment.

Liver chemistry elevations consistent with immune reconstitution syndrome were observed in somehepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liverchemistries is recommended in patients with hepatitis B and/or C co-infection. (See ‘Patients withchronic hepatitis B or C’ earlier in this section and also see section 4.8).

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which ismost pronounced with stavudine, didanosine and zidovudine. There have been reports ofmitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleosideanalogues, these have predominantly concerned treatment with regimens containing zidovudine. Themain adverse reactions reported are haematological disorders (anaemia, neutropenia), and metabolicdisorders (hyperlactatemia, hyperlipasemia). These reactions have often been transitory. Some late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).

Whether such neurological disorders are transient or permanent is currently unknown. These findingsshould be considered for any child exposed in utero to nucleoside and nucleotide analogues, whopresents with severe clinical findings of unknown aetiology, particularly neurologic findings. Thesefindings do not affect current national recommendations to use antiretroviral therapy in pregnantwomen to prevent vertical transmission of HIV.

Although the available data from clinical and observational studies with abacavir show inconsistentresults, several studies suggest an increased risk of cardiovascular events (notably myocardialinfarction) in patients treated with abacavir. Therefore, when prescribing Triumeq, action should betaken to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

In addition, alternative treatment options to the abacavir containing regimen should be consideredwhen treating patients with a high cardiovascular risk.

Although the aetiology is considered to be multifactorial (including corticosteroid use,bisphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases ofosteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-termexposure to CART. Patients should be advised to seek medical advice if they experience joint achesand pain, joint stiffness or difficulty in movement.

Patients should be advised that Triumeq or any other antiretroviral therapy does not cure HIVinfection and that they may still develop opportunistic infections and other complications of HIVinfection. Therefore, patients should remain under close clinical observation by physiciansexperienced in the treatment of these associated HIV diseases.

Patients with a creatinine clearance between 30 and 49 mL/min receiving Triumeq may experience a1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50mL/min. There are no safety data from randomised, controlled trials comparing Triumeq to theindividual components in patients with a creatinine clearance between 30 and 49 mL/min whoreceived dose-adjusted lamivudine. In the original lamivudine registrational trials in combination withzidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities(neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in<1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepaticdisorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Triumeq shouldbe monitored for lamivudine-related adverse events, notably hematologic toxicities. If new orworsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudineprescribing information, is indicated, which cannot be achieved with Triumeq. Triumeq should bediscontinued and the individual components should be used to construct the treatment regimen.

The use of Triumeq is not recommended for patients with integrase inhibitor resistance. This isbecause the recommended dose of dolutegravir is 50 mg twice daily for adult patients with resistanceto integrase inhibitors and there are insufficient data to recommend a dose of dolutegravir in integraseinhibitor resistant adolescents, children and infants.

The recommended dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin,carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John’s wort, etravirine (without boostedprotease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir (see section 4.5).

Triumeq should not be co-administered with polyvalent cation-containing antacids. Triumeq isrecommended to be administered 2 hours before or 6 hours after these medicinal products (see section4.5).

When taken with food, Triumeq and supplements or multivitamins containing calcium, iron ormagnesium can be taken at the same time. If Triumeq is administered under fasting conditions,supplements or multivitamins containing calcium, iron or magnesium are recommended to be taken 2hours after or 6 hours before Triumeq (see section 4.5).

Dolutegravir increased metformin concentrations. A dose adjustment of metformin should beconsidered when starting and stopping coadministration of dolutegravir with metformin, to maintainglycaemic control (see section 4.5). Metformin is eliminated renally and therefore it is of importanceto monitor renal function when co-treated with dolutegravir. This combination may increase the riskfor lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45-59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should behighly considered.

The combination of lamivudine with cladribine is not recommended (see section 4.5).

Triumeq should not be taken with any other medicinal products containing dolutegravir, abacavir,lamivudine or emtricitabine, except where a dose adjustment of dolutegravir is indicated due to drug-drug interactions (see section 4.5).

Triumeq contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially ‘sodiumfree’.

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

Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyltransferase (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 andother medicinal products that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp maytherefore increase dolutegravir plasma concentration. Medicinal products that induce those enzymes ortransporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect ofdolutegravir (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 ofinducers (e.g. rifampicin, carbamazepine and phenytoin) or inhibitors (e.g. valproic acid) of UGTenzymes 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 throughthe OCT2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (aninhibitor 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 OCT2and MATE1 inhibitor; however, lamivudine concentrations were similar with or without co-administration of dolutegravir based on a cross study analysis, indicating that dolutegravir has noeffect 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 dueto 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 absolutebioavailability of abacavir and lamivudine, (see section 5.2), inhibitors of these efflux transporters areunlikely to result in a clinically relevant impact on abacavir or lamivudine concentrations.

In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/orin vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that aresubstrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for moreinformation see section 5.2).

In vitro, dolutegravir inhibited the renal transporters OCT2 and MATE1. In vivo, a 10-14% decreaseof creatinine clearance (secretory fraction is dependent on OCT2 and MATE1 transport) was observedin patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in whichexcretion 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. Basedon the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibitionof OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increaseplasma concentrations of medicinal products in which excretion is dependent upon OAT3.

In vitro, abacavir demonstrated the potential to inhibit CYP1A1 and limited potential to inhibitmetabolism mediated by CYP3A4. Abacavir was an inhibitor of MATE1; the clinical consequencesare 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 medicinalproducts are listed in Table 1.

Interactions between dolutegravir, abacavir, lamivudine and co-administered medical products arelisted in Table 1 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under theconcentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentrationat end of dosing interval as “Cτ”). The table should not be considered exhaustive but is representativeof 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 (Non-NRTIs)

Etravirine without boosted Dolutegravir  Etravirine without boosted proteaseprotease inhibitors/ AUC  71% inhibitors decreased plasma dolutegravir

Dolutegravir Cmax  52% concentration. The recommended dose

C  88% of dolutegravir is 50 mg twice daily forpatients taking etravirine without

Etravirine  boosted protease inhibitors. As Triumeq(induction of UGT1A1 is a fixed dose tablet, an additionaland CYP3A enzymes) 50 mg tablet of dolutegravir should beadministered, approximately 12 hoursafter Triumeq for the duration of theetravirine without boosted proteaseinhibitor co-administration (a separatepreparation of dolutegravir is availablefor this dose adjustment, see section4.2).

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 additional50 mg tablet of dolutegravir should be

Efavirenz  (historical administered, approximately 12 hourscontrols) after Triumeq for the duration of the(induction of UGT1A1 efavirenz co-administration (a separateand CYP3A enzymes) preparation of dolutegravir is availablefor this dose adjustment, see section4.2).

Nevirapine/Dolutegravir Dolutegravir  Co-administration with nevirapine may(Not studied, a similar decrease dolutegravir plasmareduction in exposure as concentration due to enzyme inductionobserved with efavirenz is and has not been studied. Effect ofexpected, due to nevirapine on dolutegravir exposure isinduction) likely similar to or less than that ofefavirenz. The recommended dose ofdolutegravir is 50 mg twice daily whenco-administered with nevirapine. As

Triumeq is a fixed dose tablet, anadditional 50 mg tablet of dolutegravirshould be administered, approximately12 hours after Triumeq for the durationof the nevirapine co-administration (aseparate preparation of dolutegravir isavailable for this dose adjustment, seesection 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 

Emtricitabine, didanosine, Interaction not studied Triumeq is not recommended for use instavudine, zidovudine. combination with emtricitabinecontaining products, since bothlamivudine (in Triumeq) andemtricitabine are cytidine analogues (i.e.

risk for intracellular interactions, (seesection 4.4))

Protease inhibitors

Atazanavir/Dolutegravir Dolutegravir  No dose adjustment is necessary.

AUC  91%

Cmax  50%

C  180%

Atazanavir  (historicalcontrols)(inhibition of UGT1A1and 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, anadditional 50 mg tablet of dolutegravirshould be administered, approximately

Tipranavir  12 hours after Triumeq for the duration

Ritonavir  of the tipranavir/ritonavir co-(induction of UGT1A1 administration (a separate preparation ofand CYP3A enzymes) dolutegravir is available for this doseadjustment, 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 UGT1A1and 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 UGT1A1and 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 transporterinhibition)

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 Triumeqfor the duration of the rifampicin co-administration (a separate preparation ofdolutegravir is available for this doseadjustment, see section 4.2).

Rifabutin Dolutegravir  No dose adjustment is necessary.

AUC  5%

Cmax  16%

Cτ  30%(induction of UGT1A1and 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, anadditional 50 mg tablet of dolutegravirshould be administered, approximately12 hours after Triumeq for the durationof the carbamazepine co-administration(a separate preparation of dolutegravir isavailable for this dose adjustment, seesection 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 metabolicof UGT1A1 and CYP3A inducers. As Triumeq is a fixed doseenzymes, a similar tablet, an additional 50 mg tablet ofreduction in exposure as dolutegravir should be administered,observed with approximately 12 hours after Triumeqcarbamazepine is for the duration of the co-administrationexpected) with these metabolic inducers (a separatepreparation of dolutegravir is availablefor this dose adjustment, see section4.2).

Antihistamines (histamine H2 receptor antagonists)

Ranitidine Interaction not studied. No dose adjustment necessary.

Clinically significantinteraction unlikely.

Cimetidine Interaction not studied. No dose adjustment necessary.

Clinically significantinteraction unlikely.

Cytotoxics

Cladribine/Lamivudine Interaction not studied. Concomitant use of Triumeq withcladribine is not recommended (see

In vitro lamivudine section 4.4).inhibits the intracellularphosphorylation ofcladribine leading to apotential risk of cladribineloss of efficacy in case ofcombination in theclinical setting. Someclinical findings alsosupport a possibleinteraction betweenlamivudine 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 may600mg 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 givencommon pathway ofelimination via alcoholdehydrogenase (abacavir-component).

Miscellaneous

Alcohol

Ethanol/Dolutegravir Interaction not studied No dose adjustment necessary.

Ethanol/Lamivudine (Inhibition of alcoholdehydrogenase)

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 chronic13.4 g)/Lamivudine oral solution 300 mg coadministration of Triumeq withmedicinal 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 viralload when chronic coadministrationcannot be avoided.

Potassium channel blockers

Fampridine (also known as Fampridine  Co-administration of dolutegravir hasdalfampridine)/Dolutegravir the potential to cause seizures due toincreased fampridine plasmaconcentration via inhibition of OCT2transporter; co-administration has notbeen studied. Fampridine co-administration with Triumeq iscontraindicated (see section 4.3).

Antacids and supplements

Magnesium/ Dolutegravir  Magnesium/ aluminium-containingaluminium-containing AUC  74% antacids should be taken well separatedantacids/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 andsupplements/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%

C  56% The stated reductions in dolutegravir(Complex binding to exposure were observed with the intakepolyvalent ions) of dolutegravir and these supplements

Multivitamins (containing Dolutegravir  during fasted conditions. In fed state, thecalcium, iron and magnesium) AUC  33% changes in exposure following intake/Dolutegravir C together with calcium or ironmax  35%

C  32% supplements were modified by the foodeffect, resulting in an exposure similar tothat obtained with dolutegraviradministered in the fasted state.

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 ofwith 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 increasedwith 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. Asof UGT1A1 and CYP3A Triumeq is a fixed dose tablet, anenzymes, a similar additional 50 mg tablet of dolutegravirreduction in exposure as should be administered, approximatelyobserved with 12 hours after Triumeq for the durationcarbamazepine is of the St John’s wort co-administrationexpected) (a separate preparation of dolutegravir isavailable for this dose adjustment, seesection 4.2).

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 oforal 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 inhibitsinformation for dosing

CYP1A1. Concomitantrecommendations.administration of a singledose of riociguat (0.5 mg)to HIV patients receiving

Triumeq led to anapproximately three-foldhigher riociguat AUC(0-∞)when compared tohistorical riociguat

AUC(0-∞) reported inhealthy subjects.

Interaction studies have only been performed in adults.

Triumeq can be used during pregnancy if clinically needed.

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate nomalformative nor feto/ neonatal toxicity associated with dolutegravir. In pregnant women treated withabacavir, a large amount of data (more than 1000 exposed outcomes) indicate no malformative norfeto/ neonatal toxicity. In pregnant women treated with lamivudine, a large amount of data (more than1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity.

There are no or limited amount of data (less than 300 pregnancy outcomes) on the use of this triplecombination in pregnancy.

Two large birth outcome surveillance studies (more than 14,000 pregnancy outcomes) in Botswana(Tsepamo) and Eswatini, and other sources, do not indicate an increased risk for neural tube defectsafter dolutegravir exposure.

The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 livebirths (0.05-0.1%).

Data from the Tsepamo study show no significant difference in the prevalence of neural tube defects(0.11%) in infants whose mothers were taking dolutegravir at conception (more than 9,400 exposures)compared to those taking non-dolutegravir containing antiretroviral regimens at conception (0.11%),or compared to women without HIV (0.07%).

Data from the Eswatini study show the same prevalence of neural tube defects (0.08%) in infantswhose mothers were taking dolutegravir at conception (more than 4,800 exposures), as infants ofwomen without HIV (0.08%).

Data analysed from the Antiretroviral Pregnancy Registry (APR) of more than 1000 pregnancies withfirst trimester dolutegravir treatment, more than 1000 pregnancies with first trimester abacavirtreatment and more than 1000 pregnancies with first trimester lamivudine treatment do not indicate anincreased risk of major birth defects with dolutegravir, lamivudine or abacavir compared to thebackground rate or women with HIV. There are no or limited amount of APR data (less than 300 firsttrimester exposures) from the use of dolutegravir + lamivudine + abacavir in pregnant women.

In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes,including neural tube defects, were identified (see section 5.3).

Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetalumbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with thematernal peripheral plasma concentration.

There is insufficient information on the effects of dolutegravir on neonates.

Animal studies with abacavir have shown toxicity to the developing embryo and foetus in rats, but notin rabbits. Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits butnot in rats (see section 5.3).

Abacavir and lamivudine may inhibit cellular DNA replication and abacavir has been shown to becarcinogenic in animal models (see section 5.3). The clinical relevance of these findings is unknown.

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variabledegree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Dolutegravir is excreted in human milk in small amounts (a median dolutegravir breast milk tomaternal plasma ratio of 0.033 has been shown). There is insufficient information on the effects ofdolutegravir in neonates/infants.

Abacavir and its metabolites are excreted into the milk of lactating rats. Abacavir is also excreted intohuman milk.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine inbreastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) andprogressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There areno data available on the safety of abacavir and lamivudine when administered to babies less than threemonths old.

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

There are no data on the effects of dolutegravir, abacavir or lamivudine on human male or femalefertility. Animal studies indicate no effects of dolutegravir, abacavir or lamivudine on male or femalefertility (see section 5.3).

Triumeq has no or negligible influence on the ability to drive and use machines. Patients should beinformed that dizziness has been reported during treatment with dolutegravir. The clinical status of thepatient and the adverse reaction profile of Triumeq should be borne in mind when considering thepatient’s ability to drive or operate machinery.

The most frequently reported adverse reactions related to dolutegravir and abacavir/lamivudine werenausea (12%), insomnia (7%), dizziness (6%) and headache (6%).

Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea,fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of thesesymptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4).

Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysishave been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinalproducts containing abacavir should be permanently discontinued.

The most severe adverse reaction related to the treatment with dolutegravir and abacavir/lamivudine,seen in individual patients, was a hypersensitivity reaction that included rash and severe liver effects(see section 4.4 and Description of selected adverse reactions in this section).

The adverse reactions with the components of Triumeq from clinical study and post-marketingexperience are listed in Table 2 by body system, organ class and absolute frequency. Frequencies aredefined as very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1 000 to < 1/100),rare ( 1/10 000 to < 1/1 000), very rare (< 1/10 000).

Table 2: Tabulated list of adverse reactions associated with the combination of dolutegravir +abacavir/lamivudine in an analysis of pooled data from: Phase IIb to Phase IIIb clinical studies or post-marketing experience; and adverse reactions to treatment with dolutegravir, abacavir and lamivudinefrom clinical studies and post-marketing experience when used with other antiretrovirals

Frequency Adverse reaction

Blood and lymphatic systems disorders:

Uncommon: Neutropenia1, anaemia1, thrombocytopenia1

Very rare: pure red cell aplasia1

Common: hypersensitivity (see section 4.4)

Uncommon: immune reconstitution syndrome (see section 4.4)

Common: anorexia1

Uncommon: hypertriglyceridaemia, hyperglycaemia

Very rare: lactic acidosis1

Very common: insomnia

Common: abnormal dreams, depression, anxiety1, nightmare, sleepdisorder

Uncommon: suicidal ideation or suicide attempt (particularly in patientswith a pre-existing history of depression or psychiatricillness), panic attack

Rare: completed suicide (particularly in patients with a pre-existinghistory of depression or psychiatric illness)

Very common: headache

Common: dizziness, somnolence, lethargy1

Very rare: peripheral neuropathy1, paraesthesia1

Common: cough1, nasal symptoms1

Very common: nausea, diarrhoea

Common: vomiting, flatulence, abdominal pain, abdominal pain upper,abdominal distension, abdominal discomfort, gastro-oesophageal reflux disease, dyspepsia

Rare: pancreatitis1

Common: alanine aminotransferase (ALT) and/or aspartateaminotransferase (AST) elevations

Uncommon: hepatitis

Rare: acute hepatic failure1, increased bilirubin2

Common: rash, pruritus, alopecia1

Very rare: erythema multiform1, Stevens-Johnson syndrome1, toxicepidermal necrolysis1

Common: Arthralgia1, muscle disorders1(including myalgia1)

Rare: rhabdomyolysis1

Very common: fatigue

Common: asthenia, fever1, malaise1

Common: CPK elevations, weight increased

Rare: amylase elevations11This adverse reaction was identified from clinical studies or post-marketing experiencefor dolutegravir, abacavir or lamivudine when used with other antiretrovirals or post-marketing experience with Triumeq.2In combination with increased transaminases.

Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR), whichwere observed more commonly with abacavir. Hypersensitivity reaction observed for each of thesemedicinal products (described below) share some common features such as fever and/or rash withother symptoms indicating multi-organ involvement. Time to onset was typically 10-14 days for bothabacavir and dolutegravir-associated reactions, although reactions to abacavir may occur at any timeduring therapy. Treatment with Triumeq must be stopped without delay if HSR cannot be ruled out onclinical grounds, and therapy with Triumeq or other abacavir or dolutegravir containing products mustnever be re-initiated. Please refer to section 4.4 for further details on patient management in the eventof a suspected HSR to Triumeq.

Symptoms have included rash, constitutional findings, and sometimes, organ dysfunction, includingsevere liver reactions.

The signs and symptoms of this HSR are listed below. These have been identified either from clinicalstudies or post marketing surveillance. Those reported in at least 10% of patients with ahypersensitivity reaction are in bold text.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usuallymaculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash orfever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such aslethargy and malaise.

Skin Rash (usually maculopapular or urticarial)

Gastrointestinal tract Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration

Respiratory tract Dyspnoea, cough, sore throat, adult respiratory distress syndrome,respiratory failure

Miscellaneous Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension,conjunctivitis, anaphylaxis

Neurological/Psychiatry Headache, paraesthesia

Haematological Lymphopenia

Liver/pancreas Elevated liver function tests, hepatitis, hepatic failure

Musculoskeletal Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase

Urology Elevated creatinine, renal failure

Symptoms related to this HSR worsen with continued therapy and can be life-threatening and in rareinstance, have been fatal.

Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours.

This recurrence of the HSR is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Similar reactions have also occurred infrequently after restartingabacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior tostopping abacavir; and on very rare occasions have also been seen in patients who have restartedtherapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavirtolerant).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4)

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (seesection 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment (see section 4.4).

Increases in serum creatinine occurred within the first week of treatment with dolutegravir andremained stable through 96 weeks. In the SINGLE study a mean change from baseline of 12.6 mol/Lwas observed after 96 weeks of treatment. These changes are not considered to be clinically relevantsince they do not reflect a change in glomerular filtration rate.

Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have alsobeen reported with dolutegravir therapy.

In dolutegravir Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrolprovided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN).

Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observedin patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalitieswere higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups.

Based on data from IMPAACT 2019 study in 57 HIV-1 infected children (aged less than 12 years andweighing at least 6 kg) who received the recommended doses of either the Triumeq film-coated tabletor dispersible tablets, there were no additional safety issues beyond those observed in the adultpopulation.

Based on available data with dolutegravir used in combination with other antiretroviral agents to treatinfants, children and adolescents, there were no additional safety issues identified beyond thoseobserved in the adult population.

The individual preparations of abacavir and lamivudine have been investigated separately, and as adual nucleoside backbone, in combination antiretroviral therapy to treat ART- naive and ART-experienced HIV- infected paediatric patients (data available on the use of abacavir and lamivudine ininfants less than three months are limited). No additional types of adverse reactions have beenobserved beyond those characterised for the adult population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific symptoms or signs have been identified following acute overdose with dolutegravir,abacavir or lamivudine, apart from those listed as adverse reactions.

Further management should be as clinically indicated or as recommended by the national poisonscentre, where available. There is no specific treatment for an overdose of Triumeq. If overdoseoccurs, the patient should be treated supportively with appropriate monitoring, as necessary. Sincelamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose,although this has not been studied. It is not known whether abacavir can be removed by peritonealdialysis or haemodialysis. As dolutegravir is highly bound to plasma proteins, it is unlikely that it willbe significantly removed by dialysis.

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections,combinations. ATC code: J05AR13

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strandtransfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIVreplication cycle.

Abacavir and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Both abacavir andlamivudine are metabolised sequentially by intracellular kinases to the respective 5'-triphosphates (TP)which are the active moieties with extended intracellular half-lives supporting once daily dosing (seesection 5.2). Lamivudine-TP (an analogue for cytidine) and carbovir-TP (the active triphosphate formof abacavir, an analogue for guanosine) are substrates for and competitive inhibitors of HIV reversetranscriptase (RT). However, their main antiviral activity is through incorporation of themonophosphate form into the viral DNA chain, resulting in chain termination. Abacavir andlamivudine triphosphates show significantly less affinity for host cell DNA polymerases.

Dolutegravir, abacavir and lamivudine have been shown to inhibit replication of lab-strains andclinical isolates of HIV in a number of cell types, including transformed T cell lines,monocyte/macrophage derived lines and primary cultures of activated peripheral blood mononuclearcells (PBMCs) and monocyte/macrophages. The concentration of active substance necessary to effectviral replication by 50% (IC50 - half maximal inhibitory concentration) varied according to virus andhost cell type.

The IC50 for dolutegravir in various lab-strains using PBMC was 0.5 nM, and when using MT-4 cellsit ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major differencebetween subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O themean IC50 value was 0.2 nM (range 0.02-2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM(range 0.09-0.61).

The mean IC50 for abacavir against lab-strains of HIV-1IIIB and HIV-1HXB2 ranged from 1.4 to5.8 M. The median or mean IC50 values for lamivudine against lab-strains of HIV-1 ranged from0.007 to 2.3 M. The mean IC50 against lab-strains of HIV-2 (LAV2 and EHO) ranged from 1.57 to7.5 M for abacavir and from 0.16 to 0.51 M for lamivudine.

The IC50 values of abacavir against HIV-1 Group M subtypes (A-G) ranged from 0.002 to 1.179 M,against Group O from 0.022 to 1.21 M, and against HIV-2 isolates, from 0.024 to 0.49 M. Forlamivudine, the IC50 values against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 M, against

Group O from 0.030 to 0.160 M and against HIV-2 isolates from 0.002 to 0.120 M in peripheralblood mononuclear cells.

HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37untreated patients in Africa and Asia were susceptible to abacavir (IC50 fold changes < 2.5), andlamivudine (IC50 fold changes < 3.0), except for two CRF02_AG isolates with fold changes of 2.9 and3.4 for abacavir. Group O isolates from antiviral naïve patients tested for lamivudine activity werehighly sensitive.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture againstnon-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates.

No antagonistic effects in vitro were seen with dolutegravir and other antiretrovirals (tested agents:

stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir andraltegravir). In addition, ribavirin had no apparent effect on dolutegravir activity.

The antiviral activity of abacavir in cell culture was not antagonized when combined with thenucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine,tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI)nevirapine, or the protease inhibitor (PI) amprenavir.

No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents:

abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).

In 100% human serum, the mean fold shift for dolutegravir activity was 75-fold, resulting in proteinadjusted IC90 of 0.064 ug/mL. Plasma protein binding studies in vitro indicate that abacavir binds onlylow to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudineexhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma proteinbinding (less than 36%).

Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIVIII duringpassage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and

F. These mutations were not selected in patients treated with dolutegravir in the clinical studies. Usingstrain NL432 mutations E92Q (fold change 3) and G193E (fold change 3) were selected. Thesemutations have been selected in patients with pre-existing raltegravir resistance and who were thentreated with dolutegravir (listed as secondary mutations for dolutegravir).

In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in allfive isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrasesubstitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported fromtwo individual patients with subtype B and subtype C in the clinical program for ART experienced,

INI naive subjects, but without effects on dolutegravir susceptibility in vitro. G118R lowers thesusceptibility to dolutegravir in site directed mutants (fold change 10), but was not detected in patientsreceiving dolutegravir in the Phase III program.

Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, T66I) do notaffect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed assecondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to primarymutations (excluding at Q148) in experiments with site directed mutants, dolutegravir susceptibilityremains at or near wildtype level. In the case of the Q148-mutation viruses, increasing dolutegravirfold change is seen as the number of secondary mutations increase. The effect of the Q148-basedmutations (H/R/K) was also consistent with in vitro passage experiments with site directed mutants.

In serial passage with strain NL432-based site directed mutants at N155H or E92Q, no furtherselection of resistance was seen (fold change unchanged around 1). In contrast, starting passage withmutants with mutation Q148H (fold change 1), a variety of raltegravir associated secondary mutationsaccumulated with a consequent increase of fold change to values >10.

A clinically relevant phenotypic cut-off value (fold change vs wild type virus) has not beendetermined; genotypic resistance was a better predictor for outcome.

Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients wereanalyzed for susceptibility to dolutegravir. Dolutegravir has a <10-fold change against 94% of the 705clinical isolates.

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, nodevelopment of resistance to the integrase class, or to the NRTI class was seen (n=876, follow-up of48-96 weeks).

In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integraseinhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir,which was given in combination with an investigator selected background regimen (BR). Of thesefour, two subjects had a unique R263K integrase substitution, with a maximum fold change of 1.93,one subject had a polymorphic V151V/I integrase substitution, with maximum fold change of 0.92,and one subject had pre-existing integrase mutations and is assumed to have been integraseexperienced or infected with integrase resistant virus by transmission. The R263K mutation was alsoselected in vitro (see above).

Abacavir-resistant isolates of HIV-1 have been selected in vitro and in vivo and are associated withspecific genotypic changes in the RT codon region (codons M184V, K65R, L74V and Y115F). Duringin vitro abacavir selection the M184V mutation occurred first and resulted in about a 2-fold increase in

IC50, below the abacavir clinical cut-off of 4.5-fold change. Continued passage in increasingconcentrations of drug resulted in selection for double RT mutants 65R/184V and 74V/184V or triple

RT mutant 74V/115Y/184V. Two mutations conferred a 7 to 8-fold change in abacavir susceptibilityand combinations of three mutations were required to confer more than an 8-fold change insusceptibility.

HIV-1 resistance to lamivudine involves the development of a M184I or M184V amino acid changeclose to the active site of the viral RT. This variant arises both in vitro and in HIV-1 infected patientstreated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reducedsusceptibility to lamivudine and show diminished viral replicative capacity in vitro. M184V isassociated with about a 2-fold increase in abacavir resistance but does not confer clinical resistance forabacavir.

Isolates resistant to abacavir may also show reduced sensitivity to lamivudine. The combination ofabacavir/lamivudine has demonstrated decreased susceptibility to viruses with the substitutions K65Rwith or without the M184V/I substitution, and to viruses with L74V plus the M184V/I substitution.

Cross-resistance between dolutegravir or abacavir or lamivudine and antiretrovirals from other classese.g. PIs or NNRTIs is unlikely.

No relevant effects were seen on the QTc interval, with doses of dolutegravir exceeding the clinicaldose by approximately 3-fold. Similar studies were not conducted with either abacavir or lamivudine.

The efficacy of Triumeq in HIV-infected, therapy naive subjects is based on the analyses of data froma number of trials. The analyses included two randomised, international, double-blind, active-controlled trials, SINGLE (ING114467) and SPRING-2 (ING113086), the international, open-label,active-controlled trial FLAMINGO (ING114915), and the randomised, open-label, active-controlled,multicentre, non-inferiority study ARIA (ING117172).

The STRIIVING study (201147), was a randomised, open-label, active-controlled, multicentre, non-inferiority switch study in virologically suppressed subjects with no documented history of resistanceto any class.

In SINGLE, 833 patients were treated with dolutegravir 50 mg film-coated tablets once daily plusfixed-dose abacavir-lamivudine (DTG + ABC/3TC) or fixed-dose efavirenz-tenofovir-emtricitabine(EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% non-white,7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics were similar betweentreatment groups. Week 48 outcomes (including outcomes by key baseline covariates) are shown in

Table 3.

Table 3: Virologic Outcomes of Randomised Treatment of SINGLE at 48 Weeks (Snapshotalgorithm)48 weeks

DTG 50 mg + ABC/3TC EFV/TDF/FTConce daily once daily

N=414 N=419

HIV-1 RNA <50 copies/mL 88% 81%

Treatment Difference* 7.4% (95% CI: 2.5%, 12.3%)

Virologic non response† 5% 6%

No virologic data at Weeks7% 13%48 window

Reasons

Discontinued study/studymedicinal product due to 2% 10%adverse event or death‡

Discontinued study/studymedicinal product for other 5% 3%reasons§

Missing data during window0 <1%but on study

HIV-1 RNA <50 copies/mL by baseline covariates

Baseline Plasma Viraln/N (%) n/N (%)

Load (copies/mL)100,000 253/280 (90%) 238/288 (83%)>100,000 111/134 (83%) 100/131 (76%)

Baseline CD4+ (cells/ mm3)<200 45/57 (79%) 48/62 (77%)200 to <350 143/163 (88%) 126/159 (79%)350 176/194 (91%) 164/198 (83%)

Male 307/347 (88%) 291/356 (82%)

Female 57/67 (85%) 47/63 (75%)

White 255/284 (90%) 238 /285 (84%)

African-American/African109/130 (84%) 99/133 (74%)

Heritage/Other

Age (years)<50 319/361 (88%) 302/375 (81%)50 45/53 (85%) 36/44 (82%)

* Adjusted for baseline stratification factors.

† Includes subjects who discontinued prior to Week 48 for lack or loss of efficacy and subjectswho are 50 copies in the 48 week window.

‡ Includes subjects who discontinued due to an adverse event or death at any time point from

Day 1 through the Week 48 analysis window if this resulted in no virologic data on treatmentduring the analysis window.

§ Includes reasons such as withdrew consent, loss to follow-up, moved, protocol deviation.

Notes: ABC/3TC = abacavir 600 mg, lamivudine 300 mg in the form of Kivexa/Epzicom fixeddose combination (FDC)

EFV/TDF/FTC = efavirenz 600 mg, tenofovir disoproxil 245 mg, emtricitabine 200 mg in theform of Atripla FDC.

In the primary 48 weeks analysis, the proportion of patients with virologic suppression in thedolutegravir + ABC/3TC arm, was superior to the EFV/TDF/FTC arm, p=0.003, the same treatmentdifference was observed in subjects defined by baseline HIV RNA level (< or > 100,000 copies/mL).

The median time to viral suppression was shorter with ABC/3TC + DTG (28 vs 84 days, p<0.0001).

The adjusted mean change in CD4+ T cell count from baseline were 267 cells versus 208 cells/mm3,respectively (p<0.001). Both the time to viral suppression and change from baseline analyses werepre-specified and adjusted for multiplicity. At 96 weeks, the response was 80% vs 72%, respectively.

The difference in the endpoint remained statistically significant (p=0.006). The statistically higherresponses on DTG+ABC/3TC were driven by a higher rate of withdrawals due to AEs in the

EFV/TDF/FTC arm, irrespective of viral load strata. Overall treatment differences at Week 96 areapplicable to patients with high and low Baseline viral loads. At 144 weeks in the open-label phase of

SINGLE, virologic suppression was maintained, the DTG +ABC/3TC arm (71%) was superior to the

EFV/TDF/FTC arm (63%), treatment difference was 8.3% (2.0, 14.6).

In SPRING-2, 822 patients were treated with either dolutegravir 50 mg film-coated tablets once dailyor raltegravir 400 mg twice daily (blinded), both with fixed-dose ABC/3TC (around 40%) or

TDF/FTC (around 60%), given open label. Baseline demographics and outcomes are summarised in

Table 4. Dolutegravir was non-inferior to raltegravir, including within the subset of patients with theabacavir/lamivudine background regimen.

Table 4: Demographics and virologic outcomes of randomised treatment of SPRING-2 (snapshotalgorithm)

DTG 50 mg RAL 400mgonce daily twice daily+ 2 NRTI + 2 NRTI

N=411 N=411

Demographics

Median Age (years) 37 35

Female 15% 14%

Non-white 16% 14%

Hepatitis B and/or C 13% 11%

CDC class C 2% 2%

ABC/3TC backbone 41% 40%

Week 48 efficacy results

HIV-1 RNA <50 copies/mL 88% 85%

Treatment difference* 2.5% (95% CI: -2.2%, 7.1%)

Virologic non response† 5% 8%

No virologic data at Weeks 48 window 7% 7%

Reasons

Discontinued study/study medicinal product due to adverse2% 1%event or death‡

Discontinued study/study medicinal product for other5% 6%reasons§

HIV-1 RNA <50 copies/mL for those on ABC/3TC 86% 87%

Week 96 efficacy results

HIV-1 RNA <50 copies/mL 81% 76%

Treatment difference* 4.5% (95% CI: -1.1%, 10.0%)

HIV-1 RNA <50 copies/mL for those on ABC/3TC 74% 76%

* Adjusted for baseline stratification factors.

† Includes subjects who discontinued prior to Week 48 for lack or loss of efficacy and subjects whoare 50 copies in the 48 week window.‡ Includes subjects who discontinued due to an adverse event or death at any time point from Day 1through the Week 48 analysis window if this resulted in no virologic data on treatment during theanalysis window.

§ Includes reasons such as protocol deviation, lost to follow up, and withdrew consent.

Notes: DTG = dolutegravir, RAL = raltegravir.

In FLAMINGO, 485 patients were treated with dolutegravir 50 mg film-coated tablets once daily ordarunavir/ritonavir (DRV/r) 800 mg/100 mg once daily, both with ABC/3TC (around 33%) or

TDF/FTC (around 67%). All treatments were given open-label. Main demographics and outcomes aresummarised in Table 5.

Table 5: Demographics and Week 48 virologic outcomes of randomised treatment of FLAMINGO(snapshot algorithm)

DTG 50 mg DRV+RTVonce daily 800mg + 100mg+ 2 NRTI once daily+2 NRTI

N=242 N=242

Demographics

Median Age (years) 34 34

Female 13% 17%

Non-white 28% 27%

Hepatitis B and/or C 11% 8%

CDC class C 4% 2%

ABC/3TC backbone 33% 33%

Week 48 Efficacy Results

HIV-1 RNA <50 copies/mL 90% 83%

Treatment Difference* 7.1% (95% CI: 0.9%, 13.2%)

Virologic non response† 6% 7%

No virologic data at Weeks 48 window 4% 10%

Reasons

Discontinued study/study medicinal product due to adverse1% 4%event or death‡

Discontinued study/study medicinal product for other2% 5%reasons§

Missing data during window but on study <1% 2%

HIV-1 RNA <50copies/mL for those on ABC/3TC 90% 85%

Median time to viral suppression** 28 days 85 days

* Adjusted for baseline stratification factors, p=0.025.

† Includes subjects who discontinued prior to Week 48 for lack or loss of efficacy and subjects who are50 copies in the 48 week window.‡ Includes subjects who discontinued due to an adverse event or death at any time point from Day 1through the Week 48 analysis window if this resulted in no virologic data on treatment during theanalysis window.

§ Includes reasons such as withdrew consent, loss to follow-up, protocol deviation.

** p<0.001.

Notes: DRV+RTV = darunavir + ritonavir, DTG = dolutegravir.

At 96 weeks, virologic suppression in the dolutegravir group (80%) was superior to the DRV/r group(68%), (adjusted treatment difference [DTG-(DRV+RTV)]: 12.4%; 95% CI: [4.7, 20.2]). Responserates at 96 weeks were 82% for DTG+ABC/3TC and 75% for DRV/r+ABC/3TC.

In ARIA (ING117172), a randomised, open-label, active-controlled, multicentre, parallel group, non-inferiority study; 499 HIV-1 infected ART naïve adult women were randomised 1:1 to receive either;

DTG/ABC/3TC FDC film-coated tablets 50 mg/600 mg/300 mg; or atazanavir 300 mg plus ritonavir100 mg plus tenofovir disproxil/emtricitabine 245 mg/200 mg (ATV+RTV+TDF/FTC FDC), alladministered once daily.

Table 6: Demographics and Week 48 virologic outcomes of randomised treatment of ARIA(snapshot algorithm)

DTG/ABC/3TC ATV+RTV+TDF/FTC

FDC FDC

N=248 N=247

Demographics

Median Age (years) 37 37

Female 100 % 100 %

Non-white 54 % 57 %

Hepatitis B and/ or C 6 % 9%

CDC class C 4 % 4 %

Week 48 Efficacy Results

HIV-1 RNA <50 copies/mL 82 % 71 %

Treatment difference 10.5 (3.1% to 17.8%) [p=0.005].

Virologic Failure 6 % 14 %

Reasons

Data in window not below 50 c/mL 2 % 6 %threshold

Discontinued for lack of efficacy 2 % <1 %

Discontinued for other reason while not 3 % 7 %below threshold

No Virologic Data 12 % 15 %

Discontinued due to AE or death 4 % 7 %

Discontinued for other reasons 6 % 6 %

Missing data during window but on study 2 % 2 %

AE = Adverse event.

HIV-1 - human immunodeficiency virus type 1

DTG/ABC/3TC FDC - abacavir/dolutegravir/lamivudine fixed-dose combination

ATV+RTV+TDF/FTC FDC -atazanavir plus ritonavir plus tenofovir disproxil/emtricitabine fixed-dose combination

STRIIVING (201147) is a 48-week, randomised, open-label, active controlled, multicentre, non-inferiority study in patients without any prior treatment failure, and without any documented resistanceto any class. Virologically suppressed (HIV-1 RNA <50 c/mL) subjects were randomly assigned (1:1)to continue their current ART regimen (2 NRTIs plus either a PI, NNRTI, or INI), or switch to

ABC/DTG/3TC FDC film-coated tablets once daily (Early Switch). Hepatitis B co-infection was oneof the main exclusion criteria.

Patients were mainly white (66%) or black (28%) of male sex (87%). Main prior transmission routeswere homosexual (73%) or heterosexual (29%) contact. The proportion with a positive HCV serologywas 7%. The median time from first starting ART was around 4.5 years.

Table 7: Outcomes of randomised treatment of STRIIVING (snapshot algorithm)

Study Outcomes (Plasma HIV-1 RNA <50 c/mL) at Week 24 and Week 48 - Snapshot Analysis(ITT-E Population)

ABC/DTG/3TC Current ART Early Switch Late Switch

FDC ABC/DTG/3TC ABC/DTG/3TC

N=275 N=278 FDC FDCn (%) n (%) N=275 N=244n (%) n (%)

Outcome Time Point Day 1 to W 24 Day 1 to W 24 Day 1 to W48 W24 to W48

Virologic Success 85 % 88 % 83 % 92 %

Virologic Failure 1 % 1 % <1 % 1 %

Reasons

Data in window not 1 % 1 % <1 % 1 %below threshold

No Virologic Data 14 % 10 % 17 % 7 %

Discontinued due to AE 4 % 0 % 4 % 2 %or death

Discontinued for other 9 % 10 % 12 % 3 %reasons

Missing data during 1 % <1 % 2 % 2 %window but on study

ABC/DTG/3TC FDC = abacavir/dolutegravir/lamivudine fixed-dose combination; AE = adverse event;

ART = antiretroviral therapy; HIV-1 = human immunodeficiency virus type 1; ITT-E = intent-to-treatexposed; W = week.

Virologic suppression (HIV-1 RNA <50 copies/mL) in the ABC/DTG/3TC FDC group (85%) wasstatistically non-inferior to the current ART groups (88%) at 24 weeks. The adjusted difference inproportion and 95% CI [ABC/DTG/3TC vs current ART] were 3.4%; 95% CI: [-9.1, 2.4]. After 24weeks all remaining subjects switched to ABC/DTG/3TC FDC (Late Switch). Similar levels ofvirologic suppression were maintained in both the Early and Late Switch groups at 48 weeks.

De novo resistance was not detected to the integrase class or the NRTI class in any patients who weretreated with dolutegravir + abacavir/lamivudine in the three studies mentioned.

For the comparators typical resistance was detected with TDF/FTC/EFV (SINGLE; six with NNRTIassociated resistance and one with major NRTI resistance) and with 2 NRTIs + raltegravir (SPRING-2; four with major NRTI resistance and one with raltegravir resistance), while no de novo resistancewas detected in patients treated with 2 NRTIs + DRV/RTV (FLAMINGO).

In a Phase I/II 48 week, open-label, multicentre, dose-finding clinical study (IMPAACT

P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of dolutegravirwere evaluated in combination with other antiretroviral medicinal products in treatment naïve ortreatment-experienced, INSTI-naïve, HIV-1-infected subjects aged ≥ 4 weeks to < 18 years. Subjectswere stratified by age cohort; subjects aged 12 to less than 18 years were enrolled in Cohort I andsubjects aged 6 to less than 12 years were enrolled in Cohort IIA. Across both cohorts, 67% (16/24) ofsubjects who received the recommended dose (determined by weight and age) achieved HIV-1 RNAless than 50 copies per mL at Week 48 (Snapshot algorithm).

DTG/ABC/3TC FDC film-coated tablets and dispersible tablets were evaluated in treatment naïve ortreatment-experienced, HIV-1 infected subjects aged <12 years and weighing ≥6 to <40 kg in an open-label, multicentre, clinical trial (IMPAACT 2019). 57 subjects weighing at least 6 kg who received therecommended dose and formulation (determined by weight band) contributed to the efficacy analysesat Week 48. Overall, 79% (45/57) and 95% (54/57) of subjects weighing at least 6 kg achieved HIV-1

RNA less than 50 copies per mL and less than 200 copies per mL, respectively, at Week 48 (Snapshotalgorithm).

Abacavir and lamivudine once daily, in combination with a third antiretroviral medicinal product,were evaluated in a randomised, multicentre trial (ARROW) in HIV-1-infected, treatment-naïvesubjects. Subjects randomised to once-daily dosing (n = 331) and who weighed at least 25 kg receivedabacavir 600 mg and lamivudine 300 mg, as either the single entities or as FDC. At Week 96, 69% ofsubjects receiving abacavir and lamivudine once-daily in combination with a third antiretroviralmedicinal product, had HIV-1 RNA less than 80 copies per mL.

Triumeq film-coated tablet has been shown to be bioequivalent to dolutegravir single entity film-coated tablet and abacavir/lamivudine fixed-dose combination tablet (ABC/3TC FDC) administeredseparately. This was demonstrated in a single dose, 2-way crossover bioequivalence study of Triumeq(fasted) versus 1 x 50 mg dolutegravir tablet, plus 1 x 600mg abacavir/300 mg lamivudine tablet(fasted) in healthy subjects (n=66).

The relative bioavailability of abacavir and lamivudine administered in dispersible tablet form iscomparable to film-coated tablets. The relative bioavailability of dolutegravir administered indispersible tablet form is approximately 1.7-fold higher as compared to film-coated tablets. Thus, the

Triumeq dispersible tablets are not directly interchangeable with Triumeq film-coated tablets (seesection 4.2).

The pharmacokinetic properties of dolutegravir, lamivudine and abacavir are described below.

Dolutegravir, abacavir and lamivudine are rapidly absorbed following oral administration. Theabsolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oralabacavir and lamivudine in adults is about 83% and 80-85% respectively. The mean time to maximalserum concentrations (tmax) is about 2 to 3 hours (post dose for tablet formulation), 1.5 hours and1.0 hour for dolutegravir, abacavir and lamivudine, respectively.

Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects.

In HIV-1-infected adult subjects following dolutegravir 50 mg film-coated tablets once daily, thesteady-state pharmacokinetic parameters (geometric mean [%CV]) based on populationpharmacokinetic analyses were AUC(0-24) = 53.6 (27) g.h/mL, Cmax = 3.67 (20) g/mL, and Cmin = 1.11(46) g/mL. Following a single dose of 600 mg of abacavir, the mean (CV) Cmax is 4.26 µg/ml (28%)and the mean (CV) AUC is 11.95 µg.h/ml (21%). Following multiple-dose oral administration oflamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is 2.04 µg/ml (26%) andthe mean (CV) AUC24 is 8.87 µg.h/ml (21%).

The effect of a high fat meal on Triumeq film-coated tablet was evaluated in a subgroup of subjects(n=12) of the single dose, 2-way crossover bioequivalence study. Plasma Cmax and AUC ofdolutegravir following administration of Triumeq film-coated tablets with a high fat meal were 37%and 48% higher, respectively, than those following administration of Triumeq film-coated tablets inthe fasted state. For abacavir there was a decrease in Cmax with 23% and AUC was unchanged. Theexposure of lamivudine was similar with and without food. These results indicate that Triumeq film-coated tablets can be taken with or without food.

The apparent volume of distribution of dolutegravir (following oral administration of suspensionformulation, Vd/F) is estimated at 12.5 L. Intravenous studies with abacavir and lamivudine showedthat the mean apparent volume of distribution is 0.8 and 1.3 l/kg respectively.

Dolutegravir is highly bound (> 99%) to human plasma proteins based on in vitro data. Binding ofdolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood and plasmadrug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimalassociation of radioactivity with blood cellular components. The unbound fraction of dolutegravir inplasma is increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderatehepatic impairment. Plasma protein binding studies in vitro indicate that abacavir binds only low tomoderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibitslinear pharmacokinetics over the therapeutic dose range and displays limited plasma protein binding invitro (< 36%).

Dolutegravir, abacavir and lamivudine are present in cerebrospinal fluid (CSF).

In 13 treatment-naïve subjects on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravirconcentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and abovethe IC50). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. Theobserved values of the peak concentrations are 9-fold greater than the IC50 of abacavir of 0.08 µg/mlor 0.26 µM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudineconcentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNSpenetration of lamivudine and its relationship with any clinical efficacy is unknown.

Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervicaltissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semenwas 7% and 17% in rectal tissue of those in corresponding plasma at steady state.

Dolutegravir is primarily metabolised via UGT1A1 with a minor CYP3A component (9.7% of totaldose administered in a human mass balance study). Dolutegravir is the predominant circulatingcompound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose).

Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part ofthis is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, whichcan be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the totaloral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of totaldose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at thebenzylic carbon (3.0% of total dose).

Abacavir is primarily metabolised by the liver with approximately 2% of the administered dose beingrenally excreted, as unchanged compound. The primary pathways of metabolism in man are by alcoholdehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide whichaccount for about 66% of the administered dose. These metabolites are excreted in the urine.

Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared byrenal excretion of unchanged lamivudine. The likelihood of metabolic drug interactions withlamivudine is low due to the small extent of hepatic metabolism (5-10%).

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymescytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A,

UGT1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, organic anion transporting polypeptide1B1 (OATP1B1), OATP1B3, OCT1, MATE2-K, multidrug resistance-associated protein 2 (MRP2) or

MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Based on this data,dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates ofmajor enzymes or transporters (see section 4.5).

In vitro, dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.

In vitro, abacavir did not inhibit or induce CYP enzymes (other than CY1A1 and CYP3A4 [limitedpotential], see section 4.5) and demonstrates no or weak inhibition of OATP1B1, OAT1B3, OCT1,

OCT2, BCRP and P-gp or MATE2-K. Abacavir is therefore not expected to affect the plasmaconcentrations of medicinal products that are substrates of these enzymes or transporters.

Abacavir was not significantly metabolised by CYP enzymes. In vitro, abacavir was not a substrate of

OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4 thereforemedicinal products that modulate these transporters are not expected to affect abacavir plasmaconcentrations.

In vitro, lamivudine did not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or CYP2D6)and demonstrated no or weak inhibition of OATP1B1, OAT1B3, OCT3, BCRP, P-gp, MATE1 or

MATE2-K. Lamivudine is therefore not expected to affect the plasma concentrations of medicinalproducts that are substrates of these enzymes or transporters.

Lamivudine was not significantly metabolised by CYP enzymes.

Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) isapproximately 1 L/hr in HIV-infected patients based on a population pharmacokinetic analysis.

The mean half-life of abacavir is about 1.5 hours. The geometric mean terminal half-life ofintracellular active moiety carbovirtriphosphate (TP) at steady-state is 20.6 hours. Following multipleoral doses of abacavir 300 mg twice a day there is no significant accumulation of abacavir.

Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarilyin the urine. The metabolites and unchanged abacavir account for about 83% of the administeredabacavir dose in the urine. The remainder is eliminated in the faeces.

The observed lamivudine half-life of elimination is 18 to 19 hours. For patients receiving lamivudine300 mg once daily, the terminal intracellular half-life of lamivudine-TP was 16 to 19 hours. The meansystemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance(> 70%) via the organic cationic transport system. Studies in patients with renal impairment showlamivudine elimination is affected by renal dysfunction. Dose reduction is required for patients withcreatinine clearance < 30 mL/min (see section 4.2).

In a randomised, dose-ranging trial, HIV-1-infected subjects treated with dolutegravir monotherapy(ING111521) demonstrated rapid and dose-dependent antiviral activity with mean decline in HIV-1

RNA of 2.5 log10 at day 11 for 50 mg dose. This antiviral response was maintained for 3 to 4 daysafter the last dose in the 50 mg group.

The geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours,compared to the geometric mean abacavir plasma half-life of 2.6 hours. The terminal intracellular half-life of lamivudine-TP was prolonged to 16-19 hours, supporting once daily dosing of ABC and 3TC.

Pharmacokinetic data has been obtained for dolutegravir, abacavir and lamivudine separately.

Dolutegravir is primarily metabolised and eliminated by the liver. A single dose of 50 mg ofdolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B)and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma wassimilar, a 1.5 to 2-fold increase in unbound exposure to dolutegravir was observed in subjects withmoderate hepatic impairment compared to healthy controls. No dose adjustment is considerednecessary for patients with mild to moderate hepatic impairment. The effect of severe hepaticimpairment on the pharmacokinetics of dolutegravir has not been studied.

Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied inpatients with mild hepatic impairment (Child-Pugh score 5-6) receiving a single 600 mg dose. Theresults showed that there was a mean increase of 1.89-fold [1.32; 2.70] in the abacavir AUC, and 1.58[1.22; 2.04] fold in the elimination half-life. No recommendation on dose reduction is possible inpatients with mild hepatic impairment due to substantial variability of abacavir exposure.

Data obtained in patients with moderate to severe hepatic impairment show that lamivudinepharmacokinetics are not significantly affected by hepatic dysfunction.

Based on data obtained for abacavir, Triumeq is not recommended in patients with moderate or severehepatic impairment.

Pharmacokinetic data have been obtained for dolutegravir, lamivudine and abacavir separately.

Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. Astudy of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment(CrCl <30 mL/min). No clinically important pharmacokinetic differences between subjects with severerenal impairment (CrCl <30 mL/min) and matching healthy subjects were observed. Dolutegravir hasnot been studied in patients on dialysis, though differences in exposure are not expected.

Abacavir is primarily metabolised by the liver with approximately 2% of abacavir excreted unchangedin the urine. The pharmacokinetics of abacavir in patients with end-stage renal disease is similar topatients with normal renal function.

Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renaldysfunction due to decreased clearance.

Based on the lamivudine data, Triumeq is not recommended for patients with creatinine clearance of< 30 mL/min.

Population pharmacokinetic analysis of dolutegravir using data from HIV-1 infected adults showedthat there was no clinically relevant effect of age on dolutegravir exposure.

Pharmacokinetic data for dolutegravir, abacavir and lamivudine in subjects >65 years of age arelimited.

The pharmacokinetics of dolutegravir film-coated and dispersible tablets in HIV-1 infected infants,children and adolescents aged ≥ 4 weeks to < 18 years were evaluated in two on-going studies(IMPAACT P1093/ING112578 and ODYSSEY/201296). Mean dolutegravir AUC0-24h and C24h in

HIV-1-infected paediatric subjects weighing at least 6 kg were comparable to those in adults after 50mg once daily or 50 mg twice daily. Mean Cmax is higher in paediatrics, but the increase is notconsidered clinically significant as the safety profiles were similar in paediatric and adult subjects.

The pharmacokinetics of Triumeq film-coated and dispersible tablets in HIV-1 infected, treatmentnaïve or treatment-experienced, children aged <12 years were evaluated in a study (IMPAACT 2019).

Mean dolutegravir, abacavir and lamivudine AUC0-24h, C24h and Cmax at recommended doses for

Triumeq film-coated and dispersible tablets in HIV-1 infected paediatric subjects weighing at least6 kg to less than 40 kg were within the observed exposure ranges at the recommended doses ofindividual products in adults and paediatrics.

Pharmacokinetic data are available for abacavir and lamivudine in children and adolescents receivingrecommended dose regimens of the oral solution and tablet formulations. Pharmacokinetic parametersare comparable to those reported in adults. In children and adolescents weighing 6 kg to less than25 kg, at recommended doses, predicted exposures (AUC0-24h) for abacavir and lamivudine with

Triumeq dispersible tablets are within the predicted exposure range of the individual componentsbased on population pharmacokinetic modelling and simulation.

There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravirpharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomicssamples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypesconferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher

AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1(n=41).

Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trialsrevealed no clinically relevant effect of gender on the exposure of dolutegravir. There is no evidencethat a dose adjustment of dolutegravir, abacavir or lamivudine would be required based on the effectsof gender on PK parameters.

Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trialsrevealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics ofdolutegravir following single dose oral administration to Japanese subjects appear similar to observedparameters in Western (US) subjects. There is no evidence that a dose adjustment of dolutegravir,abacavir or lamivudine would be required based on the effects of race on PK parameters.

Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinicallyrelevant effect on the exposure to dolutegravir. There are limited pharmacokinetic data on subjectswith hepatitis B co-infection (see section 4.4).

There are no data available on the effects of the combination of dolutegravir, abacavir and lamivudinein animals, except a negative in vivo rat micronucleus test which tested the effects of the combinationof abacavir and lamivudine.

Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammaliancells, and an in vivo rodent micronucleus assay.

Neither abacavir nor lamivudine were mutagenic in bacterial tests, but consistent with other nucleosideanalogues, inhibit cellular DNA replication in in vitro mammalian tests such as the mouse lymphomaassay. The results of an in vivo rat micronucleus test with abacavir and lamivudine in combinationwere negative.

Lamivudine has not shown any genotoxic activity in the in vivo studies. Abacavir has a weak potentialto cause chromosomal damage both in vitro and in vivo at high tested concentrations.

The carcinogenic potential of a combination of dolutegravir, abacavir and lamivudine has not beentested. Dolutegravir was not carcinogenic in long term studies in the mouse and rat. In long-term oralcarcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential.

Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in theincidence of malignant and non-malignant tumours. Malignant tumours occurred in the preputial glandof males and the clitoral gland of females of both species, and in rats in the thyroid gland of males andin the liver, urinary bladder, lymph nodes and the subcutis of females.

The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and600 mg/kg/day in rats. The exception was the preputial gland tumour which occurred at a dose of110 mg/kg in mice. The systemic exposure at the no effect level in mice and rats was equivalent to 3and 7 times the human systemic exposure during therapy. While the clinical relevance of thesefindings is unknown, these data suggest that a potential carcinogenic risk to humans is outweighed bythe clinical benefit.

The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeatoral dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primaryeffect of dolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses thatproduce systemic exposures approximately 38 and 1.5 times the 50 mg human clinical exposure basedon AUC, respectively. Because gastrointestinal (GI) intolerance is considered to be due to local activesubstance administration, mg/kg or mg/m2 metrics are appropriate determinates of safety cover for thistoxicity. GI intolerance in monkeys occurred at 30 times the human mg/kg equivalent dose (based on50 kg human), and 11 times the human mg/m2 equivalent dose for a total daily clinical dose of 50 mg.

In toxicology studies abacavir was shown to increase liver weights in rats and monkeys. The clinicalrelevance of this is unknown. There is no evidence from clinical studies that abacavir is hepatotoxic.

Additionally, autoinduction of abacavir metabolism or induction of the metabolism of other medicinalproducts hepatically metabolised has not been observed in humans.

Mild myocardial degeneration in the heart of mice and rats was observed following administration ofabacavir for two years. The systemic exposures were equivalent to 7 to 21 times the expected systemicexposure in humans. The clinical relevance of this finding has not been determined.

In reproductive toxicity studies in animals, dolutegravir, lamivudine and abacavir were shown to crossthe placenta.

Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (50 times the50 mg human clinical exposure when administered in combination with abacavir and lamivudinebased on AUC).

Oral administration of dolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to18 of gestation did not elicit developmental toxicity or teratogenicity (0.74 times the 50mg humanclinical exposure when administered in combination with abacavir and lamivudine based on AUC). Inrabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weightgain) was observed at 1000 mg/kg (0.74 times the 50 mg human clinical exposure when administeredin combination with abacavir and lamivudine based on AUC).

Lamivudine was not teratogenic in animal studies but there were indications of an increase in earlyembryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved inhumans. A similar effect was not seen in rats even at very high systemic exposure.

Abacavir demonstrated toxicity to the developing embryo and foetus in rats, but not in rabbits. Thesefindings included decreased foetal body weight, foetal oedema, and an increase in skeletalvariations/malformations, early intra-uterine deaths and still births. No conclusion can be drawn withregard to the teratogenic potential of abacavir because of this embryo-foetal toxicity.

Fertility studies in rats have shown that dolutegravir, abacavir and lamivudine have no effect on maleor female fertility.

Mannitol (E421)

Microcrystalline cellulose

Povidone (K29/32)

Sodium starch glycollate

Magnesium stearate

Poly(vinyl) alcohol - partially hydrolysed

Titanium dioxide

Macrogol

Talc

Iron oxide black

Iron oxide red

Not applicable.

3 years

Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do notremove the desiccant.

This medicinal product does not require any special temperature storage conditions.

White HDPE (high density polyethylene) bottles closed with polypropylene child-resistant closures,with a polyethylene faced induction heat seal liner.

Each bottle contains 30 film-coated tablets and a desiccant.

Multipacks containing 90 (3 packs of 30) film-coated tablets. Each pack of 30 film-coated tabletscontains a desiccant.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/14/940/001

EU/1/14/940/002

Date of first authorisation: 1st September 2014

Date of latest renewal: 20th June 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu