JULUCA 50mg / 25mg tablets medication leaflet

Juluca 50 mg/25 mg film-coated tablets

Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir and rilpivirinehydrochloride equivalent to 25 mg rilpivirine.

Each film-coated tablet contains 52 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Pink, oval, biconvex tablets, approximately 14 x 7 mm, debossed with ‘SV J3T’ on one side.

Juluca is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adultswho are virologically-suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at leastsix months with no history of virological failure and no known or suspected resistance to any non-nucleosidereverse transcriptase inhibitor or integrase inhibitor (see section 5.1).

Dolutegravir/rilpivirine should be prescribed by physicians experienced in the management of HIV infection.

The recommended dose of Juluca is one tablet once daily. The tablet must be taken with a meal (see section5.2).

Separate preparations of dolutegravir or rilpivirine are available in cases where discontinuation or doseadjustment of one of the active substances is indicated (see section 4.5). In these cases the physician shouldrefer to the Summary of Product Characteristics for these medicinal products.

If the patient misses a dose of Juluca, the patient should take the missed dose with a meal as soon as possible,providing the next dose is not due within 12 hours. If the next dose is due within 12 hours, the patient shouldnot take the missed dose and simply resume the usual dosing schedule.

If a patient vomits within 4 hours of taking dolutegravir/rilpivirine, another dolutegravir/rilpivirine tabletshould be taken with a meal. If a patient vomits more than 4 hours after taking dolutegravir/rilpivirine, thepatient does not need to take another dose of dolutegravir/rilpivirine until the next regularly scheduled dose.

There are limited data available on the use of Juluca in patients aged 65 years and over. There is no evidencethat elderly patients require a different dose than younger adult patients (see section 5.2).

No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severerenal impairment or end-stage renal disease, dolutegravir/rilpivirine should be used with caution, asrilpivirine plasma concentrations may be increased secondary to renal dysfunction (see sections 4.5 and 5.2).

No data are available in subjects receiving dialysis although haemodialysis or peritoneal dialysis are notexpected to affect dolutegravir or rilpivirine exposure (see section 5.2).

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or

B). Dolutegravir/rilpivirine should be used with caution in patients with moderate hepatic impairment. Nodata are available in patients with severe hepatic impairment (Child-Pugh score C); thereforedolutegravir/rilpivirine is not recommended in these patients (see section 5.2).

The safety and efficacy of Juluca in children and adolescents aged less than 18 years have not yet beenestablished. Currently available data are described in section 5.2, but no recommendation on a posology canbe made.

Oral use

Juluca must be taken orally, once daily with a meal (see section 5.2). It is recommended that the film-coatedtablet be swallowed whole with water and not be chewed or crushed.

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

Co-administration with the following medicinal products:

- fampridine (also known as dalfampridine);

- carbamazepine, oxcarbazepine, phenobarbital, phenytoin;

- rifampicin, rifapentine;

- proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole;

- systemic dexamethasone, except as a single dose treatment;

- St John's wort (Hypericum perforatum).

Hypersensitivity reactions have been reported with dolutegravir, and were characterised by rash,constitutional findings, and sometimes, organ dysfunction, including severe liver reactions.

dolutegravir/rilpivirine 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 dolutegravir/rilpivirine after the onset of hypersensitivity mayresult 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.

At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation ofthe QTc interval of the electrocardiogram (ECG) (see sections 4.5 and 5.1). Rilpivirine at the recommendeddose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Dolutegravir/rilpivirineshould be used with caution when co-administered with medicinal products with a known risk of Torsade de

Pointes.

Patients should be advised that dolutegravir/rilpivirine does not cure HIV infection and that they may stilldevelop opportunistic infections and other complications of HIV infection. Therefore, patients should remainunder close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

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 with hepatitis B or C

No clinical data are available in patients with hepatitis B co-infection. Physicians should refer to currenttreatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus.

Limited data is available in patients with hepatitis C co-infection. A higher incidence of liver chemistryelevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected withhepatitis C compared to those who were not co-infected. Monitoring of liver function is recommended inpatients with hepatitis B and/or C co-infection.

Dolutegravir/rilpivirine should not be administered with other antiretroviral medicinal products for thetreatment of HIV (see section 4.5).

Juluca should not be taken with any other medicinal product containing dolutegravir or rilpivirine, except incase of co-administration with rifabutin (see section 4.5).

H2-receptor antagonists

Dolutegravir/rilpivirine should not be co-administered at the same time as H2-receptor antagonists. Thesemedicinal products are recommended to be administered 12 hours before or 4 hours afterdolutegravir/rilpivirine (see section 4.5).

Antacids

Dolutegravir/rilpivirine should not be co-administered at the same time as antacids. These medicinalproducts are recommended to be administered 6 hours before or 4 hours after dolutegravir/rilpivirine (seesection 4.5).

Supplements and multivitamins

Calcium or iron supplements, or multivitamins should be co-administered at the same time asdolutegravir/rilpivirine, with a meal. If calcium or iron supplements, or multivitamins cannot be taken at thesame time as dolutegravir/rilpivirine, these supplements are recommended to be administered 6 hours beforeor 4 hours after taking dolutegravir/rilpivirine (see section 4.5).

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

Immune Reconstitution Syndrome

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. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occurin the setting of immune reconstitution, however, the reported time to onset is more variable and these eventscan occur many months after initiation of treatment.

Juluca contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Juluca is intended for use as a complete regimen for the treatment of HIV-1 infection and should not beadministered with other antiretroviral medicinal products for the treatment of HIV. Therefore, informationregarding drug-drug interactions with other antiretroviral medicinal products is not provided. Juluca containsdolutegravir and rilpivirine, therefore any interactions identified with these active substances are relevant to

Juluca. Interaction studies have only been performed in adults.

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

Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase(UGT)1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, cytochrome P450 (CYP)3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP); therefore medicinal products that inducethose enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect ofdolutegravir (see Table 1). Co-administration of dolutegravir/rilpivirine and other medicinal products thatinhibit these enzymes may increase dolutegravir plasma concentration (see Table 1).

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

Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may thusaffect the clearance of rilpivirine (see section 5.2). Co-administration of dolutegravir/rilpivirine withmedicinal products that induce CYP3A may result in decreased plasma concentrations of rilpivirine, whichcould reduce the therapeutic effect of dolutegravir/rilpivirine (see Table 1). Co-administration ofdolutegravir/rilpivirine with medicinal products that inhibit CYP3A may result in increased plasmaconcentrations of rilpivirine (see Table 1). In patients with severe renal impairment or end stage renaldisease, the combination of dolutegravir/rilpivirine with a strong CYP3A inhibitor should only be used if thebenefit outweighs the risk (see section 4.2).

Co-administration of dolutegravir/rilpivirine with medicinal products that increase gastric pH may result indecreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect ofdolutegravir/rilpivirine.

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

Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinalproducts that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (formore information see section 5.2).

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxinextrusion transporter 1 (MATE1). In vivo, a 10-14% decrease of creatinine clearance (secretory fraction isdependent on OCT2 and MATE1 transport) was observed in patients. In vivo, dolutegravir may increaseplasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE1(e.g. fampridine [also known as dalfampridine], metformin) (see Table 1 and sections 4.3 and 4.4).

In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT)1 and OAT3.

Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibitionof OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasmaconcentrations of medicinal products in which excretion is dependent upon OAT3.

Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinalproducts metabolised by CYP enzymes.

Rilpivirine inhibits P-gp in vitro (IC50 is 9.2 μM). In a clinical study, rilpivirine did not significantly affectthe pharmacokinetics of digoxin. However, it may not be completely excluded that rilpivirine can increasethe exposure to other medicinal products transported by P-gp that are more sensitive to intestinal P-gpinhibition, e.g. dabigatran etexilate.

Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM. The clinicalimplications of this finding are currently unknown.

Selected established and theoretical interactions between dolutegravir, rilpivirine and co-administeredmedicinal 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”, minimum observed concentration as“Cmin”concentration at end of dosing interval as “Cτ”).

Table 1: Drug Interactions

Medicinal products Interaction Recommendations concerningby therapeutic areas Geometric mean change co-administration(%)

Antiviral active substances

Tenofovir disoproxil/Dolutegravir  No dose adjustment is required.

Dolutegravir1 AUC  1%

Cmax  3%

Cτ  8%

Tenofovir 

Tenofovir disoproxil /

Rilpivirine1,2 Rilpivirine

AUC ↔

Cmin ↔

Cmax ↔

Tenofovir

AUC ↑ 23%

Cmin ↑ 24%

Cmax ↑ 19%

Tenofovir alafenamide Dolutegravir  No dose adjustment is required.

/ Dolutegravir (Not studied)

Tenofovir alafenamide/ Rilpivirine1 Rilpivirine 

Lamivudine/ Dolutegravir  No dose adjustment is required.

Dolutegravir

Lamivudine/ Rilpivirine 

Rilpivirine (Not studied)

Entecavir/ Dolutegravir  No dose adjustment is required.

Dolutegravir (Not studied)

Entecavir/ Rilpivirine Rilpivirine (Not studied)

Daclatasvir/ Dolutegravir  No dose adjustment is required.

Dolutegravir1 AUC  33%

Cmax  29%

C  45%

Daclatasvir 

Daclatasvir/ Rilpivirine 

Rilpivirine

Simeprevir/ Dolutegravir  No dose adjustment is required.

Dolutegravir

Simeprevir/ Rilpivirine 

Rilpivirine AUC 

Cmin  25%

Cmax 

Simeprevir 

AUC 

Cmin 

Cmax  10%

Sofosbuvir/Dolutegravir  No dose adjustment is required.

Dolutegravir1 (Not studied)

Sofosbuvir/Rilpivirine 

Rilpivirine AUC 

Cmin 

Cmax 

Sofosbuvir 

AUC 

Cmax  21%

Sofosbuvir metabolite GS-331007 

AUC 

Cmax 

Ledipasvir/Sofosbuvir Dolutegravir  No dose adjustment is required.

/ Dolutegravir1 (Not studied)

Ledipasvir/Sofosbuvir Rilpivirine / Rilpivirine AUC  5%

Cmin  7%

Cmax  3%

Ledipasvir 

AUC  2%

Cmin  2%

Cmax  1%

Sofosbuvir 

AUC  5%

Cmax  4%

Sofosbuvir metabolite GS-331007 

AUC  8%

Cmin  10%

Cmax  8%

Sofosbuvir/ Dolutegravir  No dose adjustment is required.

Velpatasvir/ (Not studied)

Dolutegravir1

Sofosbuvir/ Rilpivirine 

Velpatasvir/ AUC 

Rilpivirine Cmin 

Cmax 

Sofosbuvir 

AUC 

Cmax 

Sofosbuvir metabolite GS-331007 

AUC 

Cmin 

Cmax 

Velpatasvir 

AUC 

Cmin 

Cmax 

Ribavirin/ Dolutegravir  No dose adjustment is required.

Dolutegravir (Not studied)

Ribavirin/ Rilpivirine Rilpivirine (Not studied)

Other active substances

Antiarrhythmics

Digoxin/ Dolutegravir Dolutegravir  No dose adjustment is required.

(Not studied)

Digoxin/ Rilpivirine1 Rilpivirine 

AUC ↔

Cmin NA

Cmax ↔

Anticonvulsants

Carbamazepine/ Dolutegravir  Metabolic inducers may significantly decrease

Dolutegravir1 AUC  49% dolutegravir/rilpivirine plasma concentrations,

Cmax  33% resulting in loss of therapeutic effect.

C  73% Co-administration of dolutegravir/rilpivirine withthese metabolic inducers is contraindicated (see

Carbamazepine/ Rilpivirine section 4.3).

Rilpivirine Not studied. Significantdecreases in rilpivirineplasma concentrations areexpected (induction of

CYP3A enzymes).

Oxcarbazepine Dolutegravir  Metabolic inducers may significantly decrease

Phenytoin Not studied. Decrease dolutegravir/rilpivirine plasma concentrations,

Phenobarbital/ expected due to induction of resulting in loss of therapeutic effect.

Dolutegravir UGT1A1 and CYP3A Co-administration of dolutegravir/rilpivirine withenzymes, a similar reduction these metabolic inducers is contraindicated (seein exposure as observed section 4.3).

with carbamazepine isexpected.

Oxcarbazepine

Phenytoin Rilpivirine 

Phenobarbital/ Not studied. Significant

Rilpivirine decreases in rilpivirineplasma concentrations areexpected(induction of CYP3Aenzymes).

Azole anti-fungals

Ketoconazole/ Dolutegravir  No dose adjustment is required.

Dolutegravir (Not studied)

Ketoconazole/ Rilpivirine

Rilpivirine1,2 AUC ↑ 49%

Cmin ↑ 76%

Cmax ↑ 30%(inhibition of CYP3Aenzymes).

Ketoconazole

AUC ↓ 24%

Cmin ↓ 66%

Cmax ↔(induction of CYP3A due tohigh rilpivirine dose in thestudy).

Fluconazole Dolutegravir  No dose adjustment is required.

Itraconazole (Not studied)

Isavuconazole

Posaconazole

Voriconazole/

Dolutegravir

Fluconazole Rilpivirine ↑

Itraconazole Not studied. May cause an

Isavuconazole increase in the

Posaconazole plasma concentrations of

Voriconazole/ rilpivirine

Rilpivirine (inhibition of CYP3Aenzymes).

Herbal products

St. John’s wort/ Dolutegravir  Co-administration may cause significant decreases

Dolutegravir Not studied. Decrease in rilpivirine plasma concentrations. This mayexpected due to induction of result in loss of therapeutic effect of

UGT1A1 and CYP3A dolutegravir/rilpivirine. Co-administration ofenzymes, a similar reduction dolutegravir/rilpivirine with St. John’s wort isin exposure as observed contraindicated (see section 4.3).

with carbamazepine isexpected.

St. John’s wort/

Rilpivirine Rilpivirine 

Not studied. Significantdecreases in rilpivirineplasma concentrations areexpected(induction of CYP3Aenzymes).

Potassium channel blockers

Fampridine (also Fampridine  Co-administration of dolutegravir has the potentialknown as to cause seizures due to increased fampridinedalfampridine)/ plasma concentration via inhibition of OCT2

Dolutegravir transporter; co-administration has not been studied.

Fampridine co-administration withdolutegravir/rilpivirine is contraindicated (seesection 4.3).

Omeprazole Dolutegravir  Co-administration may significantly decrease

Lansoprazole (Not studied) rilpivirine plasma concentration. This may result in

Rabeprazole loss of therapeutic effect of

Pantoprazole dolutegravir/rilpivirine. Co-administration of

Esomeprazole/ dolutegravir/rilpivirine with proton pump

Dolutegravir inhibitors is contraindicated (see section 4.3).

Omeprazole/ Rilpivirine

Rilpivirine1,2 AUC ↓ 40%

Cmin ↓ 33%

Cmax ↓ 40%(reduced absorption due togastric pH increase).

AUC ↓ 14%

Cmin NA

Cmax ↓ 14%

Lansoprazole Rilpivirine 

Rabeprazole Not studied. Significant

Pantoprazole decreases in rilpivirine

Esomeprazole/ plasma concentrations are

Rilpivirine expected(reduced absorption due togastric pH increase).

H2-recepter antagonists

Famotidine Dolutegravir  The combination of dolutegravir/rilpivirine and

Cimetidine (Not studied) H2-receptor antagonists should be used with

Nizatidine particular caution. Only H2-receptor antagonists

Ranitidine/ that can be dosed once daily should be used.

Dolutegravir

H2-receptor antagonists should be taken well

Famotidine/ Rilpivirine separated in time from the administration of

Rilpivirine1,2 AUC ↓ 9% dolutegravir/rilpivirine (minimum 4 hours after or40 mg single dose Cmin NA 12 hours before)taken 12 hours before Cmax ↔rilpivirine

Famotidine/ Rilpivirine

Rilpivirine1,2 AUC ↓ 76%40 mg single dose Cmin NAtaken 2 hours before Cmax ↓ 85%rilpivirine (reduced absorption due togastric pH increase).

Famotidine/ Rilpivirine

Rilpivirine1,2 AUC ↑ 13%40 mg single dose Cmin NAtaken 4 hours after Cmax ↑ 21%rilpivirine

Cimetidine Rilpivirine 

Nizatidine Not studied. Significant

Ranitidine/ decreases in rilpivirine

Rilpivirine plasma concentrations areexpected (reducedabsorption due to gastric pHincrease).

Antacids and supplements

Antacids (e.g., Dolutegravir  The combination of dolutegravir/rilpivirine andaluminium AUC  74% antacids should be used with particular caution.

magnesium hydroxide, Cmax  72% Antacids should be taken well separated in timeand/or calcium C24  74% from the administration of dolutegravir/rilpivirinecarbonate)/ (Complex binding to (minimum 6 hours before or 4 hours after).

Dolutegravir1 polyvalent ions).

Rilpivirine 

Antacids (e.g., Not studied. Significantaluminium decreases in rilpivirinemagnesium hydroxide, plasma concentrations areand/or calcium expectedcarbonate)/ Rilpivirine (reduced absorption due togastric pH increase).

Calcium supplements/ Dolutegravir  The combination of dolutegravir/rilpivirine and

Dolutegravir1 AUC  39% supplements should be used with particular

Cmax  37% caution. Calcium supplements, iron supplements or

C24  39% multivitamins should be co-administered at the(Complex binding to same time as dolutegravir/rilpivirine with a meal.

polyvalent ions).

Iron supplements/ Dolutegravir  If calcium supplements, iron supplements or

Dolutegravir1 AUC  54% multivitamins cannot be taken at the same time as

Cmax  57% dolutegravir/rilpivirine, these supplements should

C24  56% be taken well separated in time from the(Complex binding to administration of dolutegravir/rilpivirinepolyvalent ions). (minimum 6 hours before or 4 hours after).

Multivitamin/ Dolutegravir 

Dolutegravir1 AUC  33%

Cmax  35%

C24  32%(Complex binding topolyvalent ions).

Prednisone/ Dolutegravir  No dose adjustment is required.

Dolutegravir1 AUC  11%

Cmax  6%

Cτ  17%

Prednisone/ Rilpivirine 

Rilpivirine (Not studied)

Dexamethasone/ Dolutegravir  Co-administration may cause significant decreases

Dolutegravir (Not studied) in rilpivirine plasma concentrations. This mayresult in loss of therapeutic effect of

Dexamethasone/ Rilpivirine  dolutegravir/rilpivirine. Co-administration of

Rilpivirine Not studied. Dose dependent dolutegravir/rilpivirine with systemic(systemic, except for decreases in rilpivirine dexamethasone is contraindicated (except as asingle dose use) plasma concentrations are single dose) see section 4.3. Alternatives should beexpected considered, particularly for long-term use.

(induction of CYP3Aenzymes).

Antidiabetics

Metformin/ Metformin  A dose adjustment of metformin should be

Dolutegravir1 AUC  79% considered when starting and stopping co-

Cmin NA administration of dolutegravir/rilpivirine with

Cmax  66% metformin, to maintain glycaemic control. Inpatients with moderate renal impairment a dose

Metformin/ Metformin adjustment of metformin should be considered

Rilpivirine1 AUC ↔ when co-administered with dolutegravir, because

Cmin NA of the increased risk for lactic acidosis in patients

Cmax ↔ with moderate renal impairment due to increasedmetformin concentration (section 4.4).

Antimycobacterials

Rifampicin/ Dolutegravir  Co-administration may cause significant decreases

Dolutegravir1 AUC  54% in rilpivirine plasma concentrations. This may

Cmax  43% result in loss of therapeutic effect of

Cτ 72% dolutegravir/rilpivirine. Co-administration of(induction of UGT1A1 and dolutegravir/rilpivirine with rifampicin is

CYP3A enzymes). contraindicated (see section 4.3).

Rifampicin/ Rilpivirine

Rilpivirine1,2 AUC ↓ 80%

Cmin ↓ 89%

Cmax ↓ 69%(induction of CYP3Aenzymes).

AUC ↔

Cmin NA

Cmax ↔25-desacetyl-rifampicin

AUC ↓ 9%

Cmin NA

Cmax ↔

Rifabutin/ Dolutegravir  Co-administration is likely to cause significant

Dolutegravir1 AUC  5% decreases in rilpivirine plasma concentrations

Cmax  16% (induction of CYP3A enzymes). When Juluca is

Cτ  30% co-administered with rifabutin, an additional 25(induction of UGT1A1 and mg tablet of rilpivirine per day should be taken at

CYP3A enzymes). the same time with Juluca, for the duration of therifabutin co-administration (a separate formulation

Rifabutin/ Rilpivirine1 Rifabutin of rilpivirine is available for this dose adjustment,300 mg once daily2 AUC ↔ see section 4.2).

Cmin ↔

Cmax ↔25-O-desacetyl-rifabutin

AUC ↔

Cmin ↔

Cmax ↔300 mg once daily Rilpivirine(+ 25 mg once daily AUC ↓ 42%rilpivirine) Cmin ↓ 48%

Cmax ↓ 31%300 mg once daily Rilpivirine(+ 50 mg once daily AUC ↑ 16%*rilpivirine) Cmin ↔*

Cmax ↑ 43%*

* compared to 25 mg oncedaily rilpivirine alone(induction of CYP3Aenzymes).

Rifapentine/ Dolutegravir ↓ Co-administration may cause significant decreases

Dolutegravir (Not studied) in rilpivirine plasma concentrations. This mayresult in loss of therapeutic effect of

Rifapentine/ Rilpivirine ↓ dolutegravir/rilpivirine (induction of CYP3A

Rilpivirine Not studied. Significant enzymes). Co-administration ofdecreases in rilpivirine dolutegravir/rilpivirine with rifapentine isplasma concentrations are contraindicated (see section 4.3).

expected.

Antimalarials

Artemether/ Dolutegravir  The combination of dolutegravir/rilpivirine and

Lumefantrine/ (Not studied) artemether/lumefantrine should be used with

Dolutegravir caution.

Artemether/ Rilpivirine ↓

Lumefantrine/ Not studied. Decreased

Rilpivirine exposure of rilpivirine isexpected(induction of CYP3Aenzymes).

Atovaquone/ Dolutegravir  No dose adjustment is required.

Proguanil/ (Not studied)

Dolutegravir

Atovaquone/ Rilpivirine ↔

Proguanil/ (Not studied).

Rilpivirine

Clarithromycin Dolutegravir  Where possible, alternatives such as azithromycin

Erythromycin (Not studied) should be considered.

/Dolutegravir

Clarithromycin Rilpivirine 

Erythromycin Not studied. Increased/Rilpivirine exposure of rilpivirine isexpected(inhibition of CYP3Aenzymes).

Ethinyl estradiol (EE)1 Dolutegravir  Dolutegravir or rilpivirine did not change ethinyland Norelgestromin EE  estradiol and norelgestromin (dolutegravir) or(NGMN)1/ AUC  3% norethindrone (rilpivirine) plasma concentrations

Dolutegravir Cmax  1% to a clinically relevant extent. No dose adjustmentof oral contraceptives is required when

NGMN  co-administered with Juluca.

AUC  2%

Cmax  11%

Ethinyl estradiol (EE)1 Rilpivirine *and Norethindrone1/ EE 

Rilpivirine AUC 

Cmin 

Cmax  17%

Norethindrone 

AUC 

Cmin 

Cmax 

*based on historic controls.

Analgesics

Methadone/ Dolutegravir  No dose adjustments are required when initiating

Dolutegravir1 Methadone  co-administration of methadone with

AUC  2% dolutegravir/rilpivirine. However, clinical

Cmax  0% monitoring is recommended as methadone

C  1% maintenance therapy may need to be adjusted insome patients.

Methadone/Rilpivirine:

Rilpivirine1 AUC: ↔*

Cmin: ↔*

Cmax: ↔*

R(-) methadone:

AUC: ↓ 16%

Cmin: ↓ 22%

Cmax: ↓ 14%

*based on historic controls.

Paracetamol/ Dolutegravir  No dose adjustment is required.

Dolutegravir (Not studied)

Paracetamol/Rilpivirine

Rilpivirine1,2 AUC ↔

Cmin ↑ 26%

Cmax ↔

AUC ↔

Cmin NA

Cmax ↔

Anticoagulants

Dabigatran etexilate/ Dolutegravir  The combination of dolutegravir/rilpivirine and

Dolutegravir (Not studied) dabigatran etexilate should be used with caution.

Dabigatran etexilate/ Rilpivirine 

Rilpivirine Not studied. Dabigatranetexilate 

A risk for increases indabigatran plasmaconcentrations cannot beexcluded(inhibition of intestinal P-gp).

HMG CO-A reductase inhibitors

Atorvastatin/ Dolutegravir ↔ No dose adjustment is required.

Dolutegravir (Not studied)

Atorvastatin/ Rilpivirine

Rilpivirine1,2 AUC ↔

Cmin ↔

Cmax ↓ 9%

AUC ↔

Cmin ↓ 15%

Cmax ↑ 35%

Phosphodiesterase type 5 (PDE-5) inhibitors

Sildenafil/Dolutegravir ↔ No dose adjustment is required.

Dolutegravir

Sildenafil/ Rilpivirine

Rilpivirine1,2 AUC ↔

Cmin ↔

Cmax ↔

Sildenafil

AUC ↔

Cmin NA

Cmax ↔

Vardenafil Dolutegravir ↔ No dose adjustment is required.

Tadalafil/ (Not studied)

Dolutegravir

Vardenafil Rilpivirine ↔

Tadalafil/ (Not studied)

Rilpivirine1 The interaction between dolutegravir and/or rilpivirine and the medicinal product was evaluated in aclinical study. All other drug-drug interactions shown are predicted.2 This interaction study has been performed with a dose higher than the recommended dose forrilpivirine assessing the maximal effect on the co-administered medicinal product.

NA = Not applicable

QT prolonging medicinal products

There is limited information available on the potential for a pharmacodynamic interaction between rilpivirineand medicinal products that prolong the QTc interval of the ECG. In a study of healthy subjects,supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolongthe QTc interval of the ECG (see section 5.1). Dolutegravir/rilpivirine should be used with caution when co-administered with a medicinal product with a known risk of Torsade de Pointes.

Lower exposures of dolutegravir and rilpivirine were observed during pregnancy (see sections 5.1, pct. 5.2). Inphase 3 studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated withan increased risk of virological failure. The use of Juluca during pregnancy is not recommended.

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformativenor feto/ neonatal toxicity associated with dolutegravir. A moderate amount of data on pregnant women(between 300-1000 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of rilpivirine.

There are no or limited amount (less than 300 exposed outcomes) from the use of this dual combination inpregnancy.

The safety and efficacy of a dual therapy with dolutegravir + rilpivirine 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 between 300-1000 pregnancies with first trimester rilpivirine treatment,do not indicate an increased risk of major birth defects with either dolutegravir or rilpivirine 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 + rilpivirine in pregnant women.

In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, includingneural tube defects, were identified. For rilpivirine, animal studies do not indicate reproductive toxicity (seesection 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.

It is unknown if rilpivirine is excreted in human milk. Available toxicological data in animals has shownexcretion of rilpivirine in milk. Dolutegravir is excreted in human milk in small amounts (a mediandolutegravir breast milk to maternal plasma ratio of 0.033 has been shown). There is insufficent informationon the effects of dolutegravir in newborns/infants.

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 rilpivirine on human male or female fertility. Animalstudies indicate no clinically relevant effects on male or female fertility (see section 5.3).

Juluca has no or negligible influence on the ability to drive and use machines. Patients should be informedthat fatigue, dizziness and somnolence have been reported during treatment with the components of Juluca.

The clinical status of the patient and the adverse reaction profile of Juluca should be borne in mind whenconsidering the patient's ability to drive or operate machinery.

The most frequently reported adverse reactions with Juluca (from clinical studies - see section 5.1) werediarrhoea (2%) and headache (2%).

The most severe adverse reaction, related to the treatment with dolutegravir (from pooled Phase IIb and

Phase III clinical studies), seen in an individual patient, was a hypersensitivity reaction that included rashand severe liver effects (see section 4.4).

The sources of information for the safety database include 2 identical, randomised, open-label studies

SWORD-1 and SWORD-2 (see section 5.1), pooled studies from individual components and post-marketingexperience.

The adverse reactions considered at least possibly related to treatment with the components of Juluca fromclinical studies and post-marketing experience are listed in Table 2 by body system, organ class andfrequency. Frequencies are defined as very common (1/10), common (1/100 to <1/10), uncommon (1/1000 to <1/100), rare (1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated fromthe available data).

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

System organ class Frequency Adverse drug reactions(SOC) category*

Blood and lymphatic common decreased white blood cell countsystems disorders:

decreased haemoglobindecreased platelet count

Immune system uncommon hypersensitivity (see section 4.4)disorders not known immune reconstitution syndrome

Metabolism and very common increased total cholesterol (fasted)nutrition disordersincreased LDL cholesterol (fasted)common decreased appetiteincreased triglycerides (fasted)

Psychiatric disorders very common insomniacommon abnormal dreamsdepressionsleep disordersdepressed moodanxietyuncommon suicidal ideation or suicide attempt (particularly inpatients with a pre-existing history of depression orpsychiatric illness), panic attackrare completed suicide (particularly in patients with a pre-existing history of depression or psychiatric illness)

Nervous system very common headachedisordersdizzinesscommon somnolence

Gastrointestinal very common nauseadisordersincreased pancreatic amylasediarrhoeacommon abdominal painvomitingflatulenceincreased lipaseabdominal discomfortupper abdominal paindry mouth

Hepatobiliary very common increased transaminasesdisorders (alanine aminotransferase (ALT) and/or aspartateaminotransferase (AST) elevations)common increased bilirubinuncommon hepatitisrare acute hepatic failure**

Skin and subcutaneous common rashtissue disorderspruritus

Musculoskeletal and uncommon arthralgiaconnective tissuedisorders myalgia

General disorders and common fatigueadministration siteconditions

Investigations common creatine phosphokinase (CPK) elevations, weightincreased

* Frequencies are assigned based on the maximum frequencies observed in the pooled

SWORD studies or studies with the individual components

** This adverse reaction was identified through post-marketing surveillance for dolutegravirin combination with other ARVs. The frequency category of rare was estimated based on post-marketing reports.

Dolutegravir or rilpivirine have been associated with increases in serum creatinine occurring in the first weekof treatment when administered with other antiretroviral medicinal products. Increases in serum creatinineoccurred within the first four weeks of treatment with dolutegravir/rilpivirine and remained stable through148 weeks. A mean change from baseline of 9.86 mol/L (SD 10.4 mol/L) was observed after 148 weekstreatment. These changes are related to inhibition of active transport, and are not considered to be clinicallyrelevant as they do not reflect a change in glomerular filtration rate.

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

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 or rilpivirineapart from those listed as adverse reactions.

Further management should be as clinically indicated or as recommended by the national poisons centre,where available. There is no specific treatment for an overdose of dolutegravir/rilpivirine. If overdose occurs,the patient should be treated supportively with appropriate monitoring, including monitoring of vital signsand ECG (QT interval), as necessary. As dolutegravir and rilpivirine are highly bound to plasma proteins,dialysis is unlikely to result in significant removal of the active substances.

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections,combinations. ATC code: J05AR21

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.

Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1.

Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT).

Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.

The IC50 for dolutegravir against various laboratory strains using PBMC was 0.5 nM, and when using MT-4cells it 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 the mean

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).

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell linewith a median IC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited in vitroactivity against HIV-2 with IC50 values ranging from 2 510 to 10 830 nM.

Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D,

F, G, H) primary isolates with IC50 values ranging from 0.07 to 1.01 nM and group O primary isolates with

EC50 values ranging from 2.88 to 8.45 nM.

Effect of human serum and serum proteins

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

IC90 of 0.064 g/mL.

A reduction in the antiviral activity of rilpivirine was observed in the presence of 1 mg/mL alpha-1-acidglycoprotein, 45 mg/mL human serum albumin, and 50% human serum as demonstrated by median IC50rates of 1.8, 39.2 and 18.5, respectively.

Serial passage is used to study resistance evolution in vitro. For dolutegravir, when using the laboratorystrain HIV-1 IIIB during passage over 112 days, mutations selected appeared slowly, with substitutions atpositions S153Y and F; these mutations were not selected in patients treated with dolutegravir in the clinicalstudies. Using strain NL432, integrase mutations E92Q (fold change [FC] 3) and G193E (FC 3) wereselected. These mutations have been selected in patients with pre-existing raltegravir resistance and whowere then treated with dolutegravir (listed as secondary mutations for dolutegravir).

In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all fiveisolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution

R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two individualpatients with subtype B and subtype C in the Phase III clinical program for ART experienced, INI naivesubjects, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility todolutegravir in site directed mutants (FC 10), but was not detected in patients receiving dolutegravir in the

Phase III program.

Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, T66I) do not affectthe in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integraseinhibitor associated mutations (for raltegravir/elvitegravir) are added to primary mutations (excluding at

Q148) in experiments with site directed mutants, dolutegravir susceptibility remains at or near wildtypelevel. In the case of the Q148-mutation viruses, increasing dolutegravir FC is seen as the number ofsecondary mutations increase. The effect of the Q148-based mutations (H/R/K) was also consistent with invitro passage experiments with site directed mutants. In serial passage with strain NL432-based site directedmutants at N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). Incontrast, starting passage with mutants with mutation Q148H (FC 1), a variety of raltegravir associatedsecondary mutations accumulated with a consequent increase of FC to values >10.

A clinically relevant phenotypic cut-off value (FC vs wild type virus) has not been determined; genotypicresistance was a better predictor for outcome.

Rilpivirine-resistant strains were selected in cell culture starting from wild type HIV-1 of different originsand clades as well as NNRTI-resistant HIV-1. The most commonly observed amino acid substitutions thatemerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I. Resistance torilpivirine was considered present when FC in EC50 value was above the biological cut-off (BCO) of theassay.

Through 48 Weeks with comparative data two subjects receiving dolutegravir plus rilpivirine and twosubjects continuing their current antiretroviral regimen (CAR) experienced confirmed virologic failureleading to withdrawal (CVW) criteria across the pooled SWORD-1 (201636) and SWORD-2 (201637)studies. Overall eleven subjects receiving dolutegravir plus rilpivirine met CVW through Week 148, see

Table 3. The NNRTI-associated substitutions E138E/A and M230M/L were detected in three and twosubjects at time of withdrawal.

Table 3: Summary of resistance by drug class for subjects with confirmed virologic withdrawalin early and late switch phases of the SWORD studies

Regimen/Mutation by Drug Class

HIV-1 RNA (c/mL) ***

Treatment mutation (FC)(time point)exposure INI NNRTI(weeks)*

SVW CVW** BL VW BL VW

DTG+RPV/88 466 G193E

G193E none none36 (Wk24) (Wk24UNS) (1.02)

DTG+RPV/1,059,771 1018 K101K/Enone none none47 (Wk36) (Wk36UNS) (0.75)

DTG+RPV/ 162 217

L74I NR V108I NR21 (Wk64) (Wk76)

DTG+RPV/833 1174 N155N/H V151V/Inone none17 (Wk64) (Wk64UNS) G163G/R (NR)

DTG+RPV/278 2571 E138E/Anone none none88 (Wk76) (Wk88) (1.61)

DTG+RPV/147 289 K103N

ND none NR92 (Wk88) (Wk88UNS) (5.24)

DTG+RPV/280 225none none none none105 (Wk88) (Wk100)

K101E,

DTG+RPV/651 1105 K101E, E138A,

G193E NR105 (Wk100) (Wk100UNS) E138A M230M/L(31)

E157Q E157Q,

DTG+RPV/118 230 M230M/L

G193E, G193E none120 (Wk112) (Wk112UNS) (2)

T97T/A (1.47)

E138A,

DTG+RPV/4294 7247

NR NR NR L100L/I101 (Wk136) (Wk136UNS)(4.14)

* The resistance testing at virologic failure time failed for one subject, therefore, details are notincluded in this table.

** CVW was met with 2 consecutive viral loads after Day 1 ≥50 c/mL, with the second one being>200 c/mL.

*** The baseline assay only provides genotypic data, and not phenotypic data.

CAR = current antiretroviral regimen; DTG+RPV = dolutegravir plus rilpivirine

SVW = suspected virologic withdrawal criteria; CVW = confirmatory virologic withdrawal criteria;

BL = baseline resistance testing results; VW = resistance testing results when CVW criteria have beenmet; Wk = week; UNS = unscheduled visit; “ND” Baseline testing was not performed as

PBMC/Whole blood samples were note collected; “none” indicates no resistance observed; 'NR'indicates data are not reported due to assay failure or sample unavailability.

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no developmentof resistance to the integrase class, or to the NRTI class was seen (n=876, follow-up of 48-96 weeks).

In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitorsubstitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which wasgiven in combination with an investigator selected background regimen (BR). Of these four, two subjectshad a unique R263K integrase substitution, with a maximum FC of 1.93, one subject had a polymorphic

V151V/I integrase substitution, with maximum FC of 0.92, and one subject had pre-existing integrasemutations and is assumed to have been integrase inhibitor experienced or infected with integrase inhibitorresistant virus by transmission. The R263K mutation was also selected in vitro (see above).

From rilpivirine Phase IIIstudies, in the week 48 pooled resistance analysis conducted with previouslyuntreated patients, 62 (of a total of 72) virologic failures in the rilpivirine arm had resistance data at baselineand time of failure. In this analysis, the resistance-associated mutations (RAMs) associated with NNRTIresistance that developed in at least 2 rilpivirine virologic failures were: V90I, K101E, E138K, E138Q,

V179I, Y181C, V189I, H221Y, and F227C. In thestudies, the presence of the mutations V90I and V189I, atbaseline, did not affect response. The E138K substitution emerged most frequently during rilpivirinetreatment, commonly in combination with the M184I substitution. In the week 48 analysis, 31 out of 62 ofrilpivirine virologic failures had concomitant NNRTI and NRTI RAMs; 17 of those 31 had the combinationof E138K and M184I. The most common mutations were the same in the week 48 and week 96 analyses.

From the week 48 to the week 96 analysis, 24 (3.5%) and 14 (2.1%) additional virologic failures occurred inthe rilpivirine and efavirenz arm, respectively.

Site-directed INI mutant virus

Dolutegravir activity was determined against a panel of 60 INI-resistant site-directed mutant HIV-1 viruses(28 with single substitutions and 32 with 2 or more substitutions). The single INI-resistance substitutions

T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H,

G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at

E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).

Site-directed NNRTI mutant virus

In a panel of 67 HIV-1 recombinant laboratory strains with one amino acid substitution at RT positionsassociated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirineshowed antiviral activity (FC≤BCO) against 64 (96%) of these strains. The single amino acid substitutionsassociated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V. The K103Nsubstitution did not result in reduced susceptibility to rilpivirine by itself, but the combination of K103N and

L100I resulted in a 7-fold reduced susceptibility to rilpivirine.

Considering all of the available in vitro and in vivo data, the following amino acid substitutions, whenpresent at baseline, are likely to affect the activity of rilpivirine: K101E, K101P, E138A, E138G, E138K,

E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I or M230L.

Recombinant clinical isolates

Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analysed forsusceptibility to dolutegravir. Dolutegravir had a <10 FC against 94% of the 705 clinical isolates.

Rilpivirine retained sensitivity (FC ≤ BCO) against 62% of 4786 HIV-1 recombinant clinical isolatesresistant to efavirenz and/or nevirapine.

Previously untreated HIV-1 infected adult patients

In a Week 96 pooled analyses of virologic failures with baseline viral load ≤100,000 copies/mL andresistance to rilpivirine (n = 5), subjects had cross-resistance to efavirenz (n = 3), etravirine (n = 4), andnevirapine (n = 1).

The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated ina randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthyadults, with 13 measurements over 24 hours at steady-state. Rilpivirine at the recommended dose of 25 mgonce daily is not associated with a clinically relevant effect on QTc.

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine were studied inhealthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcFinterval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) ms, respectively. Steady-state administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean Cmaxapproximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state Cmax observed with therecommended 25 mg once daily dose of rilpivirine (see section 4.4).

No relevant effects were seen with dolutegravir on the QTc interval, with doses exceeding the clinical doseby approximately three fold.

The efficacy and safety of switching from an antiretroviral regimen (containing 2 NRTIs plus either an INI,an NNRTI, or a PI) to a dual regimen of dolutegravir 50 mg and rilpivirine 25 mg was evaluated in 2identical 148-week, randomised, open-label, multicentre, parallel-group, non-inferiority studies SWORD-1(201636) and SWORD-2 (201637). Subjects were enrolled if they were on their first or second antiretroviralregimen with no history of virological failure, had no suspected or known resistance to any antiretroviral andhad been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening. Subjectswere randomised 1:1 to continue their CAR or be switched to a two-agent regimen dolutegravir plusrilpivirine administered once daily. The primary efficacy endpoint for the SWORD studies was theproportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm for the ITT-

E population).

At baseline, in the pooled analysis, characteristics were similar between treatment arms with the median ageof subjects of 43 years (28%, 50 years of age or older; 3%, 65 years of age or older), 22% female, 20% non-white and 77% were CDC Class A. Median CD+cell count was about 600 cells per mm3 with 11% having

CD4+ cell count less than 350 cells per mm3. In the pooled analysis, 54%, 26%, and 20% of subjects werereceiving an NNRTI, PI, or INI (respectively) as their baseline third treatment agent class prior torandomisation.

The pooled primary analysis demonstrated that dolutegravir plus rilpivirine is non-inferior to CAR, with 95%of subjects in both arms achieving the primary endpoint of <50 copies/mL plasma HIV-1 RNA at Week 48based on the Snapshot algorithm (Table 4).

The primary endpoint and other outcomes (including outcomes by key baseline covariates) for the pooled

SWORD-1 and SWORD-2 studies are shown in Table 4.

Table 4: Virologic outcomes of randomised treatment at week 48 (Snapshot algorithm)

SWORD-1 and SWORD-2 Pooled

Data***

DTG + RPV CAR

N=513 N=511n (%) n (%)

HIV-1 RNA <50 copies/mL 486 (95%) 485 (95%)

Treatment Difference* -0.2 (-3.0, 2.5)

Virologic non response** 3 (<1%) 6 (1%)

Reasons

Data in window not <50 copies/mL 0 2 (<1%)

Discontinued for lack of efficacy 2 (<1%) 2 (<1%)

Discontinued for other reasons while not <501 (<1%) 1 (<1%)copies/mL

Change in ART 0 1 (<1%)

No virologic data at Week 48 window 24 (5%) 20 (4%)

Reasons

Discontinued study/study agent due to adverse17 (3%) 3 (<1%)event or death

Discontinued study/study agent for other reasons 7 (1%) 16 (3%)

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

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

Baseline CD4+ (cells/ mm3)<350 51/58 (88%) 46/52 (88%)350 435/455 (96%) 439/459 (96%)

Baseline Third Treatment Agent Class

INI 99/105 (94%) 92/97 (95%)

NNRTI 263/275 (96%) 265/278 (95%)

PI 124/133 (93%) 128/136 (94%)

Male 375/393 (95%) 387/403 (96%)

Female 111/120 (93%) 98/108 (91%)

White 395/421 (94%) 380/400 (95%)

African-America/African Heritage/Other 91/92 (99%) 105/111 (95%)

Age (years)<50 350/366 (96%) 348/369 (94%)50 136/147 (93%) 137/142 (96%)

* Adjusted for baseline stratification factors and assessed using a non-inferiority marginof - 8%.

** Non-inferiority of dolutegravir plus rilpivirine to CAR, in the proportion of subjectsclassified as virologic non-responders, was demonstrated using a non-inferiority margin of 4%.

Adjusted difference (95% CI) -0.6 (-1.7, 0.6).

*** The results of the pooled analysis are in line with those of the individual studies, for whichdifferences in proportions meeting the primary endpoint of <50 copies/mL plasma HIV-1 RNAat Week 48 (based on the Snapshot algorithm) for DTG+RPV versus CAR were -0.6 (95% CI:

- 4.3; 3.0) for SWORD-1 and 0.2 (95% CI: -3.9; 4.2) for SWORD-2 with a preset non-inferiority margin of -10%.

N = Number of subjects in each treatment arm

CAR = current antiretroviral regimen; DTG+RPV = dolutegravir plus rilpivirine;

INI = Integrase inhibitor; NNRTI = Non-nucleoside reverse transcriptase inhibitor;

PI = Protease Inhibitor

At Week 148 in the pooled SWORD-1 and SWORD-2 studies, 84% of subjects who received dolutegravirplus rilpivirine as of study start had plasma HIV-1 RNA < 50 copies/mL based on the Snapshot algorithm. Insubjects who initially remained on their CAR and switched to dolutegravir plus rilpivirine at Week 52, 90%had plasma HIV-1 RNA < 50 copies/mL at Week 148 based on the Snapshot algorithm, which wascomparable to the response rate (89%) observed at Week 100 (similar exposure duration) in subjectsreceiving dolutegravir plus rilpivirine as of study start.

Effects on bone

In a DEXA substudy mean bone mineral density (BMD) increased from Baseline to Week 48 in subjectswho switched to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with thosewho continued on treatment with a TDF-containing antiretroviral regimen (0.05% total hip and 0.15%lumbar spine. Any beneficial effect on fracture rate was not studied.

No efficacy and safety data are available for the combination of dolutegravir and rilpivirine in pregnancy.

Rilpivirine in combination with a background regimen was evaluated in a clinical study of 19 pregnantwomen during the second and third trimesters, and postpartum. The pharmacokinetic data demonstrate thattotal exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30% lowerduring pregnancy compared with postpartum (6-12 weeks). Of the 12 subjects that completed the study, 10subjects were suppressed at the end of the study; in the other 2 subjects an increase in viral load wasobserved postpartum, for 1 subject due to suspected suboptimal adherence. No mother to child transmissionoccurred in all 10 infants born to the mothers who completed the study and for whom the HIV status wasavailable. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1infected adults.

In limited data from small numbers of women who received dolutegravir 50 mg once daily in combinationwith a background regimen, the total exposure (AUC) to dolutegravir was 37% lower during the 2ndtrimester of pregnancy, and 29% lower during the 3rd trimester of pregnancy, compared with postpartum (6-12 weeks). Of the 29 subjects that completed the study, 27 subjects were suppressed at the end of the study.

No mother to child transmission was identified. While 24 infants were confirmed to be uninfected, 5 wereindeterminate due to incomplete testing, see section 5.2.

The European Medicines Agency has deferred the obligation to submit the results of studies with Juluca inone or more subsets of the paediatric population in the treatment of HIV infection (see section 4.2 forinformation on paediatric use).

Juluca is bioequivalent to a dolutegravir 50 mg tablet and a rilpivirine 25 mg tablet administered togetherwith a meal.

Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability ofdolutegravir is low to moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC and

Cmax ranged from ~20 to 40% and C from 30 to 65% across studies. The between-subject PK variability ofdolutegravir was higher in HIV-infected subjects than healthy subjects. Within-subject variability (CVw%) islower than between-subject variability.

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adultantiretroviral treatment-naïve HIV-1 infected patients. Systemic exposure to rilpivirine was generally lowerin HIV-1 infected patients than in healthy subjects.

Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose fortablet formulation. After oral administration, the maximum plasma concentration of rilpivirine is generallyachieved within 4-5 hours.

Juluca must be taken with a meal to obtain optimal absorption of rilpivirine (see section 4.2). When Julucawas taken with a meal, the absorption of both dolutegravir and rilpivirine was increased. Moderate and highfat meals increased the dolutegravir AUC(0-) by approximately 87% and Cmax by approximately 75%.

Rilpivirine AUC(0-) was increased by 57% and 72% and Cmax by 89% and 117%, with moderate and highfat meals respectively, compared to fasted conditions. Taking Juluca in fasted condition or with only aprotein-rich nutritional drink may result in decreased plasma concentrations of rilpivirine, which couldpotentially reduce the therapeutic effect of Juluca.

The absolute bioavailability of dolutegravir or rilpivirine has not been established.

Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data. The apparent volumeof distribution is 17 L to 20 L in HIV-infected patients, based on a population pharmacokinetic analysis.

Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood andplasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimalassociation of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasmais increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment.

Dolutegravir is present in cerebrospinal fluid (CSF). In 13 treatment-naïve subjects on a stable dolutegravirplus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable tounbound plasma concentration, and above the IC50).

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.

Rilpivirine is approximately 99.7% bound to plasma proteins in vitro, primarily to albumin. The distributionof rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has notbeen evaluated in humans.

Dolutegravir is primarily metabolised through glucuronidation via UGT1A1 with a minor CYP3Acomponent. Dolutegravir is the predominant circulating compound in plasma; renal elimination ofunchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excretedunchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliaryexcretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in thegut lumen. Thirty-two percent of the total oral dose is excreted in the urine, mainly represented by etherglucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and ametabolite formed by oxidation at the benzylic carbon (3.0% of total dose).

In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the

CYP3A system.

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, uridine diphosphateglucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1,

OATP1B3, OCT1, MATE2-K, 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 medicinalproducts that are substrates of major enzymes or transporters (see section 4.5).

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

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

The terminal elimination half-life of rilpivirine is approximately 45 hours. After single dose oraladministration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in faecesand urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of the administereddose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine.

Neither Juluca nor the combination dolutegravir and rilpivirine as single entities have been studied inchildren. Dose recommendations for paediatric patients cannot be made due to insufficient data (see section4.2).

The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents(12 to <18 years of age and weighing ≥40 kg) showed that dolutegravir 50 mg once daily oral dosageresulted in dolutegravir exposure comparable to that observed in adults who received dolutegravir 50 mgorally once daily. The pharmacokinetics was evaluated in 11 children 6 to 12 years of age and showed that25 mg once daily in patients weighing at least 20 kg and 35 mg once daily in patients weighing at least 30 kgresulted in dolutegravir exposure comparable to adults.

The pharmacokinetics of rilpivirine in 36 antiretroviral treatment-naïve HIV-1 infected adolescent subjects(12 to <18 years of age) receiving rilpivirine 25 mg once daily were comparable to those in treatment-naïve

HIV-1 infected adults receiving rilpivirine 25 mg once daily. There was no impact of body weight onrilpivirine pharmacokinetics in paediatric subjects in study C213 (33 to 93 kg), similar to what was observedin adults.

Population pharmacokinetic analysis using data in HIV-1 infected adults showed that there was no clinicallyrelevant effect of age on dolutegravir or rilpivirine exposures. Pharmacokinetic data in subjects >65 years oldare very limited.

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) and matched healthy controls. The exposure to dolutegravir was decreased by approximately40% in subjects with severe renal impairment. The mechanism for the decrease is unknown. Thepharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency.

Renal elimination of rilpivirine is negligible. No dose adjustment is needed for patients with mild ormoderate renal impairment. In patients with severe renal impairment or end-stage renal disease,dolutegravir/rilpivirine should be used with caution, as rilpivirine plasma concentrations may be increaseddue to alteration of drug absorption, distribution and/or metabolism secondary to renal dysfunction. Inpatients with severe renal impairment or end-stage renal disease, the combination of dolutegravir/rilpivirinewith a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. Dolutegravir/rilpivirinehas not been studied in patients on dialysis. As dolutegravir and rilpivirine are highly bound to plasmaproteins, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis (seesection 4.2).

Dolutegravir and rilpivirine are both primarily metabolised and eliminated by the liver. A single dose of50 mg of dolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh score

B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar,a 1.5- to 2-fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepaticimpairment compared to healthy controls.

In a rilpivirine study comparing 8 patients with mild hepatic impairment (Child-Pugh score A) to 8 matchedcontrols, and 8 patients with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, themultiple dose exposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5%higher in patients with moderate hepatic impairment. However, it may not be excluded that thepharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate hepaticimpairment.

No dose adjustment is considered necessary for patients with mild to moderate hepatic impairment (Child-

Pugh score A or B). Dolutegravir/rilpivirine should be used with caution in patients with moderate hepaticimpairment. The effect of severe hepatic impairment (Child-Pugh score C) on the pharmacokinetics ofdolutegravir or rilpivirine has not been studied, therefore dolutegravir/rilpivirine is not recommended in thesepatients.

Population pharmacokinetic analyses from studies with the individual components revealed that gender hadno clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine.

No clinically important pharmacokinetic differences of dolutegravir or rilpivirine due to race have beenidentified.

Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevanteffect on the exposure to dolutegravir or rilpivirine. Subjects with hepatitis B co-infection or hepatitis Cinfection in need of anti-HCV therapy were excluded from studies with the dual combination of dolutegravirand rilpivirine.

No pharmacokinetic data are available for the combination of dolutegravir and rilpivirine in pregnancy. Inlimited data from small numbers of women in study IMPAACT P1026 who received dolutegravir 50 mgonce daily during the 2nd trimester of pregnancy, mean intra-individual values for total dolutegravir Cmax,

AUC24h and C24h values were, respectively, 26%, 37% and 51% lower as compared to postpartum; during the3rd trimester of pregnancy, Cmax, AUC24h and Cmin values were, respectively, 25%, 29% and 34% lower ascompared to postpartum (see section 4.6).

In women receiving rilpivirine 25 mg once daily during the 2nd trimester of pregnancy, mean intra-individual values for total rilpivirine Cmax, AUC24h and Cmin values were, respectively, 21%, 29% and 35%lower as compared to postpartum; during the 3rd trimester of pregnancy, Cmax, AUC24h and Cmin values were,respectively, 20%, 31% and 42% lower as compared to postpartum (see section 4.6).

Non-clinical data for dolutegravir and rilpivirine reveal no special hazard for humans based on conventionalstudies of safety pharmacology, repeated dose toxicity and genotoxicity. While dolutegravir was notcarcinogenic in long-term animal studies, rilpivirine caused an increase in hepatocellular neoplasms in micethat may be species specific.

Reproductive toxicology studies

In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta.

Dolutegravir did not affect male or female fertility in rats at 33 times higher exposures than the AUC-exposure at 50 mg human clinical dose.

Oral administration of dolutegravir to pregnant rats did not elicit maternal toxicity, developmental toxicity orteratogenicity (38 times the 50 mg human clinical exposure based on AUC).

Oral administration of dolutegravir to pregnant rabbits did not elicit developmental toxicity or teratogenicity(0.56 times the 50 mg human clinical exposure based on AUC).

Rilpivirine studies in rats and rabbits have shown no teratogenicity and no evidence of relevant embryonic orfoetal toxicity or an effect on reproductive function at exposures respectively 15 and 70 times higher than theexposure in humans at the recommended dose of 25 mg once daily.

Mannitol (E421)

Magnesium stearate

Microcrystalline cellulose

Povidone (K29/32)

Sodium starch glycolate

Sodium stearyl fumarate

Lactose monohydrate

Croscarmellose sodium

Povidone (K30)

Polysorbate 20

Silicified microcrystalline cellulose

Polyvinyl alcohol- part hydrolysed

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide yellow (E172)

Iron oxide red (E172)

Not applicable.

3 years.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not removethe 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 apolyethylene faced induction heat seal liner. Each pack consists of one bottle containing 30 film-coatedtablets and a desiccant.

Multipacks containing 90 (3 packs of 30) film-coated tablets. Each pack of 30 film-coated tablets contains adesiccant.

Not all pack sizes may be marketed.

No special requirements for disposal.

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/18/1282/001

EU/1/18/1282/002

Date of first authorisation: 16 May 2018

Date of latest renewal: 12 January 2023

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

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