DOVATO 50mg / 300mg tablets medication leaflet

Dovato 50 mg/300 mg film-coated tablets

Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir and 300 mglamivudine.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Oval, biconvex, white, film coated tablet, approximately 18.5 x 9.5 mm, debossed with “SV 137” on one face.

Dovato is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adultsand adolescents above 12 years of age weighing at least 40 kg, with no known or suspected resistance to theintegrase inhibitor class, or lamivudine (see section 5.1).

Dovato should be prescribed by physicians experienced in the management of HIV infection.

Adults and adolescents (above 12 years of age weighing at least 40 kg).

The recommended dose of Dovato in adults and adolescents is one 50 mg/300 mg tablet once daily.

A separate preparation of dolutegravir is available where a dose adjustment is indicated due to drug-druginteractions (e.g. rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John’s wort,etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir, see sections 4.4and 4.5). In these cases the physician should refer to the individual product information for dolutegravir.

If the patient misses a dose of Dovato, the patient should take Dovato as soon as possible, providing the nextdose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the misseddose and simply resume the usual dosing schedule.

There are limited data available on the use of Dovato in patients aged 65 years and over. No dose adjustmentis necessary (see section 5.2).

Dovato is not recommended for use in patients with a creatinine clearance < 30 mL/min (see section 5.2). Nodose adjustment is required in patients with mild or moderate renal impairment. However, the lamivudineexposure is significantly increased in patients with a creatinine clearance < 50 mL/min (see section 4.4).

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh grade Aor B). No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore

Dovato should be used with caution in these patients (see section 5.2).

The safety and efficacy of Dovato in children aged less than 12 years and in adolescents weighing less than40 kg have not been established. No data are available.

Oral use.

Dovato 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 of organiccation transporter (OCT) 2, including but not limited to fampridine (also known as dalfampridine; see section4.5).

Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash,constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dovato and othersuspect medicinal products should be discontinued immediately if signs or symptoms of hypersensitivityreactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes,fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema,eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should bemonitored. Delay in stopping treatment with Dovato or other suspect active substances after the onset ofhypersensitivity may result in a life-threatening allergic reaction.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Suchchanges may in part be linked to disease control and lifestyle. For lipids and weight, there is in some casesevidence for a treatment effect. For monitoring of blood lipids and glucose reference is made to established

HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increasedrisk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy forhepatitis B or C, please refer also to the relevant product information for these medicinal products.

Dovato includes lamivudine, which is active against hepatitis B. Dolutegravir lacks such activity.

Lamivudine monotherapy is generally not considered an adequate treatment for hepatitis B, since the risk forhepatitis B resistance development is high. If Dovato is used in patients co-infected with hepatitis B anadditional antiviral is therefore generally needed. Reference should be made to treatment guidelines.

If Dovato is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liverfunction tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result inan acute exacerbation of hepatitis.

Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased frequency ofliver function abnormalities during combination antiretroviral therapy, and should be monitored according tostandard practice. If there is evidence of worsening liver disease in such patients, interruption ordiscontinuation of treatment must be considered.

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, suchreactions have been observed within the first few weeks or months of initiation of CART. Relevant examplesare Cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveciipneumonia (often referred to as PCP). Any inflammatory symptoms should be evaluated and treatmentinstituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported to occur in the setting of immune reactivation; however, the reported time to onset is morevariable and these events can occur many months after initiation of treatment.

Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis

B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver chemistries isrecommended in patients with hepatitis B and/or C co-infection. (See ‘Liver disease’ earlier in this sectionand also see section 4.8).

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is mostpronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues, these havepredominantly concerned treatment with regimens containing zidovudine. The main adverse reactionsreported are haematological disorders (anaemia, neutropenia), and metabolic disorders (hyperlactatemia,hyperlipasemia). These reactions have often been transitory. Some late-onset neurological disorders havebeen reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders aretransient or permanent is currently unknown. These findings should be considered for any child exposed inutero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknownaetiology, particularly neurologic findings. These findings do not affect current national recommendations touse antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates,alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should beadvised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty inmovement.

Patients should be advised that dolutegravir, lamivudine or any other antiretroviral therapy does not cure

HIV infection and that they may still develop opportunistic infections and other complications of HIVinfection. Therefore, patients should remain under close clinical observation by physicians experienced in thetreatment of these associated HIV diseases.

Patients with a creatinine clearance between 30 and 49 mL/min receiving Dovato may experience a 1.6-to3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There areno safety data from randomized, controlled trials comparing Dovato to the individual components in patientswith a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In theoriginal lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures wereassociated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuationsdue to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse reactions(such as gastro-intestinal and hepatic disorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Dovato should bemonitored for lamivudine-related adverse reactions, notably haematologic toxicities. If new or worseningneutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, isindicated, which cannot be achieved with Dovato. Dovato should be discontinued and the individualcomponents should be used to construct the treatment regimen.

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).

Dovato should not be co-administered with polyvalent cation-containing antacids. Polyvalent cation-containing antacids are recommended to be taken 2 hours after or 6 hours before Dovato (see section 4.5).

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

Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be consideredwhen starting and stopping coadministration of Dovato with metformin, to maintain glycaemic control (seesection 4.5). Metformin is eliminated renally and, therefore, it is of importance to monitor renal functionwhen co-treated with Dovato. This combination may increase the risk for lactic acidosis in patients withmoderate renal impairment (stage 3a creatinine clearance 45- 59 mL/min) and a cautious approach isrecommended. Reduction of the metformin dose should be highly considered.

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

Dovato should not be taken with any other medicinal product containing dolutegravir, lamivudine oremtricitabine, except where a dose adjustment of dolutegravir is indicated due to drug-drug interactions (seesection 4.5).

No drug interaction studies have been conducted using Dovato. Dovato contains dolutegravir andlamivudine, therefore any interactions identified for these individually are relevant to Dovato. No clinicallysignificant drug interactions are expected between dolutegravir and lamivudine.

Effect of other medicinal products on the pharmacokinetics of dolutegravir and lamivudine

Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase(UGT) 1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-glycoprotein (P-gp), andbreast cancer resistance protein (BCRP). Co-administration of Dovato and other medicinal products thatinhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may, therefore, increase dolutegravir plasmaconcentration. Medicinal products that induce those enzymes or transporters may decrease dolutegravirplasma concentration and reduce the therapeutic effect of dolutegravir.

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

Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through the

OCT2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (an inhibitorof these transporters) has been shown to increase lamivudine plasma concentrations, however the resultingincrease was not clinically significant (see Table 1). Dolutegravir is an OCT2 and MATE1 inhibitor;however, lamivudine concentrations were similar with or without co-administration of dolutegravir based ona cross study analysis, indicating that dolutegravir has no relevant effect on lamivudine exposure in vivo.

Lamivudine is also substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minorrole in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinicalsignificance.

Although lamivudine is a substrate of BCRP and P-gp in vitro, given its high absolute bioavailability, (seesection 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact onlamivudine concentrations.

Effect of dolutegravir and lamivudine on the pharmacokinetics of other medicinal products

In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitrodata, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates ofany major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2).

In vitro, dolutegravir inhibited the renal transporters OCT2 and MATE1. In vivo, a 10-14% decrease ofcreatinine clearance (secretory fraction is dependent on OCT2 and MATE1 transport) was observed inpatients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretionis dependent upon OCT2 and/or MATE1 (e.g. fampridine [also known as dalfampridine], metformin) (see

Table 1 and section 4.3).

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

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

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

Interactions between dolutegravir, lamivudine and co-administered medical products are listed in Table 1(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus timecurve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as“Cτ”). The table should not be considered exhaustive but is representative of the classes studied.

Table 1: Drug Interactions

Medicinal products by Interaction geometric Recommendations concerning co-therapeutic areas mean change (%) administration

Antiretroviral medicinal products

Non-nucleoside reverse transcriptase inhibitors

Etravirine without boosted Dolutegravir  Etravirine without boosted 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 Dovato(induction of UGT1A1 is a fixed-dose tablet, an additionaland CYP3A enzymes) 50 mg tablet of dolutegravir should beadministered, approximately 12 hoursafter Dovato for the duration of theetravirine without boosted proteaseinhibitor co-administration (a separateformulation 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

Cmax  39% co-administered with efavirenz. As

C  75% Dovato is a fixed-dose tablet, anadditional 50 mg tablet of dolutegravir

Efavirenz  (historical should be administered, approximatelycontrols) 12 hours after Dovato for the duration of(induction of UGT1A1 the efavirenz co-administration (aand CYP3A enzymes) separate formulation of dolutegravir isavailable for this dose adjustment, seesection 4.2).

Nevirapine/Dolutegravir Dolutegravir  The recommended dose of dolutegravir(Not studied, a similar is 50 mg twice daily whenreduction in exposure as co-administered with nevirapine. Asobserved with efavirenz is Dovato is a fixed-dose tablet, anexpected, due to additional 50 mg tablet of dolutegravirinduction) should be administered, approximately12 hours after Dovato for the duration ofthe nevirapine co-administration (aseparate formulation of dolutegravir isavailable for this dose adjustment, seesection 4.2).

Rilpivirine/Dolutegravir Dolutegravir  No dose adjustment is necessary.

AUC  12%

Cmax  13%

Cτ  22%

Rilpivirine 

Nucleoside reverse transcriptase inhibitors (NRTIs)

Tenofovir disoproxil Dolutegravir  No dose adjustment is necessary when

AUC  1% Dovato is combined with tenofovir,

Cmax  3% didanosine, stavudine or zidovudine.

Cτ  8%

Tenofovir  Dovato is not recommended for use incombination with emtricitabinecontaining products, since both

Emtricitabine, didanosine, Interaction not studied lamivudine (in Dovato) andstavudine, tenofovir emtricitabine are cytidine analogues (i.e.

alafenamide, zidovudine 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

Cmax  47% co administered with

C  76% tipranavir/ritonavir. As Dovato is afixed-dose tablet, an additional 50 mg

Tipranavir  tablet of dolutegravir should be

Ritonavir  administered, approximately 12 hours(induction of UGT1A1 after Dovato for the duration of theand CYP3A enzymes) tipranavir/ritonavir co-administration (aseparate formulation of dolutegravir isavailable for this dose adjustment, seesection 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 

Darunavir+ritonavir/ Dolutegravir  No dose adjustment is necessary.

Dolutegravir AUC  22%

Cmax  11%

C  38%

Darunavir 

Ritonavir (induction of UGT1A1and CYP3A enzymes)

Other antiviral active substances

Daclatasvir/Dolutegravir Dolutegravir  Daclatasvir did not change dolutegravir

AUC  33% plasma concentration to a clinically

Cmax  29% relevant extent. Dolutegravir did not

C  45% change daclatasvir plasma concentration.

Daclatasvir  No dose adjustment is necessary.

Ledipasvir/Sofosbuvir/ Lamivudine  No dosage adjustment necessary.

Lamivudine (with abacavir) Ledipasvir 

Sofosbuvir 

Sofosbuvir/ Dolutegravir  No dosage adjustment necessary.

Velpatasvir/Dolutegravir Sofosbuvir 

Velpatasvir

Ribavirin Interaction not studied. No dosage adjustment necessary.

Clinically significantinteraction unlikely.

Anti-infective products

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

Trimethoprim:

AUC 

Sulfamethoxazole:

AUC (organic cation transporterinhibition)

Antimycobacterials

Rifampicin/Dolutegravir Dolutegravir  The recommended dose of dolutegravir

AUC  54% is 50 mg twice daily when

Cmax  43% co-administered with rifampicin. As

C  72% Dovato is a fixed-dose tablet, an(induction of UGT1A1 additional 50 mg tablet of dolutegravirand CYP3A enzymes) should be administered, approximately12 hours after Dovato for the duration ofthe rifampicin co-administration (aseparate formulation of dolutegravir isavailable for this dose adjustment, seesection 4.2).

Rifabutin/Dolutegravir 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

Cmax  33% co-administered with these metabolic

C  73% inducers. As Dovato is a fixed-dosetablet, an additional 50 mg tablet of

Phenobarbital/Dolutegravir Dolutegravir  dolutegravir should be administered,

Phenytoin/Dolutegravir (Not studied, decrease approximately 12 hours after Dovato for

Oxcarbazepine/Dolutegravir expected due to induction the duration of the co-administrationof UGT1A1 and CYP3A with these metabolic inducers (a separateenzymes, a similar formulation of dolutegravir is availablereduction in exposure as for this dose adjustment, see sectionobserved with 4.2).

carbamazepine isexpected).

Antihistamines (histamine H2 receptor antagonists)

Ranitidine Interaction not studied. No dosage adjustment necessary.

Clinically significantinteraction unlikely.

Cimetidine Interaction not studied. No dosage adjustment necessary.

Clinically significantinteraction unlikely.

Cytotoxics

Cladribine/Lamivudine Interaction not studied. Concomitant use of Dovato 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 andcladribine.

Miscellaneous

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 Dovato 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 Dovato 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

Dovato (minimum 2 hours after or(Complex binding to 6 hours before).

polyvalent ions)

Calcium Dolutegravir  - When taken with food, Dovato andsupplements/Dolutegravir AUC  39% supplements or multivitamins containing(fasted intake) Cmax  37% calcium, iron or magnesium can be taken

C24  39% at the same time.

(Complex binding to - If Dovato is taken in a fasted state,polyvalent ions) such supplements should be taken a

Iron supplements/Dolutegravir Dolutegravir  minimum 2 hours after or 6 hours before(fasted intake) AUC  54% the intake of Dovato.

Cmax  57%

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 Cmax  35% together with calcium or iron(fasted intake) C24  32% supplements were modified by the food(Complex binding to effect, resulting in an exposure similar topolyvalent ions) that obtained with dolutegraviradministered in the fasted state.

Omeprazole Dolutegravir  No dosage adjustment necessary.

Prednisone/Dolutegravir Dolutegravir  No dose adjustment is necessary.

AUC  11%

Cmax  6%

Cτ  17%

Antidiabetics

Metformin/Dolutegravir Metformin  A dose adjustment of metformin should

Dolutegravir  be considered when starting and

When co-administered stopping coadministration of Dovatowith dolutegravir 50 mg with metformin, to maintain glycaemic

QD: control. In patients with moderate renal

Metformin impairment a dose adjustment of

AUC  79% metformin should be considered when

Cmax  66% coadministered with Dovato, because of

When co-administered the increased risk for lactic acidosis inwith dolutegravir 50 mg patients with moderate renal impairment

BID: due to increased metformin

Metformin concentration (section 4.4).

AUC  145 %

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 Dovato 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 Dovato for the duration ofcarbamazepine is the St. John’s wort co-administration (aexpected). separate formulation 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 Dovato.

NGMN 

AUC  2%

Cmax  11%

Interaction studies have only been performed in adults.

Dovato can be used during pregnancy if clinically needed.

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformativenor feto/ neonatal toxicity associated with dolutegravir. A large amount of data on pregnant women (morethan 1000 exposed outcomes) indicate no malformative nor feto/neonatal toxicity with lamivudine.

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

The safety and efficacy of a dual therapy with dolutegravir + lamivudine has not been studied 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 defects afterdolutegravir exposure.

The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births(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 tothose taking non-dolutegravir containing antiretroviral regimens at conception (0.11%), or compared towomen without HIV (0.07%).

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

HIV (0.08%).

Data analysed from the Antiretroviral Pregnancy Registry (APR) of more than 1000 pregnancies with firsttrimester dolutegravir treatment and more than 1000 pregnancies with first trimester lamivudine treatment,do not indicate an increased risk of major birth defects with either dolutegravir or lamivudine compared tothe background 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 in pregnant women.

In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, includingneural 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 the maternalperipheral plasma concentration.

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

Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats (seesection 5.3).

Animal studies showed lamivudine may inhibit cellular DNA replication (see section 5.3). The clinicalrelevance of these findings is unknown.

Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degreeof mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infantsexposed 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 to maternalplasma ratio of 0.033 has been shown). There is insufficient information on the effects of dolutegravir inneonates/infants.

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfedinfants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressivelydecrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available onthe safety of lamivudine when administered to babies less than three months old.

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

There are no data on the effects of dolutegravir or lamivudine on human male or female fertility. Animalstudies indicate no effects of dolutegravir or lamivudine on male or female fertility (see section 5.3).

Dovato has no or negligible influence on the ability to drive and use machines. Patients should be informedthat dizziness and somnolence has been reported during treatment with dolutegravir. The clinical status ofthe patient and the adverse reaction profile of Dovato should be borne in mind when considering the patient’sability to drive or operate machinery.

The most frequently reported adverse reactions are headache (3%), diarrhoea (2%), nausea (2%) andinsomnia (2%).

The most severe adverse reaction reported with dolutegravir was a hypersensitivity reaction that includedrash and severe liver effects (see section 4.4).

The adverse reactions from clinical study and post-marketing experience are listed in Table 2 by bodysystem, organ class and absolute frequency. Frequencies are defined 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), notknown (cannot be estimated from the available data).

Table 2: Tabulated summary of adverse reactions to Dovato based on clinical study and post-marketing experience with Dovato and its individual components

Frequency Adverse reaction

Blood and lymphatic systems disorders:

Uncommon: neutropenia, anaemia, thrombocytopenia

Very rare: pure red cell aplasia

Uncommon: hypersensitivity (see section 4.4), immune reconstitutionsyndrome (see section 4.4)

Very rare: lactic acidosis

Common: depression, anxiety, insomnia, abnormal dreams

Uncommon: suicidal ideation*, suicide attempt*, panic attack

*particularly in patients with a pre-existing history ofdepression or psychiatric illness.

Rare: completed suicide*

*particularly in patients with a pre-existing history ofdepression or psychiatric illness.

Very common: headache

Common: dizziness, somnolence

Very rare: peripheral neuropathy, paraesthesia

Very common: nausea, diarrhoea

Common: vomiting, flatulence, abdominal pain/ discomfort

Rare: pancreatitis

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

Uncommon: hepatitis

Rare: acute hepatic failure1, increased bilirubin2

Common: rash, pruritus, alopecia

Rare: angioedema

Common: arthralgia, muscle disorders (including myalgia)

Rare: rhabdomyolysis

Common: fatigue

Common: creatine phosphokinase (CPK) elevations, weight increased

Rare: amylase elevations1 This adverse reaction was identified through post-marketing surveillance fordolutegravir in combination with other ARVs. The frequency category of rare wasestimated based on post-marketing reports.

2 In combination with increased transaminases.

Dolutegravir has been associated with an increase in serum creatinine occuring in the first week of treatmentwhen administered with other antiretroviral medicinal products. Increases in serum creatinine occurredwithin the first four weeks of treatment with dolutegravir plus lamivudine and remained stable through48 weeks. In the pooled GEMINI studies a mean change from baseline of 10.3 µmol/L (range: -36.3 µmol/Lto 55.7 µmol/L) was observed after 48 weeks of treatment. These changes are linked to the inhibiting effectof dolutegravir on renal tubular transporters of creatinine. The changes are not considered to be clinicallyrelevant and do not reflect a change in glomerular filtration rate.

In the Phase III studies for the dolutegravir single agent, patients with hepatitis B and/or C co-infection werepermitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit ofnormal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to thatobserved in 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. Liver chemistryelevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis Band/or C co-infection at the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapywas withdrawn (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

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

Immune response syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviraltherapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported;however, the reported time to onset is more variable and these events can occur many months after initiationof treatment (see section 4.4).

There are no clinical study data on the effects of Dovato in the paediatric population. Individual componentshave been investigated in adolescents (12 to 17 years).

Based on limited available data with the dolutegravir single entity or lamivudine single entity used incombination with other antiretroviral agents to treat adolescents (12 to 17 years), there were no additionaltypes of adverse reactions beyond those observed in the adult population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

There is no specific treatment for an overdose of Dovato. If overdose occurs, the patient should be treatedsupportively with appropriate monitoring, as necessary. Since lamivudine is dialysable, continuoushaemodialysis could be used in the treatment of overdose, although this has not been studied. As dolutegraviris highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections,combinations. ATC code: J05AR25

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

Lamivudine, via its active metabolite 5'-triphosphates (TP) (an analogue for cytidine), inhibits reversetranscriptase of HIV-1 and HIV-2 through incorporation of the monophosphate form into the viral DNAchain, resulting in chain termination. Lamivudine triphosphate shows significantly less affinity for host cell

DNA polymerases.

Dolutegravir and lamivudine have been shown to inhibit replication of lab-strains and clinical isolates of

HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage derived lines andprimary cultures of activated peripheral blood mononuclear cells (PMBCs) and monocyte/macrophages. Theconcentration of active substance necessary to effect viral replication by 50% (IC50 - half maximal inhibitoryconcentration) varied according to virus and host cell type.

The IC50 for dolutegravir in various lab-strains using PBMC was 0.5 nM, and when using MT-4 cells itranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference betweensubtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 valuewas 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 median or mean IC50 values for lamivudine against lab-strains of HIV-1 ranged from 0.007 to 2.3 M.

The mean IC50 against lab-strains of HIV-2 (LAV2 and EHO) ranged from 0.16 to 0.51 M for lamivudine.

The IC50 values of lamivudine 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 peripheral bloodmononuclear cells.

HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37 untreatedpatients in Africa and Asia were susceptible to lamivudine (IC50 fold changes < 3.0). Group O isolates fromantiviral naïve patients tested for lamivudine activity were highly sensitive.

In 100% human serum, the mean fold shift for dolutegravir activity was 75 fold, resulting in protein adjusted

IC90 of 0.064 g/mL. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range anddisplays low plasma protein binding (less than 36%).

Dovato is indicated in the absence of documented or suspected resistance to the integrase inhibitor class andto lamivudine (see section 4.1). For information around in vitro resistance, and cross resistance to otheragents of the integrase- and NRTI class, please refer to the SmPCs of dolutegravir and lamivudine.

None of the twelve subjects in the dolutegravir plus lamivudine group or the nine subjects in the dolutegravirplus tenofovir disoproxil/emtricitabine FDC group that met virological withdrawal criteria through Week144 across the GEMINI-1 (204861) and GEMINI-2 (205543) studies had treatment emergent integraseinhibitor or NRTI class resistance.

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no developmentof resistance to the integrase inhibitor class, or to the NRTI class was seen (n=1118 follow-up of48-96 weeks).

No relevant effects were seen with dolutegravir on the QTc interval, with doses exceeding the clinical doseby approximately three fold. A similar study was not conducted with lamivudine.

Antiretroviral naïve subjects

The efficacy of Dovato is supported by data from 2 identical 148-week, Phase III, randomised, double-blind,multicentre, parallel-group, non-inferiority controlled trials GEMINI-1 (204861) and GEMINI-2 (205543). Atotal of 1433 HIV-1 infected antiretroviral treatment-naïve adult subjects received treatment in the trials.

Subjects were enrolled with a screening plasma HIV-1 RNA of 1000 c/mL to ≤500,000 c/mL. Subjects wererandomised to a two-drug regimen of dolutegravir 50 mg plus lamivudine 300 mg once daily or dolutegravir50 mg plus tenofovir disoproxil/emtricitabine 245/200 mg once daily. The primary efficacy endpoint foreach GEMINI trial was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48(Snapshot algorithm for the ITT-E population). Double blind therapy continued up to week 96, followed byopen label therapy up to week 148.

At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% were female, 69% werewhite, 9% were CDC Stage 3 (AIDS), 20% had HIV-1 RNA >100,000 copies/mL, and 8% had CD4+ cellcount less than 200 cells per mm3; these characteristics were similar between studies and treatment arms.

In the primary week 48 analysis, dolutegravir plus lamivudine was non-inferior to dolutegravir plus tenofovirdisoproxil/emtricitabine FDC in GEMINI-1 and GEMINI-2 studies. This was supported by the pooledanalysis, see Table 3.

Table 3 Virologic Outcomes of Randomised Treatment of GEMINI at Week 48 (Snapshotalgorithm)

GEMINI-1 and GEMINI-2 Pooled

Data*

DTG + 3TC DTG + TDF/FTC

N=716 N=717

HIV-1 RNA <50 copies/mL 91% 93%

Treatment Difference† (95% confidence intervals) -1.7 (-4.4, 1.1)

Virologic non response 3% 2%

Reasons

Data in window and ≥50 copies/mL 1% <1%

Discontinued for lack of efficacy <1% <1%

Discontinued for other reasons and ≥50 copies/mL <1% <1%

Change in ART <1% <1%

No virologic data at Week 48 window 6% 5%

Reasons

Discontinued study due to adverse event or death 1% 2%

Discontinued study for other reasons 4% 3%

Missing data during window but on study <1% 0%

HIV-1 RNA <50 copies/mL by baseline covariatesn/N (%) n/N (%)

Baseline Plasma Viral Load (copies/mL)≤100,000 526/576 (91%) 531/564 (94%)>100,000 129/140 (92%) 138/153 (90%)

Baseline CD4+ (cells/ mm3)≤200 50/63 (79%) 51/55 (93%)>200 605/653 (93%) 618/662 (93%)

HIV-1 subtype

B 424/467 (91%) 452/488 (93%)

A 84/86 (98%) 74/78 (95%)

Other 147/163 (90%) 143/151 (95%)

Male 555/603 (92%) 580/619 (94%)

Female 100/113 (88%) 89/98 (91%)

White 451/484 (93%) 473/499 (95%)

African-American/African Heritage/Other 204/232 (88%) 196/218 (90%)

* The results of the pooled analysis are in line with those of the individual studies, for which the primaryendpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at Week 48 based on the

Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil/emtricitabine FDC) was met. The adjusted difference was -2.6 (95% CI: -6.7; 1.5) for GEMINI-1 and -0.7 (95% CI: -4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 10%.

† Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma

HIV-1 RNA (≤100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count(≤200 cells/mm3 vs. >200 cells/mm3). Pooled analysis also stratified by study. Assessed using anon-inferiority margin of 10%.

N = Number of subjects in each treatment group

At 96 weeks and at 144 weeks in the GEMINI studies, the lower bound of the 95% confidence interval forthe adjusted treatment difference of proportion of subjects with HIV-1 RNA <50 copies/mL (Snapshot) wasgreater than the non-inferiority margin of -10%, for the individual studies as well as pooled analysis, see

Table 4.

Table 4 Virologic Outcomes of Randomised Treatment of GEMINI at Weeks 96 and 144(Snapshot algorithm)

GEMINI-1 and GEMINI-2 Pooled Data*

DTG + DTG + DTG + DTG +3TC TDF/FTC 3TC TDF/FTC

N=716 N=717 N=716 N=717

Week 96 Week 144

HIV-1 RNA <50 copies/mL 86% 90% 82% 84%

Treatment Difference†

- 3.4% (-6.7, 0.0) -1.8% (-5.8; 2.1)(95% confidence intervals)

Virologic non response 3% 2% 3% 3%

Reasons

Data in window, ≥50 cps/mL <1% <1% <1% <1%

Discontinued, lack of efficacy 1% <1% 1% <1%

Discontinued, other reasons, ≥50 cps/mL <1% <1% <1% 2%

Change in ART <1% <1% <1% <1%

No virologic data at Week 96/Week 144 11% 9% 15% 14%window

Reasons

Discontinued study due to AE or death 3% 3% 4% 4%

Discontinued study for other reasons 8% 5% 11% 9%

Loss to follow-up 3% 1% 3% 3%

Withdrew consent 3% 2% 4% 3%

Protocol deviations 1% 1% 2% 1%

Physicians decision 1% <1% 2% 1%

Missing data in window, on study 0% <1% <1% <1%

* The results of the pooled analysis are in line with those of the individual studies.

† Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1 RNA(≤100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (≤200 cells/mm3 vs. >200 cells/mm3). Pooled analysis alsostratified by study. Assessed using a non-inferiority margin of 10%.

N = Number of subjects in each treatment group

The mean increase in CD4+ T-cell counts through week 144 was 302 cells/mm3 in the dolutegravir pluslamivudine arm and 300 cells/mm3 in the dolutegravir plus tenofovir/emtricitabine arm.

Virologically suppressed subjects

The efficacy of dolutegravir/lamivudine in virologically suppressed subjects is supported by data from arandomised, open-label, trial (TANGO [204862]). A total of 741 adult HIV-1 infected subjects, without anyevidence of resistance to the NRTI or integrase inhibitor (INSTI) class and who were on a stable suppressivetenofovir alafenamide based regimen (TBR) received treatment in the studies. Subjects were randomised in a1:1 ratio to receive dolutegravir/lamivudine FDC or continue with TBR for up to 200 weeks. Randomisationwas stratified by baseline core agent class (protease inhibitor [PI], INSTI, or non-nucleoside reversetranscriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma

HIV-1 RNA ≥50 c/mL (virologic non-response) as per the FDA Snapshot category at Week 48 (adjusted forrandomisation stratification factor).

At baseline the median age of subjects was 39 years, 8% were female and 21% non-white, 5% were CDC

Class C (AIDS) and 98% subjects had Baseline CD4+ cell count ≥200 cells/mm3; these characteristics weresimilar between treatment arms. Subjects had been on ART for a median of around 3 years prior to Day 1

Around 80% were on INSTI-based TBR (mainly elvitegravir/c) at baseline.

In the primary 48 week analysis, dolutegravir/lamivudine was non-inferior to TBR, with <1% of subjects inboth arms experiencing virologic failure (HIV-1 RNA ≥50 c/mL) (Table 5).

Table 5 Virologic Outcomes of Randomised Treatment of TANGO at Week 48 (Snapshotalgorithm)

DTG/3TC TBR

N=369 N=372

HIV-1 RNA <50 copies/mL* 93% 93%

Virologic non response (50 copies/mL)** <1% <1%

Treatment Difference† (95% confidence intervals) -0.3 (-1.2, 0.7)

Reasons for virologic non response:

Data in window and ≥50 copies/mL 0% 0%

Discontinued for lack of efficacy 0% <1%

Discontinued for other reasons and ≥50 copies/mL <1% 0%

Change in ART 0% 0%

No virologic data at Week 48 window 7% 6%

Reasons

Discontinued study due to adverse event or death 3% <1%

Discontinued study for other reasons 3% 6%

Missing data during window but on study 0% <1%

*Based on an 8% non-inferiority margin, DTG/3TC is non-inferior to TBR at Week 48 in the secondaryanalysis (proportion of subjects achieving <50 copies/mL plasma HIV-1 RNA).

**Based on a 4% non-inferiority margin, DTG/3TC is non-inferior to TBR at Week 48 in the primaryanalysis (proportion of subjects with plasma HIV-1 RNA ≥50 c/mL).

†Based on CMH-stratified analysis adjusting for Baseline third agent class (PI, NNRTI, INSTI).

N = Number of subjects in each treatment group; TBR = tenofovir alafenamide based regimen.

Treatment outcomes between treatment arms at week 48 were similar across the stratification factor, baselinethird agent class and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage,and countries. The median change from baseline in CD4+ count at Week 48 was 22.5 cells per mm3 insubjects who switched to dolutegravir/lamivudine and 11.0 cells per mm3 in subjects who stayed on TBR.

At 96 weeks in the TANGO study, the proportion of subjects with HIV-1 RNA ≥50 c/mL (Snapshot) was0.3% and 1.1% in the dolutegravir/lamivudine and TBR groups, respectively. Based on a non-inferioritymargin of 4%, dolutegravir/lamivudine remained non-inferior to TBR, as the upper bound of the 95% CI forthe adjusted treatment difference (-2.0%; 0.4%) was less than 4% for the ITT E Population.

The median change from baseline in CD4+ T-cell counts at week 96 was 61 cells/mm3 in thedolutegravir/lamivudine arm and 45 cells/mm3 in the TBR arm.

At 144 weeks, the proportion of subjects with HIV-1 RNA ≥50 c/mL (Snapshot) was 0.3% and 1.3% in thedolutegravir/lamivudine and TBR groups, respectively. Based on a non-inferiority margin of 4%,dolutegravir/lamivudine remained non-inferior to TBR, as the upper bound of the 95% CI for the adjustedtreatment difference (-2.4%, 0.2%) was less than 4% for the ITT E Population.

The median change from baseline in CD4+ T-cell counts at Week 144 was 36 cells/mm3 in thedolutegravir/lamivudine arm and 35 cells/mm3 in the TBR arm.

The efficacy of Dovato, or the dual combination of dolutegravir plus lamivudine (as single entities) has notbeen studied in children or adolescents.

The European Medicines Agency has deferred the obligation to submit the results of studies with Dovato inone or more subsets of the paediatric population in the treatment of HIV infection.

When administered in fasted state, bioequivalence regarding Cmax was achieved for dolutegravir, whencomparing Dovato to dolutegravir 50 mg co-administered with lamivudine 300 mg. Dolutegravir AUC0-t was16% higher for Dovato than for dolutegravir 50 mg co-administered with lamivudine 300 mg. This increaseis not considered clinically relevant.

When administered in fasted state, bioequivalence was achieved for lamivudine AUC, when comparing

Dovato to lamivudine 300 mg co-administered with dolutegravir 50 mg. Lamivudine Cmax for Dovato was32% higher than lamivudine 300 mg co-administered with dolutegravir 50 mg. The higher lamivudine Cmax,is not considered clinically relevant.

Dolutegravir and lamivudine are rapidly absorbed following oral administration. The absolute bioavailabilityof dolutegravir has not been established. The absolute bioavailability of oral lamivudine in adults isapproximately 80-85%. For Dovato, the median time to maximal plasma concentration (tmax) is 2.5 hours fordolutegravir and 1.0 hour for lamivudine, when dosed under fasted conditions.

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

HIV-1-infected adult subjects following dolutegravir 50 mg once daily, the steady-state pharmacokineticparameters (geometric mean [%CV]) based on population pharmacokinetic 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 multiple-dose oral administration of lamivudine 300 mg once daily for seven days, the mean (CV) steady-state Cmax is2.04 µg/mL (26%) and the mean (CV) AUC(0-24) is 8.87 µg.h/mL (21%).

Administration of a single Dovato tablet with a high fat meal increased dolutegravir AUC(0-) and Cmax by33% and 21%, respectively, and decreased the lamivudine Cmax by 30% compared to fasted conditions. Thelamivudine AUC(0-) was not affected by a high fat meal. These changes are not clinically significant. Dovatomay be administered with or without food.

The apparent volume of distribution of dolutegravir (Vd/F) is 17-20 L. Intravenous studies with lamivudineshowed that the mean apparent volume of distribution is 1.3 L/kg.

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 plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association ofradioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma is increased atlow levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment. Lamivudineexhibits linear pharmacokinetics over the therapeutic dose range and displays limited plasma protein bindingin vitro (< 16%- 36% to serum albumin).

Dolutegravir and lamivudine are present in cerebrospinal fluid (CSF). In 13 treatment-naïve subjects on astable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL(comparable to unbound plasma concentration, and above the IC50). The mean ratio of CSF/serumlamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of

CNS penetration 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, cervical tissue andvaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% and 17%in rectal tissue of those in corresponding plasma at steady state.

Dolutegravir is primarily metabolized via UGT1A1 with a minor CYP3A component (9.7% of total doseadministered in a human mass balance study). Dolutegravir is the predominant circulating compound inplasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent oftotal oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbedactive substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to formthe parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine,represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% oftotal dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).

Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared by renalexcretion of unchanged lamivudine. The likelihood of metabolic drug interactions with lamivudine is lowdue to the small extent of hepatic metabolism (5-10%).

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome

P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, UGT1A1 or

UGT2B7, or the transporters Pgp, BCRP, BSEP, organic anion transporting polypeptide (OATP) 1B1,

OATP1B3, OCT1, MATE2-K, multidrug resistance-associated protein (MRP) 2 or MRP4. In vitro,dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. Based on this data, dolutegravir is not expectedto affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters (seesection 4.5).

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

In vitro, lamivudine did not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or CYP2D6) anddemonstrated 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 medicinal products that aresubstrates 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) is approximately1 L/hr in HIV-infected patients based on a population pharmacokinetic analysis.

The observed lamivudine half-life of elimination is 18 to 19 hours. For patients receiving lamivudine 300 mgonce daily, the terminal intracellular half-life of lamivudine-TP was 16 to 19 hours. The mean systemicclearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance (> 70%) via theorganic cationic transport system. Studies in patients with renal impairment show lamivudine elimination isaffected by renal dysfunction. Dose reduction is required for patients with creatinine clearance < 30 mL/min(see section 4.2).

In a randomized, 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 of2.5 log10 at day 11 for 50 mg dose. This antiviral response was maintained for 3 to 4 days after the last dosein the 50 mg group.

The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents(12 to 17 years) showed that dolutegravir 50 mg once daily dosage resulted in dolutegravir exposurecomparable to that observed in adults who received dolutegravir 50 mg once daily.

Limited data are available in adolescents receiving a daily dose of 300 mg of lamivudine. Pharmacokineticparameters are comparable to those reported in adults.

Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that therewas no clinically relevant effect of age on dolutegravir exposure.

Pharmacokinetic data for dolutegravir and lamivudine in subjects >65 years of age are limited.

Pharmacokinetic data have been obtained for dolutegravir and lamivudine separately.

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

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

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

Pharmacokinetic data has been obtained for dolutegravir and lamivudine separately.

Dolutegravir is primarily metabolized and eliminated by the liver. A single dose of 50 mg of dolutegravirwas administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 8 matchedhealthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5 to 2 foldincrease in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairmentcompared to healthy controls. No dosage adjustment is considered necessary for patients with mild tomoderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics ofdolutegravir has not been studied.

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

There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravirpharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samplescollected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poordolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared withsubjects with genotypes associated with normal metabolism via UGT1A1 (n=41).

Population PK analyses using pooled pharmacokinetic data from clinical studies where dolutegravir orlamivudine was administered to adults in combination with other ARVs revealed no clinically relevant effectof gender on the exposure of dolutegravir or lamivudine. There is no evidence that a dose adjustment ofdolutegravir or lamivudine would be required based on the effects of gender on PK parameters.

Population PK analyses using pooled pharmacokinetic data from clinical studies where dolutegravir wasadministered to adults in combination with other ARVs revealed no clinically relevant effect of race on theexposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to

Japanese subjects appear similar to observed parameters in Western (US) subjects. There is no evidence thata dose adjustment of dolutegravir or lamivudine would be required based on the effects of race on PKparameters.

Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevanteffect on the exposure to dolutegravir. There are limited pharmacokinetic data on subjects with hepatitis Bco-infection (see section 4.4).

There are no data available on the effects of the combination of dolutegravir and lamivudine in animals.

Carcinogenesis and mutagenesis

Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells,and an in vivo rodent micronucleus assay. Lamivudine was not mutagenic in bacterial tests, but consistentwith other nucleoside analogues, inhibits cellular DNA replication in in vitro mammalian tests such as themouse lymphoma assay. The results from two in vivo rat micronucleus tests with lamivudine were negative.

Lamivudine has not shown any genotoxic activity in the in vivo studies.

The carcinogenic potential of a combination of dolutegravir and lamivudine has not been tested. Dolutegravirwas not carcinogenic in long term studies in the mouse and rat. In long-term oral carcinogenicity studies inrats and mice, lamivudine did not show any carcinogenic potential.

Reproductive toxicology studies

In reproductive toxicity studies in animals, dolutegravir and lamivudine were shown to cross the placenta.

Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 ofgestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (37.2 times the 50 mghuman clinical exposure, based on AUC following single dose in the fasted state). Oral administration ofdolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to 18 of gestation did not elicitdevelopmental toxicity or teratogenicity (0.55 times the 50 mg human clinical exposure, based on AUCfollowing single dose in the fasted state). In rabbits, maternal toxicity (decreased food consumption, scant/nofaeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.55 times the 50 mg humanclinical exposure, based on AUC following single dose in the fasted state).

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 in humans. Asimilar effect was not seen in rats even at very high systemic exposure.

Fertility studies in rats have shown that dolutegravir or lamivudine have no effect on male or female fertility.

The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oraldose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primary effect ofdolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemicexposures approximately 28.5 and 1.1 times the 50 mg human clinical exposure following single dose in thefasted state based on AUC, respectively. Because gastrointestinal (GI) intolerance is considered to be due tolocal active substance administration, mg/kg or mg/m2 metrics are appropriate determinates of safety coverfor this toxicity. 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.

Microcrystalline cellulose

Sodium starch glycolate

Magnesium stearate

Mannitol (E421)

Povidone (K29/32)

Sodium stearyl fumarate

Hypromellose (E464)

Macrogol

Titanium dioxide (E171)

Not applicable.

Bottle pack4 years.

Blister pack2 years.

This medicinal product does not require any special storage conditions.

Bottle pack

Opaque, white HDPE (high density polyethylene) bottles closed with child-resistant polypropylene closures,with a polyethylene faced induction heat seal liner. Each pack consists of one bottle containing 30 film-coated tablets.

Multipacks containing 90 (3 bottle packs of 30) film-coated tablets.

Blister pack

Blister strips comprising poly(chlorotrifluoroethylene) (PCTFE), both sides laminated with a Polyvinyl

Chloride (PVC) film, sealed with child-resistant push through aluminium lidding foil using a heat seallacquer. Each 30 film-coated tablets blister pack consists of four blister strips containing 7 film-coatedtablets and one blister strip containing 2 film-coated tablets.

Multipacks containing 90 (3 blister packs of 30) film-coated tablets.

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/1/19/1370/001

EU/1/19/1370/002

EU/1/19/1370/003

EU/1/19/1370/004

Date of first authorization: 1st July 2019

Date of latest renewal: 21 March 2024

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

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