Juluca

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



 

2 

This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 
4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Juluca 50 mg/25 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir and rilpivirine 
hydrochloride equivalent to 25 mg rilpivirine. 
 
Excipient with known effect  
Each film-coated tablet contains 52 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Pink, oval, biconvex tablets, approximately 14 x 7 mm, debossed with ‘SV J3T’ on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Juluca is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults 
who are virologically-suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least 
six months with no history of virological failure and no known or suspected resistance to any non-nucleoside 
reverse transcriptase inhibitor or integrase inhibitor (see section 5.1).  
 
 
4.2 Posology and method of administration  
 
Juluca should be prescribed by physicians experienced in the management of HIV infection. 
 
Posology 
 
The recommended dose of Juluca is one tablet once daily.  Juluca must be taken with a meal (see section 
5.2).  
 
Separate preparations of dolutegravir or rilpivirine are available in cases where discontinuation or dose 
adjustment of one of the active substances is indicated (see section 4.5).  In these cases the physician should 
refer to the Summary of Product Characteristics for these medicinal products. 
 
Missed doses 
If the patient misses a dose of Juluca, the patient should take Juluca 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 should 
not take the missed dose and simply resume the usual dosing schedule. 
 



 

3 

If a patient vomits within 4 hours of taking Juluca, another Juluca tablet should be taken with a meal.  If a 
patient vomits more than 4 hours after taking Juluca, the patient does not need to take another dose of Juluca 
until the next regularly scheduled dose. 
 
Elderly 
There are limited data available on the use of Juluca in patients aged 65 years and over.  There is no evidence 
that elderly patients require a different dose than younger adult patients (see section 5.2). 
 
Renal impairment 
No dosage adjustment is required in patients with mild or moderate renal impairment.  In patients with 
severe renal impairment or end stage renal disease, the combination of Juluca with a strong CYP3A inhibitor 
should only be used if the benefit outweighs the risk.  No data are available in subjects receiving dialysis 
although differences in pharmacokinetics are not expected in this population (see section 5.2). 
 
Hepatic impairment 
No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A 
or B).  Juluca should be used with caution in patients with moderate hepatic impairment.  No data are 
available in patients with severe hepatic impairment (Child-Pugh score C); therefore Juluca is not 
recommended in these patients (see section 5.2). 
 
Paediatric population 
The safety and efficacy of Juluca in children and adolescents aged less than 18 years have not yet been 
established.  Currently available data are described in section 5.2, but no recommendation on a posology can 
be made.  
 
Pregnancy 
The safety and efficacy of Juluca in pregnancy have not yet been established.  Limited data are available 
regarding the use of dolutegravir during pregnancy.  Lower exposures of dolutegravir and rilpivirine were 
observed during pregnancy.  No recommendations for dose adjustments can be made for Juluca.  Therefore, 
use of Juluca during pregnancy is not recommended (see sections 4.4, 4.6, 5.1 and 5.2). 
 
Method of administration 
 
Oral use 
Juluca must be taken orally, once daily with a meal (see section 5.2).  It is recommended that the film-
coated tablet be swallowed whole with water and not be chewed or crushed. 
 
 
4.3 Contraindications 
 
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). 
 
 
4.4 Special warnings and precautions for use 
 
Transmission of HIV 
 



 

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While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk 
of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent transmission should be 
taken in accordance with national guidelines.  
 
Hypersensitivity reactions 
 
Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, 
constitutional findings, and sometimes, organ dysfunction, including severe liver reactions.  Juluca should be 
discontinued immediately if signs or symptoms of hypersensitivity reactions 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 be monitored.  Delay in stopping treatment with 
Juluca after the onset of hypersensitivity may result in a life-threatening allergic reaction.  
 
Cardiovascular 
 
At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of 
the QTc interval of the electrocardiogram (ECG) (see sections 4.5 and 5.1).  Rilpivirine at the recommended 
dose of 25 mg once daily is not associated with a clinically relevant effect on QTc.  Juluca should be used 
with caution when co-administered with medicinal products with a known risk of Torsade de Pointes. 
 
Opportunistic infections 
 
Patients should be advised that Juluca does not cure HIV infection and that they may still develop 
opportunistic infections and other complications of HIV infection.  Therefore, patients should remain under 
close clinical observation by physicians experienced in the treatment of these associated HIV diseases. 
 
Osteonecrosis 
 
Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, 
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported in patients with advanced HIV-disease and/or long-term exposure to CART.  Patients should be 
advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in 
movement. 
 
Patients with hepatitis B or C 
 
No clinical data are available in patients with hepatitis B co-infection.  Physicians should refer to current 
treatment 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 chemistry 
elevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected with 
hepatitis C compared to those who were not co-infected.  Monitoring of liver function is recommended in 
patients with hepatitis B and/or C co-infection.     
 
Interactions with other medicinal products 
 
Juluca should not be administered with other antiretroviral medicinal products for the treatment of HIV (see 
section 4.5).   
 
Juluca should not be co-administered at the same time as H2-receptor antagonists.  These medicinal products 
are recommended to be administered 12 hours before or 4 hours after Juluca (see section 4.5). 
 
Juluca should not be co-administered at the same time as antacids.  These medicinal products are 
recommended to be administered 6 hours before or 4 hours after Juluca (see section 4.5). 
 



 

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Calcium or iron supplements, or multivitamins should be co-administered at the same time as Juluca, with a 
meal.  If calcium or iron supplements, or multivitamins cannot be taken at the same time as Juluca, these 
supplements are recommended to be administered 6 hours before or 4 hours after taking Juluca (see section 
4.5).  
 
Dolutegravir increased metformin concentrations.  A dose adjustment of metformin should be considered 
when starting and stopping co-administration of Juluca with metformin, to maintain glycaemic control (see 
section 4.5).  Metformin is eliminated renally and therefore it is of importance to monitor renal function 
when co-treated with Juluca.  This combination may increase the risk for lactic acidosis in patients with 
moderate renal impairment (stage 3a creatinine clearance [CrCl] 45– 59 mL/min) and a cautious approach is 
recommended. Reduction of the metformin dose should be highly considered.  
 
Juluca should not be taken with any other medicinal product containing dolutegravir or rilpivirine, except in 
case of co-administration with rifabutin (see section 4.5). 
 
Pregnancy 
 
The safety and efficacy of Juluca in pregnancy have not yet been established.  Limited data are available 
regarding the use of dolutegravir during pregnancy.  Lower exposures of dolutegravir or rilpivirine were 
observed when taken once daily, in combination with a background regimen, during pregnancy.  In phase 3 
studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an 
increased risk of virological failure.  No recommendations for dose adjustments can be made for Juluca.  
Therefore, use of Juluca during pregnancy is not recommended (see sections 4.6, 5.1 and 5.2).   
 
Immune Reactivation Syndrome 
 
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms.  Typically, such 
reactions have been observed within the first few weeks or months of initiation of CART.  Relevant 
examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis 
jirovecii pneumonia.  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 occur in the setting of immune reconstitution, however, the reported time to onset is more 
variable and these events can occur many months after initiation of treatment. 
 
Excipients 
 
Juluca contains lactose.  Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicine. 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Juluca is intended for use as a complete regimen for the treatment of HIV-1 infection and should not be 
administered with other antiretroviral medicinal products for the treatment of HIV.  Therefore, information 
regarding drug-drug interactions with other antiretroviral medicinal products is not provided.  Juluca 
contains dolutegravir 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 induce 
those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of 



 

6 

dolutegravir (see Table 1).  Co-administration of Juluca and other medicinal products that inhibit 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 thus 
affect the clearance of rilpivirine (see section 5.2).  Co-administration of Juluca with medicinal products that 
induce CYP3A may result in decreased plasma concentrations of rilpivirine, which could reduce the 
therapeutic effect of Juluca (see Table 1).  Co-administration of Juluca with medicinal products that inhibit 
CYP3A may result in increased plasma concentrations of rilpivirine (see Table 1). 
 
Co-administration of Juluca with medicinal products that increase gastric pH may result in decreased plasma 
concentrations of rilpivirine which could potentially reduce the therapeutic effect of Juluca. 
 
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 medicinal 
products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for 
more information see section 5.2). 
 
In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin 
extrusion transporter 1 (MATE1).  In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is 
dependent on OCT2 and MATE1 transport) was observed in patients.  In vivo, dolutegravir may increase 
plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE1 
(e.g. fampridine [also known as dalfampridine], metformin) (see Table 1 and 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 inhibition 
of OAT1 is unlikely.  Inhibition of OAT3 has not been studied in vivo.  Dolutegravir may increase plasma 
concentrations of medicinal products in which excretion is dependent upon OAT3.   
 
Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal 
products metabolised by CYP enzymes. 
 
Rilpivirine inhibits P-gp in vitro (IC50 is 9.2 μM).  In a clinical study, rilpivirine did not significantly affect 
the pharmacokinetics of digoxin.  However, it may not be completely excluded that rilpivirine can increase 
the exposure to other medicinal products transported by P-gp that are more sensitive to intestinal P-gp 
inhibition, e.g. dabigatran etexilate. 
 
Rilpivirine is an in vitro inhibitor of the transporter MATE-2K with an IC50 of < 2.7 nM.  The clinical 
implications of this finding are currently unknown. 
 
Interaction table 
 
Selected established and theoretical interactions between dolutegravir, rilpivirine and co-administered 
medicinal products are listed in Table 1.   
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time 
curve as “AUC”, maximum observed concentration as “Cmax”, minimum observed concentration as 
“Cmin”concentration at end of dosing interval as “Cτ”).   
 
Table 1: Drug Interactions 
 

Medicinal products 
by therapeutic areas 

Interaction  
Geometric mean change 
(%)  

Recommendations concerning 
co-administration 



 

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Antiviral active substances 
Tenofovir disoproxil / 
Dolutegravir1 
 
 
 
 
 
Tenofovir disoproxil / 
Rilpivirine1,2 

Dolutegravir  
   AUC  1% 
   Cmax  3% 
   Cτ   8% 
 
Tenofovir  
 
 
Rilpivirine  
   AUC ↔ 
   Cmin ↔ 
   Cmax ↔ 
 
Tenofovir  
   AUC ↑ 23%  
   Cmin ↑ 24%  
   Cmax ↑ 19%  

No dose adjustment is required. 

Tenofovir alafenamide 
/ Dolutegravir 
 
Tenofovir alafenamide 
/ Rilpivirine1 

Dolutegravir  
(Not studied) 
 
 
Rilpivirine  
 

No dose adjustment is required. 

Lamivudine/ 
Dolutegravir  
 
Lamivudine/ 
Rilpivirine 

Dolutegravir  
 
 
Rilpivirine  
(Not studied) 

No dose adjustment is required. 

Entecavir/ 
Dolutegravir 
 
Entecavir/ Rilpivirine 

Dolutegravir  
(Not studied) 
 
Rilpivirine  
(Not studied) 

No dose adjustment is required. 

Daclatasvir/ 
Dolutegravir1 
 
 
 
 
 
Daclatasvir/ 
Rilpivirine 

Dolutegravir  
   AUC  33%  
   Cmax  29% 
   C  45% 
 
Daclatasvir  
 
Rilpivirine  
 

No dose adjustment is required. 

Simeprevir/ 
Dolutegravir 
 
Simeprevir/ 
Rilpivirine 
 
 

Dolutegravir  
 
 
Rilpivirine  
   AUC  
   Cmin  25% 
   Cmax     
Simeprevir  
   AUC  
   Cmin  
   Cmax  10% 

No dose adjustment is required. 



 

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Sofosbuvir / 
Dolutegravir1 
 
Sofosbuvir / 
Rilpivirine 

Dolutegravir  
(Not studied) 
 
Rilpivirine  
   AUC  
   Cmin  
   Cmax  
Sofosbuvir  
   AUC  
   Cmax  21% 
Sofosbuvir metabolite GS-
331007  
   AUC  
   Cmax  

No dose adjustment is required. 

Ledipasvir/Sofosbuvir 
/ Dolutegravir1 
 
Ledipasvir/Sofosbuvir 
/ Rilpivirine 

Dolutegravir  
(Not studied) 
 
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% 

No dose adjustment is required. 

Sofosbuvir/ 
Velpatasvir/ 
Dolutegravir1 
 
Sofosbuvir/ 
Velpatasvir/ 
Rilpivirine 

Dolutegravir  
(Not studied) 
 
 
Rilpivirine  
   AUC  
   Cmin  
   Cmax  
Sofosbuvir  
   AUC  
   Cmax  
Sofosbuvir metabolite GS-
331007  
   AUC  
   Cmin  
   Cmax  
Velpatasvir  
   AUC  
   Cmin  
   Cmax  

No dose adjustment is required. 

Ribavirin/ 
Dolutegravir 

Dolutegravir  
(Not studied) 

No dose adjustment is required. 



 

9 

 
Ribavirin/ Rilpivirine 

 
Rilpivirine  
(Not studied) 

Other active substances 
Antiarrhythmics 
Digoxin/ Dolutegravir 
 
 
Digoxin/ Rilpivirine1 

Dolutegravir  
(Not studied) 
 
Rilpivirine  
 
Digoxin  
   AUC ↔  
   Cmin NA  
   Cmax ↔ 

No dose adjustment is required. 

Anticonvulsants 
Carbamazepine/ 
Dolutegravir1 
  
 
 
Carbamazepine/ 
Rilpivirine 

Dolutegravir  
   AUC  49% 
   Cmax  33% 
   C  73% 
 
Rilpivirine 
Not studied. Significant 
decreases in rilpivirine 
plasma concentrations are 
expected (induction of 
CYP3A enzymes). 

Metabolic inducers may significantly decrease 
dolutegravir/rilpivirine plasma concentrations, 
resulting in loss of therapeutic effect.  
Co-administration of Juluca with these metabolic 
inducers is contraindicated (see section 4.3).  

Oxcarbazepine 
Phenytoin 
Phenobarbital/ 
Dolutegravir 
 
 
 
 
Oxcarbazepine 
Phenytoin 
Phenobarbital/ 
Rilpivirine 

Dolutegravir  
Not studied. Decrease 
expected due to induction of 
UGT1A1 and CYP3A 
enzymes, a similar reduction 
in exposure as observed 
with carbamazepine is 
expected. 
 
Rilpivirine  
Not studied. Significant 
decreases in rilpivirine 
plasma concentrations are 
expected 
(induction of CYP3A 
enzymes). 

Metabolic inducers may significantly decrease 
dolutegravir/rilpivirine plasma concentrations, 
resulting in loss of therapeutic effect.  
Co-administration of Juluca with these metabolic 
inducers is contraindicated (see section 4.3). 

Azole anti-fungals  
Ketoconazole/ 
Dolutegravir 
 
Ketoconazole/ 
Rilpivirine1,2 

Dolutegravir  
(Not studied) 
 
Rilpivirine 
   AUC ↑ 49%  
   Cmin ↑ 76%  
   Cmax ↑ 30% 
(inhibition of CYP3A 
enzymes). 
 
Ketoconazole 
   AUC ↓ 24%  

No dose adjustment is required.  



 

10 

   Cmin ↓ 66%  
   Cmax ↔ 
(induction of CYP3A due to 
high rilpivirine dose in the 
study). 

Fluconazole  
Itraconazole  
Isavuconazole 
Posaconazole  
Voriconazole/ 
Dolutegravir 
 
 
Fluconazole  
Itraconazole  
Isavuconazole 
Posaconazole  
Voriconazole/ 
Rilpivirine 
 

Dolutegravir  
(Not studied) 
 
 
 
 
 
 
Rilpivirine ↑  
Not studied. May cause an 
increase in the 
plasma concentrations of 
rilpivirine 
(inhibition of CYP3A 
enzymes). 

No dose adjustment is required. 

Herbal products 
St. John’s wort/ 
Dolutegravir 
 
 
 
 
 
 
St. John’s wort/ 
Rilpivirine 
 
 

Dolutegravir  
Not studied. Decrease 
expected due to induction of 
UGT1A1 and CYP3A 
enzymes, a similar reduction 
in exposure as observed 
with carbamazepine is 
expected. 
 
Rilpivirine  
Not studied. Significant 
decreases in rilpivirine 
plasma concentrations are 
expected  
(induction of CYP3A 
enzymes). 

Co-administration may cause significant decreases 
in rilpivirine plasma concentrations. This may 
result in loss of therapeutic effect of Juluca.  
Co-administration of Juluca with St. John’s wort is 
contraindicated (see section 4.3). 

Potassium channel blockers 
Fampridine (also 
known as 
dalfampridine)/ 
Dolutegravir 
 
 

Fampridine  
 

Co-administration of dolutegravir has the potential 
to cause seizures due to increased fampridine 
plasma concentration via inhibition of OCT2 
transporter; co-administration has not been studied. 
Fampridine co-administration with Juluca is 
contraindicated (see section 4.3). 

Proton pump inhibitors 
Omeprazole 
Lansoprazole  
Rabeprazole  
Pantoprazole 
Esomeprazole/ 
Dolutegravir 
 
Omeprazole/ 
Rilpivirine1,2 
 

Dolutegravir  
(Not studied) 
 
 
 
 
 
Rilpivirine  
   AUC ↓ 40%  
   Cmin ↓ 33% 

Co-administration may significantly decrease 
rilpivirine plasma concentration. This may result in 
loss of therapeutic effect of Juluca.  
Co-administration of Juluca with proton pump 
inhibitors is contraindicated (see section 4.3). 



 

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Lansoprazole  
Rabeprazole  
Pantoprazole 
Esomeprazole/ 
Rilpivirine 

   Cmax ↓ 40% 
(reduced absorption due to 
gastric pH increase). 
 
Omeprazole 
   AUC ↓ 14%  
   Cmin NA  
   Cmax ↓ 14%  
 
 
Rilpivirine  
Not studied. Significant 
decreases in rilpivirine 
plasma concentrations are 
expected  
(reduced absorption due to 
gastric pH increase). 

H2-recepter antagonists 
Famotidine 
Cimetidine  
Nizatidine  
Ranitidine/ 
Dolutegravir 
 
Famotidine/ 
Rilpivirine1,2  
40 mg single dose 
taken 12 hours before 
rilpivirine 
 
Famotidine/ 
Rilpivirine1,2  
40 mg single dose 
taken 2 hours before 
rilpivirine 
 
 
Famotidine/ 
Rilpivirine1,2  
40 mg single dose 
taken 4 hours after 
rilpivirine 
 
Cimetidine  
Nizatidine  
Ranitidine/  
Rilpivirine 

Dolutegravir  
(Not studied) 
 
 
 
 
Rilpivirine 
   AUC ↓ 9%  
   Cmin NA  
   Cmax ↔ 
 
 
Rilpivirine 
   AUC ↓ 76%  
   Cmin NA  
   Cmax  ↓ 85%  
(reduced absorption due to 
gastric pH increase). 
 
Rilpivirine 
   AUC ↑ 13%  
   Cmin NA  
   Cmax ↑ 21% 
 
 
Rilpivirine  
Not studied. Significant 
decreases in rilpivirine 
plasma concentrations are 
expected (reduced 
absorption due to gastric pH 
increase). 

The combination of Juluca and H2-receptor 
antagonists should be used with particular caution.  
Only H2-receptor antagonists that can be dosed 
once daily should be used.  
 
H2-receptor antagonists should be taken well 
separated in time from the administration of Juluca 
(minimum 4 hours after or 12 hours before) 

Antacids and supplements 
Antacids (e.g., 
aluminium 
magnesium hydroxide, 
and/or calcium 

Dolutegravir  
   AUC  74%  
   Cmax  72% 
   C24  74% 

The combination of Juluca and antacids should be 
used with particular caution.  Antacids should be 
taken well separated in time from the 



 

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carbonate)/ 
Dolutegravir1 
 
Antacids (e.g., 
aluminium 
magnesium hydroxide, 
and/or calcium 
carbonate)/ Rilpivirine 

(Complex binding to 
polyvalent ions). 
 
Rilpivirine  
Not studied. Significant 
decreases in rilpivirine 
plasma concentrations are 
expected 
(reduced absorption due to 
gastric pH increase). 

administration of Juluca (minimum 6 hours before 
or 4 hours after). 

Calcium supplements/ 
Dolutegravir1  

Dolutegravir  
   AUC  39%  
   Cmax  37% 
   C24  39% 
(Complex binding to 
polyvalent ions). 

The combination of Juluca and supplements should 
be used with particular caution.  Calcium 
supplements, iron supplements or multivitamins 
should be co-administered at the same time as 
Juluca with a meal. 
 
If calcium supplements, iron supplements or 
multivitamins cannot be taken at the same time as 
Juluca, these supplements should be taken well 
separated in time from the administration of Juluca 
(minimum 6 hours before or 4 hours after). 

Iron supplements/ 
Dolutegravir1  

Dolutegravir  
   AUC  54%  
   Cmax  57% 
   C24  56% 
(Complex binding to 
polyvalent ions). 

Multivitamin/ 
Dolutegravir1 

Dolutegravir  
   AUC  33%  
   Cmax  35% 
   C24  32% 
(Complex binding to 
polyvalent ions). 

Corticosteroids 
Prednisone/ 
Dolutegravir1 
 
 
 
Prednisone/ 
Rilpivirine 

Dolutegravir  
   AUC  11% 
   Cmax  6% 
   Cτ  17% 
 
Rilpivirine  
(Not studied) 

No dose adjustment is required. 

Dexamethasone/ 
Dolutegravir 
 
Dexamethasone/ 
Rilpivirine 
(systemic, except for 
single dose use) 

Dolutegravir  
(Not studied) 
 
Rilpivirine  
Not studied. Dose dependent 
decreases in rilpivirine 
plasma concentrations are 
expected 
(induction of CYP3A 
enzymes). 

Co-administration may cause significant decreases 
in rilpivirine plasma concentrations. This may 
result in loss of therapeutic effect of Juluca.  
Co-administration of Juluca with systemic 
dexamethasone is contraindicated (except as a 
single dose) see section 4.3.  Alternatives should 
be considered, particularly for long-term use. 

Antidiabetics 
Metformin/ 
Dolutegravir1 
 
 
 
Metformin/ 
Rilpivirine1 

Metformin  
   AUC  79%  
   Cmin NA 
   Cmax  66% 
 
Metformin  
   AUC ↔ 
   Cmin NA 

A dose adjustment of metformin should be 
considered when starting and stopping co-
administration of Juluca with metformin, to 
maintain glycaemic control.  In patients with 
moderate renal impairment a dose adjustment of 
metformin should be considered when co-
administered with dolutegravir, because of the 
increased risk for lactic acidosis in patients with 



 

13 

   Cmax ↔ moderate renal impairment due to increased 
metformin concentration (section 4.4). 

Antimycobacterials 
Rifampicin/ 
Dolutegravir1 
 
 
 
 
 
Rifampicin/ 
Rilpivirine1,2 

Dolutegravir  
   AUC  54% 
   Cmax  43% 
   Cτ 72% 
(induction of UGT1A1 and 
CYP3A enzymes). 
 
Rilpivirine  
   AUC ↓ 80%  
   Cmin ↓ 89%  
   Cmax ↓ 69%  
(induction of CYP3A 
enzymes). 
 
Rifampicin  
   AUC ↔ 
   Cmin NA  
   Cmax ↔ 
25-desacetyl-rifampicin 
   AUC ↓ 9%  
   Cmin NA  
   Cmax ↔ 

Co-administration may cause significant decreases 
in rilpivirine plasma concentrations.  This may 
result in loss of therapeutic effect of Juluca.  
Co-administration of Juluca with rifampicin is 
contraindicated (see section 4.3). 

Rifabutin/ 
Dolutegravir1 
 
 
 
 
 
Rifabutin/ Rilpivirine1 
300 mg once daily2 
 
 
 
 
 
 
 
300 mg once daily  
(+ 25 mg once daily 
rilpivirine) 
 
 
300 mg once daily  
(+ 50 mg once daily 
rilpivirine) 
 
 

Dolutegravir  
   AUC  5% 
   Cmax  16% 
   Cτ  30% 
(induction of UGT1A1 and 
CYP3A enzymes). 
 
Rifabutin  
   AUC ↔  
   Cmin  ↔  
   Cmax  ↔  
25-O-desacetyl-rifabutin 
  AUC ↔  
  Cmin  ↔  
   Cmax  ↔ 
 
Rilpivirine  
   AUC ↓ 42%  
   Cmin ↓ 48%  
   Cmax ↓ 31% 
 
Rilpivirine  
   AUC ↑ 16%*  
   Cmin  ↔*  
   Cmax ↑ 43%*  
 
* compared to 25 mg once 
daily rilpivirine alone  
 

Co-administration is likely to cause significant 
decreases in rilpivirine plasma concentrations 
(induction of CYP3A enzymes).  When Juluca is 
co-administered with rifabutin, an additional 25 
mg tablet of rilpivirine per day should be taken at 
the same time with Juluca, for the duration of the 
rifabutin co-administration (a separate formulation 
of rilpivirine is available for this dose adjustment, 
see section 4.2).   



 

14 

(induction of CYP3A 
enzymes). 

Rifapentine/ 
Dolutegravir 
 
Rifapentine/ 
Rilpivirine 

Dolutegravir ↓ 
(Not studied) 
 
Rilpivirine ↓ 
Not studied. Significant 
decreases in rilpivirine 
plasma concentrations are 
expected. 

Co-administration may cause significant decreases 
in rilpivirine plasma concentrations.  This may 
result in loss of therapeutic effect of Juluca 
(induction of CYP3A enzymes).  
Co-administration of Juluca with rifapentine is 
contraindicated (see section 4.3).  

Antimalarials 
Artemether/ 
Lumefantrine/ 
Dolutegravir 
 
Artemether/ 
Lumefantrine/ 
Rilpivirine 

Dolutegravir  
(Not studied) 
 
 
Rilpivirine ↓ 
Not studied.  Decreased 
exposure of rilpivirine is 
expected  
(induction of CYP3A 
enzymes). 

The combination of Juluca and 
artemether/lumefantrine should be used with 
caution. 

Atovaquone/ 
Proguanil/ 
Dolutegravir 
 
Atovaquone/ 
Proguanil/ 
Rilpivirine 

Dolutegravir  
(Not studied) 
 
 
Rilpivirine ↔ 
(Not studied).   

No dose adjustment is required. 

Macrolide antibiotics 
Clarithromycin  
Erythromycin  
/Dolutegravir 
 
Clarithromycin  
Erythromycin  
/Rilpivirine 

Dolutegravir  
(Not studied) 
 
 
Rilpivirine  
Not studied. Increased 
exposure of rilpivirine is 
expected  
(inhibition of CYP3A 
enzymes). 

Where possible, alternatives such as azithromycin 
should be considered. 

Oral contraceptives 
Ethinyl estradiol (EE)1 
and Norelgestromin 
(NGMN)1 / 
Dolutegravir 
 
 
 
 
 
 
Ethinyl estradiol (EE)1 
and Norethindrone1/ 
Rilpivirine 

Dolutegravir  
EE  
   AUC  3%  
   Cmax  1% 
 
NGMN  
   AUC  2%  
   Cmax  11% 
 
 
Rilpivirine * 
EE  
   AUC  
   Cmin  
   Cmax  17% 

Dolutegravir or rilpivirine did not change ethinyl 
estradiol and norelgestromin (dolutegravir) or 
norethindrone (rilpivirine) plasma concentrations 
to a clinically relevant extent.  No dose adjustment 
of oral contraceptives is required when 
co-administered with Juluca.  



 

15 

 
Norethindrone  
   AUC  
   Cmin  
   Cmax  
 
*based on historic controls. 

Analgesics 
Methadone/ 
Dolutegravir1 
 
 
 
 
Methadone / 
Rilpivirine1 

Dolutegravir  
Methadone  
   AUC  2%  
   Cmax  0% 
   C  1% 
 
Rilpivirine:  
   AUC: ↔*  
   Cmin: ↔* 
   Cmax: ↔*  
 
R(-) methadone:   
   AUC: ↓ 16%  
   Cmin: ↓ 22%  
   Cmax: ↓ 14%  
 
*based on historic controls. 

No dose adjustments are required when initiating 
co-administration of methadone with Juluca. 
However, clinical monitoring is recommended as 
methadone maintenance therapy may need to be 
adjusted in some patients. 

Paracetamol/ 
Dolutegravir 
 
Paracetamol / 
Rilpivirine1,2 

Dolutegravir  
(Not studied) 
 
Rilpivirine  
   AUC ↔ 
   Cmin ↑ 26%  
   Cmax ↔ 
 
Paracetamol 
   AUC ↔ 
   Cmin NA  
   Cmax ↔ 

No dose adjustment is required. 

Anticoagulants 
Dabigatran etexilate/ 
Dolutegravir 
 
Dabigatran etexilate/ 
Rilpivirine 

Dolutegravir  
(Not studied) 
 
Rilpivirine  
Not studied. Dabigatran 
etexilate  
A risk for increases in 
dabigatran plasma 
concentrations cannot be 
excluded 
(inhibition of intestinal P-
gp). 

The combination of Juluca and dabigatran etexilate 
should be used with caution. 

HMG CO-A reductase inhibitors 
Atorvastatin/ 
Dolutegravir 
 

Dolutegravir ↔ 
(Not studied) 
 
Rilpivirine  

No dose adjustment is required. 



 

16 

Atorvastatin/ 
Rilpivirine1,2 

   AUC ↔ 
   Cmin ↔ 
   Cmax ↓ 9% 
 
Atorvastatin 
   AUC ↔ 
   Cmin ↓ 15%  
   Cmax ↑ 35%  

Phosphodiesterase type 5 (PDE-5) inhibitors 
Sildenafil / 
Dolutegravir 
 
Sildenafil/ 
Rilpivirine1,2 

Dolutegravir ↔ 
 
 
Rilpivirine  
   AUC ↔ 
   Cmin ↔ 
   Cmax ↔ 
 
Sildenafil 
   AUC ↔ 
   Cmin NA  
   Cmax ↔ 

No dose adjustment is required. 

Vardenafil 
Tadalafil/ 
Dolutegravir 
 
Vardenafil 
Tadalafil/ 
Rilpivirine 

Dolutegravir ↔ 
(Not studied) 
 
 
Rilpivirine ↔ 
(Not studied) 

No dose adjustment is required. 

1 The interaction between dolutegravir and/or rilpivirine and the medicinal product was evaluated in a 
clinical study.  All other drug-drug interactions shown are predicted.  
2 This interaction study has been performed with a dose higher than the recommended dose for 
rilpivirine assessing the maximal effect on the co-administered drug. 
NA = Not applicable 
 
QT prolonging medicinal products  
 
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine 
and 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 prolong 
the QTc interval of the ECG (see section 5.1).  Juluca should be used with caution when co-administered 
with a medicinal product with a known risk of Torsade de Pointes. 
 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential (WOCBP) should be counselled about the potential risk of neural tube 
defects with dolutegravir (a component of Juluca, see below), including consideration of effective 
contraceptive measures. 
 
If a woman plans pregnancy, the benefits and the risks of continuing treatment with Juluca should be 
discussed with the patient. 
 
Pregnancy 



 

17 

 
Lower exposures of dolutegravir and rilpivirine were observed during pregnancy (see sections 4.2, 4.4, 5.1, 
5.2). The use of Juluca during pregnancy is not recommended. 
 
The safety and efficacy of a dual regimen has not been studied in pregnancy. 
 
There are limited data from the use of rilpivirine in pregnant women.   
 
Human experience from a birth outcome surveillance study in Botswana shows a small increase of neural 
tube defects; 7 cases in 3,591 deliveries (0.19%; 95% CI 0.09%, 0.40%) to mothers taking dolutegravir-
containing regimens at the time of conception compared to 21 cases in 19,361 deliveries (0.11%: 95% CI 
0.07%, 0.17%) to women exposed to non-dolutegravir regimens at the time of conception. 
 
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%). Most neural tube defects occur within the first 4 weeks of embryonic development after 
conception (approximately 6 weeks after the last menstrual period). 
 
Data analysed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth 
defects in over 600 women exposed to dolutegravir during pregnancy but are currently insufficient to address 
the risk of neural tube defects. 
 
In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including 
neural tube defects, were identified (see section 5.3). Dolutegravir was shown to cross the placenta in 
animals. 
 
More than 1000 outcomes from exposure to dolutegravir during second and third trimester pregnancy 
indicate no evidence of increased risk of foeto/neonatal toxicity.  
 
Animal studies with rilpivirine do not indicate direct or indirect harmful effects with respect to reproductive 
toxicity (see section 5.3).      
 
Breast-feeding 
 
It is unknown whether dolutegravir or rilpivirine are excreted in human milk.  Available toxicological data in 
animals has shown excretion of dolutegravir and rilpivirine in milk.  In lactating rats that received a single 
oral dose of dolutegravir 50 mg/kg at 10 days postpartum, dolutegravir was detected in milk at 
concentrations typically higher than blood.  It is recommended that HIV infected women do not breast-feed 
their infants under any circumstances in order to avoid transmission of HIV. 
 
Fertility 
 
There are no data on the effects of dolutegravir or rilpivirine on human male or female fertility.  Animal 
studies indicate no clinically relevant effects on male or female fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Patients should be informed that 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 when considering the patient's ability to drive or operate machinery.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 



 

18 

Clinical safety data with Juluca is limited.  The most frequently reported adverse reactions considered 
possibly or probably related to the combined administration of dolutegravir plus rilpivirine in 513 HIV-1 
infected subjects in the Phase III clinical trials (see section 5.1), were diarrhoea (2%) and headache (2%). 
 
The most severe adverse reaction, possibly related to the treatment with dolutegravir (from pooled from 
Phase IIb and Phase III clinical studies), seen in an individual patient, was a hypersensitivity reaction that 
included rash and severe liver effects (see section 4.4). 
 
Tabulated list of adverse reactions 
 
The adverse reactions considered at least possibly related to treatment with the components of Juluca from 
clinical studies and post-marketing experience are listed in Table 2 by body system, organ class and 
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), not known (cannot be estimated 
from the available data). 
 
Table 2: Tabulated summary of adverse reactions to Juluca based on clinical study and post-
marketing experience with Juluca and its individual components 
 

System Organ Class 
(SOC) 

Frequency 
category* 

Adverse drug reactions 

Blood and lymphatic 
systems disorders: 

common decreased white blood cell count  
 
decreased haemoglobin  
 
decreased platelet count 

Immune system 
disorders 

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

Metabolism and 
nutrition disorders 

very common increased total cholesterol (fasted)  
 
increased LDL cholesterol (fasted) 

common decreased appetite  
 
increased triglycerides (fasted) 

Psychiatric disorders very common insomnia 
common abnormal dreams  

 
depression  
 
sleep disorders  
 
depressed mood 
 
anxiety 

uncommon suicidal ideation or suicide attempt (particularly in 
patients with a pre-existing history of depression or 
psychiatric illness) 

Nervous system 
disorders 

very common headache  
 
dizziness 

common somnolence 



 

19 

Gastrointestinal 
disorders 

very common nausea  
 
increased pancreatic amylase 
 
diarrhoea 

common abdominal pain  
 
vomiting  
 
flatulence 
 
increased lipase  
 
abdominal discomfort  
 
upper abdominal pain 
 
dry mouth 

Hepatobiliary 
disorders 

very common increased transaminases 
(alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) elevations) 

common increased bilirubin 
uncommon hepatitis 
rare acute hepatic failure** 

Skin and subcutaneous 
tissue disorders 

common rash 
 
pruritus 

Musculoskeletal and 
connective tissue 
disorders 

uncommon arthralgia 
 
myalgia 

General disorders and 
administration site 
conditions 

common fatigue 

Investigations common creatine phosphokinase (CPK) elevations 
* 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 dolutegravir 
in combination with other ARVs. The frequency category of rare was estimated based on post-
marketing reports. 

 
 
Description of selected adverse reactions 
 
Changes in laboratory biochemistries 
 
Dolutegravir or rilpivirine have been associated with increases in serum creatinine occuring in the first week 
of treatment when administered with other antiretroviral medicinal products.  Increases in serum creatinine 
occurred within the first four weeks of treatment with Juluca and remained stable through 48 weeks.  A mean 
change from baseline of 8.22 mol/L (range -26.5 to 51.2 mol/L) was observed after 48 weeks treatment.  
These changes are related to inhibition of active transport, and are not considered to be clinically relevant as 
they do not reflect a change in glomerular filtration rate. 
 
Reporting of suspected adverse reactions 
 



 

20 

Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It allows 
continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
No specific symptoms or signs have been identified following acute overdose with dolutegravir or rilpivirine 
apart 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 Juluca.  If overdose occurs, the patient 
should be treated supportively with appropriate monitoring, including monitoring of vital signs and 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, 
combinations.  ATC code: J05AR21 
 
Mechanism of action 
 
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer 
step 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. 
 
Pharmacodynamic effects 
 
Antiviral activity in cell culture  
The IC50 for dolutegravir against various laboratory strains using PBMC was 0.5 nM, and when using MT-4 
cells it ranged from 0.7-2 nM.  Similar IC50s were seen for clinical isolates without any major difference 
between 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 line 
with a median IC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL).  Rilpivirine demonstrated limited in vitro 
activity 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-acid 
glycoprotein, 45 mg/mL human serum albumin, and 50% human serum as demonstrated by median IC50 
rates of 1.8, 39.2 and 18.5, respectively. 



 

21 

 
Resistance 
 
Resistance in vitro  
Serial passage is used to study resistance evolution in vitro.  For dolutegravir, when using the laboratory 
strain HIV-1 IIIB during passage over 112 days, mutations selected appeared slowly, with substitutions at 
positions S153Y and F; these mutations were not selected in patients treated with dolutegravir in the clinical 
studies.  Using strain NL432, integrase mutations E92Q (fold change [FC] 3) and G193E (FC 3) were 
selected.  These mutations have been selected in patients with pre-existing raltegravir resistance and who 
were 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 five 
isolates (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 individual 
patients with subtype B and subtype C in the Phase III clinical program for ART experienced, INI naive 
subjects, but without effects on dolutegravir susceptibility in vitro.  G118R lowers the susceptibility to 
dolutegravir 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 affect 
the in vitro susceptibility of dolutegravir as single mutations.  When mutations listed as secondary integrase 
inhibitor 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 wildtype 
level. In the case of the Q148-mutation viruses, increasing dolutegravir FC is seen as the number of 
secondary mutations increase.  The effect of the Q148-based mutations (H/R/K) was also consistent with in 
vitro passage experiments with site directed mutants.  In serial passage with strain NL432-based site directed 
mutants at N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1).  In 
contrast, starting passage with mutants with mutation Q148H (FC 1), a variety of raltegravir associated 
secondary 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; genotypic 
resistance was a better predictor for outcome. 
 
Rilpivirine-resistant strains were selected in cell culture starting from wild type HIV-1 of different origins 
and clades as well as NNRTI-resistant HIV-1.  The most commonly observed amino acid substitutions that 
emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I.  Resistance 
to rilpivirine was considered present when FC in EC50 value was above the biological cut-off (BCO) of the 
assay. 
 
Resistance in vivo  
Two subjects across the pooled SWORD-1 (201636) and SWORD-2 (201637) studies from each treatment 
arm experienced confirmed virologic failure leading to withdrawal at any time through Week 48.  NNRTI 
resistance associated substitution K101K/E mixture with no decreased susceptibility to rilpivirine (FC=1.2) 
was observed in one subject with identified adherence issues that received dolutegravir plus rilpivirine.  No 
integrase resistance was observed.  This patient’s viral load was 1,059,771 copies/mL at the suspected 
virologic withdrawal visit and was <50 copies/mL at the withdrawal visit.  No treatment emergent resistance-
associated substitutions were observed for the other three subjects who experienced confirmed virologic 
failure. 
 
In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development 
of 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 inhibitor 
substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was 
given in combination with an investigator selected background regimen (BR).  Of these four, two subjects 
had a unique R263K integrase substitution, with a maximum FC of 1.93, one subject had a polymorphic 



 

22 

V151V/I integrase substitution, with maximum FC of 0.92, and one subject had pre-existing integrase 
mutations and is assumed to have been integrase inhibitor experienced or infected with integrase inhibitor 
resistant virus by transmission.  The R263K mutation was also selected in vitro (see above). 
 
From rilpivirine Phase III trials, in the week 48 pooled resistance analysis conducted with previously 
untreated patients, 62 (of a total of 72) virologic failures in the rilpivirine arm had resistance data at baseline 
and time of failure.  In this analysis, the resistance-associated mutations (RAMs) associated with NNRTI 
resistance that developed in at least 2 rilpivirine virologic failures were: V90I, K101E, E138K, E138Q, 
V179I, Y181C, V189I, H221Y, and F227C.  In the trials, the presence of the mutations V90I and V189I, at 
baseline, did not affect response.  The E138K substitution emerged most frequently during rilpivirine 
treatment, commonly in combination with the M184I substitution.  In the week 48 analysis, 31 out of 62 of 
rilpivirine virologic failures had concomitant NNRTI and NRTI RAMs; 17 of those 31 had the combination 
of 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 in 
the rilpivirine and efavirenz arm, respectively.   
 
Cross-resistance 
 
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 positions 
associated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine 
showed antiviral activity (FC≤BCO) against 64 (96%) of these strains.  The single amino acid substitutions 
associated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V.  The K103N 
substitution 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, when 
present 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 for 
susceptibility 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 isolates 
resistant 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 and 
resistance to rilpivirine (n = 5), subjects had cross-resistance to efavirenz (n = 3), etravirine (n = 4), and 
nevirapine (n = 1). 
 
Effects on electrocardiogram 
 
The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in 
a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy 
adults, with 13 measurements over 24 hours at steady-state.  Rilpivirine at the recommended dose of 25 mg 
once daily is not associated with a clinically relevant effect on QTc. 



 

23 

 
When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine were studied in 
healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF 
interval 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 Cmax 
approximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state Cmax observed with the 
recommended 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 dose 
by approximately three fold.  
 
Clinical efficacy and safety  
 
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 2 
identical 48-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 antiretroviral 
regimen with no history of virological failure, had no suspected or known resistance to any antiretroviral and 
had been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening.  Subjects 
were randomised 1:1 to continue their CAR or be switched to a two-drug regimen dolutegravir plus 
rilpivirine administered once daily.  The primary efficacy endpoint for the SWORD studies was the 
proportion 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 age 
of 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 were 
receiving an NNRTI, PI, or INI (respectively) as their baseline third treatment agent class prior to 
randomisation.   
 
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 48 
based on the Snapshot algorithm (Table 3). 
 
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 3. 
 
Table 3: Virologic Outcomes of Randomized Treatment at Week 48 (Snapshot algorithm) 
 

 SWORD-1 and SWORD-2 Pooled 
Data*** 

DTG + RPV 
N=513 
n (%) 

CAR 
N=511 
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 <50 
copies/mL 1 (<1%)  1 (<1%)  

Change in ART 0 1 (<1%)  
No virologic data at Week 48 window 24 (5%) 20 (4%)  
Reasons   



 

24 

Discontinued study/study drug due to adverse 
event or death  17 (3%) 3 (<1%)  

Discontinued study/study drug 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 covariates 
 n/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%) 
Gender   
 Male  375 / 393 (95%) 387 / 403 (96%) 
 Female  111 / 120 (93%) 98 / 108 (91%) 
Race    
 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 margin 
of - 8%. 
** Non-inferiority of dolutegravir plus rilpivirine to CAR, in the proportion of subjects 
classified 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 which 
differences in proportions meeting the primary endpoint of <50 copies/mL plasma HIV-1 RNA 
at 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 

 
Effects on bone 
In a DEXA substudy mean bone mineral density (BMD) increased from Baseline to Week 48 in subjects 
who switched to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with those 
who 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. 
 
Pregnancy 
 
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 trial of 19 pregnant women 
during the second and third trimesters, and postpartum.  The pharmacokinetic data demonstrate that total 
exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30% lower during 
pregnancy compared with postpartum (6-12 weeks).  Of the 12 subjects that completed the study, 10 subjects 
were suppressed at the end of the study; in the other 2 subjects an increase in viral load was observed 
postpartum, for 1 subject due to suspected suboptimal adherence.  No mother to child transmission occurred 
in all 10 infants born to the mothers who completed the trial and for whom the HIV status was available.  
There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected 
adults. 
 



 

25 

In limited data from small numbers of women who received dolutegravir 50 mg once daily in combination 
with a background regimen, the total exposure (AUC) to dolutegravir was 37% lower during the 2nd 
trimester 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 were 
indeterminate due to incomplete testing, see sections 4.2, 4.4 and 5.2. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with Juluca in 
one or more subsets of the paediatric population in the treatment of HIV infection. 
 
5.2 Pharmacokinetic properties 
 
Juluca is bioequivalent to a dolutegravir 50 mg tablet and a rilpivirine 25 mg tablet administered together 
with a meal. 
 
Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects.  The PK variability of 
dolutegravir 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 of 
dolutegravir was higher in HIV-infected subjects than healthy subjects.  Within-subject variability (CVw%) 
is lower than between-subject variability. 
 
The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult 
antiretroviral treatment-naïve HIV-1 infected patients.  Systemic exposure to rilpivirine was generally lower 
in HIV-1 infected patients than in healthy subjects. 
 
Absorption  
 
Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for 
tablet formulation.  After oral administration, the maximum plasma concentration of rilpivirine is generally 
achieved within 4-5 hours.   
 
Juluca must be taken with a meal to obtain optimal absorption of rilpivirine (see section 4.2).  When Juluca 
was taken with a meal, the absorption of both dolutegravir and rilpivirine was increased.  Moderate and high 
fat 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 high 
fat meals respectively, compared to fasted conditions.  Taking Juluca in fasted condition or with only a 
protein-rich nutritional drink may result in decreased plasma concentrations of rilpivirine, which could 
potentially reduce the therapeutic effect of Juluca.  
 
The absolute bioavailability of dolutegravir or rilpivirine has not been established.   
 
Distribution  
 
Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data.  The apparent volume 
of 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 and 
plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal 
association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma 
is 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 dolutegravir 
plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to 
unbound plasma concentration, and above the IC50).   
 



 

26 

Dolutegravir is present in the female and male genital tract.  AUC in cervicovaginal fluid, cervical tissue and 
vaginal 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 distribution 
of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not 
been evaluated in humans. 
 
Biotransformation 
 
Dolutegravir is primarily metabolized through glucuronidation via UGT1A1 with a minor CYP3A 
component.  Dolutegravir is the predominant circulating compound in plasma; renal elimination of 
unchanged active substance is low (< 1% of the dose).  Fifty-three percent of total oral dose is excreted 
unchanged in the faeces.  It is unknown if all or part of this is due to unabsorbed active substance or biliary 
excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the 
gut lumen.  Thirty-two percent of the total oral dose is excreted in the urine, mainly represented by ether 
glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a 
metabolite 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. 
 
Drug interactions 
 
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 diphosphate 
glucuronosyl 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 medicinal 
products 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. 
 
Elimination  
 
Dolutegravir has a terminal half-life of ~14 hours.  The apparent oral clearance (CL/F) is approximately 
1L/hr in HIV-infected patients based on a population pharmacokinetic analysis. 
 
The terminal elimination half-life of rilpivirine is approximately 45 hours.  After single dose oral 
administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in faeces 
and urine, respectively.  In faeces, unchanged rilpivirine accounted for on average 25% of the administered 
dose.  Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine. 
 
Special patient populations 
 
Children 
Neither Juluca nor the combination dolutegravir and rilpivirine as single entities have been studied in 
children.  Dosing recommendations for paediatric patients cannot be made due to insufficient data (see 
section 4.2). 
 
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 dosage 
resulted in dolutegravir exposure comparable to that observed in adults who received dolutegravir 50 mg 
orally once daily.  The pharmacokinetics was evaluated in 11 children 6 to 12 years of age and showed that 
25 mg once daily in patients weighing at least 20 kg and 35 mg once daily in patients weighing at least 30 kg 
resulted in dolutegravir exposure comparable to adults.   



 

27 

 
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 on 
rilpivirine pharmacokinetics in paediatric subjects in study C213 (33 to 93 kg), similar to what was observed 
in adults.  
 
Elderly 
Population pharmacokinetic analysis using data in HIV-1 infected adults showed that there was no clinically 
relevant effect of age on dolutegravir or rilpivirine exposures.  Pharmacokinetic data in subjects >65 years 
old are very limited. 
 
Renal impairment 
Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir.  A study 
of 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 approximately 
40% in subjects with severe renal impairment.  The mechanism for the decrease is unknown.  The 
pharmacokinetics 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 or 
moderate renal impairment.  In patients with severe renal impairment or end-stage renal disease, Juluca 
should be used with caution, as rilpivirine plasma concentrations may be increased due to alteration of drug 
absorption, distribution and/or metabolism secondary to renal dysfunction.  In patients with severe renal 
impairment or end-stage renal disease, the combination of Juluca with a strong CYP3A inhibitor should only 
be used if the benefit outweighs the risk.  Juluca has not been studied in patients on dialysis.  As dolutegravir 
and rilpivirine are highly bound to plasma proteins, it is unlikely that they will be significantly removed by 
haemodialysis or peritoneal dialysis (see section 4.2). 
 
Hepatic impairment 
Dolutegravir and rilpivirine are both primarily metabolized and eliminated by the liver.  A single dose of 
50 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 hepatic 
impairment compared to healthy controls.  
 
In a rilpivirine study comparing 8 patients with mild hepatic impairment (Child-Pugh score A) to 8 matched 
controls, and 8 patients with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the 
multiple 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 the 
pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate hepatic 
impairment. 
 
No dosage adjustment is considered necessary for patients with mild to moderate hepatic impairment (Child-
Pugh score A or B).  Juluca should be used with caution in patients with moderate hepatic impairment.  The 
effect of severe hepatic impairment (Child-Pugh score C) on the pharmacokinetics of dolutegravir or 
rilpivirine has not been studied, therefore Juluca is not recommended in these patients. 
 
Gender 
Population pharmacokinetic analyses from studies with the individual components revealed that gender had 
no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine.   
 
Race  
No clinically important pharmacokinetic differences of dolutegravir or rilpivirine due to race have been 
identified.  
 
Co-infection with Hepatitis B or C  



 

28 

Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant 
effect on the exposure to dolutegravir or rilpivirine.  Subjects with hepatitis B co-infection or hepatitis C 
infection in need of anti-HCV therapy were excluded from studies with the dual combination of dolutegravir 
and rilpivirine. 
 
Pregnancy and postpartum 
No pharmacokinetic data are available for the combination of dolutegravir and rilpivirine in pregnancy.   In 
limited data from small numbers of women in study IMPAACT P1026 who received dolutegravir 50 mg 
once 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 the 
3rd trimester of pregnancy, Cmax, AUC24h and Cmin values were, respectively, 25%, 29% and 34% lower as 
compared to postpartum (see sections 4.2, 4.4. and 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 sections 4.2, 4.4. and 4.6). 
 
 
5.3 Preclinical safety data 
 
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.  Dolutegravir was not carcinogenic in long term studies in the 
mouse and rat. 
 
Rilpivirine has tested negative in the absence and presence of a metabolic activation system in the in vitro 
Ames reverse mutation assay and the in vitro clastogenicity mouse lymphoma assay.  Rilpivirine did not 
induce chromosomal damage in the in vivo micronucleus test in mice.  Carcinogenicity studies with 
rilpivirine in mice and rats revealed tumorigenic potential specific for these species, but are regarded as of no 
relevance for humans.  
 
Reproductive toxicology studies 
 
Dolutegravir did not affect male or female fertility in rats at doses up to 1000 mg/kg/day, the highest dose 
tested (33 times the 50 mg human clinical exposure based on AUC).   
 
Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 of 
gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (38 times the 50 mg human 
clinical exposure based on AUC). 
 
Oral administration of dolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to 18 of 
gestation did not elicit developmental toxicity or teratogenicity (0.56 times the 50 mg human clinical 
exposure based on AUC).  In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, 
suppressed body weight gain) was observed at 1000 mg/kg (0.56 times the 50 mg human clinical exposure 
based on AUC).   
 
Rilpivirine studies in animals have shown no evidence of relevant embryonic or foetal toxicity or an effect 
on reproductive function.  There was no teratogenicity with rilpivirine in rats and rabbits.  The exposures at 
the embryo-foetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 15 
and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. 
 
Repeated dose toxicity 
 



 

29 

The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oral 
dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks).  The primary effect of 
dolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemic 
exposures approximately 30 and 1.2 times the 50 mg human clinical exposure based on AUC, respectively.  
Because gastrointestinal (GI) intolerance is considered to be due to local active substance administration, 
mg/kg or mg/m2 metrics are appropriate determinates of safety cover for this toxicity.  GI intolerance in 
monkeys occurred at 30 times the human mg/kg equivalent dose (based on a 50 kg human), and 11 times the 
human mg/m2 equivalent dose for a clinical dose of 50 mg.   
 
Liver toxicity associated with liver enzyme induction was observed in rodents following rilpivirine 
administration.  In dogs, cholestasis-like effects were noted. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
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  
 
Tablet coating 
 
Polyvinyl alcohol- part hydrolysed 
Titanium dioxide (E171) 
Macrogol 
Talc 
Iron oxide yellow (E172) 
Iron oxide red (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years.  
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed.  Do not 
remove the desiccant.  
 
This medicinal product does not require any special temperature storage conditions.   
 
6.5 Nature and contents of container  



 

30 

 
White HDPE (high density polyethylene) bottles closed with polypropylene child-resistant closures, with a 
polyethylene faced induction heat seal liner.  Each pack consists of one bottle containing 30 film-coated 
tablets and a desiccant.  
 
Multipacks containing 90 (3 packs of 30) film-coated tablets.  Each pack of 30 film-coated tablets contains a 
desiccant. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements for disposal. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1282/001 
EU/1/18/1282/002 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 May 2018 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



 

31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
 USE OF THE MEDICINAL PRODUCT 

 



 

32 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Glaxo Wellcome, S.A.  
Avda. Extremadura, 3 
09400 Aranda De Duero 
Burgos 
Spain 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
 Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set out in 
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation.  

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
USE OF THE MEDICINAL PRODUCT 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed 
RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the 
RMP. 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached.  

  



 

33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 

  



 

34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A. LABELLING 

  



 

35 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (INDIVIDUAL PACKS ONLY) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Juluca 50 mg/25 mg film-coated tablets 
dolutegravir/rilpivirine  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir and rilpivirine 
hydrochloride equivalent to 25 mg rilpivirine. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate.  
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed.  Do not 
remove the desiccant. 
 



 

36 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1282/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
juluca  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 
 



 

37 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (MULTIPACKS ONLY – WITH BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Juluca 50 mg/25 mg film-coated tablets 
dolutegravir/rilpivirine  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir and rilpivirine 
hydrochloride equivalent to 25 mg rilpivirine. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate.  
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 90 (3 packs of 30) tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed.  Do not 
remove the desiccant. 
 



 

38 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1282/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
juluca 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN:  
 
 
  



 

39 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INTERMEDIATE CARTON (WITHOUT BLUE BOX – COMPONENT OF MULTIPACK) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Juluca 50 mg/25 mg film-coated tablets 
dolutegravir/rilpivirine  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir and rilpivirine 
hydrochloride equivalent to 25 mg rilpivirine. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate.  
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets. Component of a multipack, can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed.  Do not 
remove the desiccant. 
 



 

40 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1282/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
juluca 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



 

41 

 
 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Juluca 50 mg/25 mg film-coated tablets 
dolutegravir/rilpivirine  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir and rilpivirine 
hydrochloride equivalent to 25 mg rilpivirine. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate.  
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed.  Do not 
remove the desiccant. 
 



 

42 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1282/001 
EU/1/18/1282/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



 

43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
B. PACKAGE LEAFLET 



 

44 

Package leaflet: Information for the patient 
 

Juluca 50 mg/25 mg film-coated tablets 
dolutegravir/rilpivirine 

 
This medicine is subject to additional monitoring.  This will allow quick identification of new safety 

information. You can help by reporting any side effects you may get.  See the end of section 4 for how to 
report side effects.  
 
Read all of this leaflet carefully before you start taking this medicine because it contains important 

information for you. 
- Keep this leaflet.  You may need to read it again.  
- If you have any further questions, ask your doctor, or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, or pharmacist.  This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What Juluca is and what it is used for  
2. What you need to know before you take Juluca  
3. How to take Juluca 
4. Possible side effects  
5. How to store Juluca  
6. Contents of the pack and other information 
 
 
1. What Juluca is and what it is used for 
 
Juluca is a medicine that contains two active ingredients used to treat human immunodeficiency virus (HIV) 
infection: dolutegravir and rilpivirine.  Dolutegravir belongs to a group of anti-retroviral medicines called 
integrase inhibitors (INIs), and rilpivirine belongs to a group of anti-retroviral medicines called non-
nucleoside reverse transcriptase inhibitors (NNRTIs). 
 
Juluca is used to treat HIV in adults aged 18 years and over who are taking other antiretroviral medicines and 
whose HIV-1 infection is under control for at least 6 months.  Juluca may replace your current antiretroviral 
medicines. 
 
Juluca keeps the amount of HIV virus in your body at a low level.  This helps maintain the number of CD4 
cells in your blood.  CD4 cells are a type of white blood cells that are important in helping your body to fight 
infection. 
 
 
2. What you need to know before you take Juluca 
 
Do not take Juluca: 
- if you are allergic to dolutegravir or rilpivirine or any of the other ingredients of this medicine (listed 

in section 6). 
 
Do not take Juluca if you are taking any of the following medicines as they may affect the way Juluca 

works: 
- fampridine (also known as dalfampridine; used in multiple sclerosis)  
- carbamazepine, oxcarbazepine, phenobarbital, phenytoin (medicines to treat epilepsy and to prevent 

fits) 
- rifampicin, rifapentine (medicines to treat some bacterial infections such as tuberculosis) 



 

45 

- omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, (medicines to prevent and treat 
stomach ulcers, heartburn or acid reflux disease) 

- dexamethasone (a corticosteroid used in many conditions such as inflammation and allergic reactions) 
when taken by mouth or injected, except as a single dose treatment 

- products that contain St John’s wort (Hypericum perforatum) (a herbal product used for depression). 
 
If you are taking any of the above, ask your doctor about alternatives. 
 
Warnings and precautions  
Talk to your doctor or, pharmacist before taking Juluca. 
 
Allergic reactions 
Juluca contains dolutegravir.  Dolutegravir can cause a serious allergic reaction known as a hypersensitivity 
reaction.  You need to know about important signs and symptoms to look out for while you’re taking Juluca. 

 Read the information ‘Allergic reactions’ in section 4 of this leaflet. 
 
Liver problems including hepatitis B and/or C 
Tell your doctor if you have or have had problems with your liver, including hepatitis B and/or C.  Your 
doctor may evaluate how severe your liver disease is before deciding if you can take Juluca.  
 
Look out for important symptoms 
Some people taking medicines for HIV infection develop other conditions, which can be serious.  These 
include: 

 symptoms of infections and inflammation 
 joint pain, stiffness and bone problems. 

You need to know about important signs and symptoms to look out for while you’re taking Juluca. 
 Read the information ‘Other possible side effects’ in section 4 of this leaflet. 
 

Protect other people 
HIV infection is spread by sexual contact with someone who has the infection, or by transfer of infected 
blood (for example, by sharing injection needles).  You can still pass on HIV when taking this medicine, 
although the risk is lowered by effective antiretroviral therapy.  Discuss with your doctor the precautions 
needed to avoid infecting other people. 
 
Children and adolescents 
 
This medicine is not for use in children or adolescents less than 18 years of age, because it has not been 
studied in these patients. 
 
Other medicines and Juluca 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
Juluca must not be taken with some other medicines (see ‘Do not take Juluca’ earlier in section 2). 
 
Some medicines can affect how Juluca works, or make it more likely that you will have side effects.  Juluca 
can also affect how some other medicines work. 
Tell your doctor if you are taking any of the medicines in the following list:  

 metformin, to treat diabetes 
 medicines that may cause a life threatening irregular heartbeat (Torsade de Pointes).  As a number of 

different medicines can cause this condition, you should ask your doctor or pharmacist if you are not 
sure 

 medicines called antacids, to treat indigestion and heartburn.  Do not take an antacid during the 
6 hours before you take Juluca, or for at least 4 hours after you take it (see also section 3, ‘How to 
take Juluca’) 



 

46 

 calcium supplements, iron supplements and multivitamins must be taken at the same time as 
Juluca with a meal.  If you can’t take these supplements at the same time as Juluca, do not take a 
calcium supplement, iron supplement or multivitamin during the 6 hours before you take Juluca, 
or for at least 4 hours after you take it (see also section 3, ‘How to take Juluca’) 

 medicines called H2 receptor antagonists (for example cimetidine, famotidine, nizatidine, 
ranitidine) to treat stomach or intestinal ulcers or used to relieve heartburn due to acid reflux.  Do 
not take these medicines during the 12 hours before you take Juluca, or for at least 4 hours after you 
take it (see also section 3, ‘How to take Juluca’) 

 any medicines to treat HIV infection 
 rifabutin, to treat tuberculosis (TB) and other bacterial infections. If you take rifabutin, your doctor 

may need to give you an additional dose of rilpivirine to treat your HIV infection (see section 3, 
‘How to take Juluca’) 

 artemether/lumefantrine used to prevent you catching malaria 
 clarithromycin and erythromycin, to treat bacterial infections 
 methadone, used in the treatment of opioid dependence 
 dabigatran etexilate, used to treat or prevent blood clots. 

 

  Tell your doctor or pharmacist if you are taking any of these.  Your doctor may decide that you 
need extra check ups.

 
 
Pregnancy  
If you are pregnant, think you may be pregnant, or if you are planning to have a baby: 
  Use of Juluca is not recommended. Ask your doctor for advice.  
 
Taking Juluca at the time of becoming pregnant or during the first six weeks of pregnancy, may also increase 
the risk of a type of birth defect, called neural tube defect, such as spina bifida (malformed spinal cord). 
 
If you could get pregnant while receiving Juluca: 
  Talk to your doctor and discuss whether there is a need for contraception, such as condom or pills. 
 
Tell your doctor immediately if you become pregnant or are planning to become pregnant. Your doctor will 
review your treatment. Do not stop taking Juluca without consulting your doctor, as this may harm you and 
your unborn child. 
 
Breast-feeding  
Women who are HIV-positive must not breast feed because HIV infection can be passed on to the baby in 
breast milk.  
 
It is not known whether the ingredients of Juluca can pass into your breast milk. 
 
If you are breast-feeding, or thinking about breast-feeding: 
  Talk to your doctor immediately.  
 
Driving and using machines 
Juluca can make you dizzy, tired or drowsy and have other side effects that make you less alert. 
  Don’t drive or operate machinery unless you are sure you’re not affected.  
 
Juluca contains lactose 
If you have been told by your doctor that you have intolerance to some sugars, speak with your doctor before 
taking this medicine. 
 
3. How to take Juluca 
 



 

47 

Always take this medicine exactly as your doctor  has told you.  Check with your doctor or pharmacist if you 
are not sure. 
 

 The recommended dose of Juluca is one tablet once a day.  Juluca must be taken with a meal. A 
meal is important to get the right levels of medicine in your body.  A protein-rich nutritional drink 
alone does not replace a meal. 

 Do not chew, crush or split the tablet, to ensure the full dose is taken. 
 
Rifabutin 
Rifabutin, a medicine to treat some bacterial infections, can lower the amount of Juluca in your body and 
make it less effective. 
If you take rifabutin, your doctor may need to give you an additional dose of rilpivirine.  Take the rilpivirine 
tablet at the same time you take Juluca.  

 Talk to your doctor for further advice on taking rifabutin with Juluca.  
 
Antacid medicines 
Antacids, to treat indigestion and heartburn, can stop Juluca being absorbed into your body and make it less 
effective. 
Do not take an antacid during the 6 hours before you take Juluca, or for at least 4 hours after you take it.   
  Talk to your doctor for further advice on taking acid-lowering medicines with Juluca. 
 
Calcium supplements, iron supplements or multivitamins 
Calcium supplements, iron supplements or multivitamins can stop Juluca being absorbed into your body and 
make it less effective. 
Calcium supplements, iron supplements or multivitamins must be taken at the same time as Juluca.  Juluca 
must be taken with a meal. 
If you can’t take these supplements at the same time as Juluca, do not take calcium supplements, iron 
supplements or multivitamins during the 6 hours before you take Juluca, or for at least 4 hours after you take 
it. 
  Talk to your doctor for further advice on taking calcium supplements, iron supplements or 
multivitamins with Juluca. 
 
H2 receptor antagonists (for example cimetidine, famotidine, nizatidine, ranitidine)  
H2 receptor antagonist medicines can stop Juluca being absorbed into your body and make it less effective. 
Do not take these medicines during the 12 hours before you take Juluca, or for at least 4 hours after you take 
it.   
  Talk to your doctor for further advice on taking these medicines with Juluca. 
 
If you take more Juluca than you should 
If you take too many tablets of Juluca contact your doctor or pharmacist immediately.  If possible, show 
them the Juluca pack. 
 
If you forget to take Juluca 
If you notice within 12 hours of the time you usually take Juluca, you must take the tablet as soon as 
possible.  The Juluca tablet must be taken with a meal.  Then take the next dose as usual.  If you notice after 
12 hours, then skip that dose and take the next doses as usual. 
 Do not take a double dose to make up for a forgotten dose. 
 
If you vomit less than 4 hours after taking Juluca, take another tablet with a meal.  If you vomit more than 4 
hours after taking Juluca you do not need to take another tablet until your next scheduled dose. 
 
Don’t stop taking Juluca without advice from your doctor 
Take Juluca for as long as your doctor recommends.  Don’t stop unless your doctor tells you to.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
4. Possible side effects 



 

48 

 
Like all medicines, this medicine can cause side effects, although not everybody gets them, so it is very 
important to talk to your doctor about any changes in your health. 
 
Allergic reactions 
Juluca contains dolutegravir.  Dolutegravir can cause a serious allergic reaction known as a hypersensitivity 
reaction.  This is an uncommon (may affect up to 1 in 100 people) reaction in people taking dolutegravir.  If 
you get any of the following symptoms: 

 skin rash 
 a high temperature (fever) 
 lack of energy (fatigue) 
 swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing 
 muscle or joint aches 
 See a doctor straight away.  Your doctor may decide to carry out tests to check your liver, kidneys 
or blood, and may tell you to stop taking Juluca. 

 
Very common side effects  
These may affect more than 1 in 10 people: 

 headache 
 dizziness 
 diarrhoea 
 feeling sick (nausea)  
 difficulty in sleeping (insomnia). 

 
Very common side effects that may show up in blood tests are: 

 increase in the level of liver enzymes (aminotransferases) 
 increase in cholesterol 
 increase in pancreatic amylase (a digestive enzyme). 

 
Common side effects  
These may affect up to 1 in 10 people: 

 loss of appetite 
 rash 
 itching (pruritus) 
 being sick (vomiting) 
 stomach (abdominal) pain or discomfort 
 wind (flatulence) 
 feeling drowsy 
 sleep disorders 
 abnormal dreams 
 lack of energy (fatigue) 
 depression (feelings of deep sadness and unworthiness) 
 depressed mood 
 anxiety 
 dry mouth. 

 
Common side effects that may show up in blood tests are: 

 increase in the level of enzymes produced in the muscles (creatine phosphokinase). 
 decreased number of platelets, which are involved in blood clotting 
 low white blood cell count 
 decrease in haemoglobin  
 increase in triglycerides (a type of fat) 
 increase in lipase (an enzyme involved in breaking down fats)  
 increase in bilirubin (a test of liver function) in your blood. 

 



 

49 

Uncommon side effects  
These may affect up to 1 in 100 people: 

 allergic (hypersensitivity) reaction (see ‘allergic reactions’ earlier in this section) 
 inflammation of the liver (hepatitis)  
 suicidal thoughts and behaviours (particularly in patients who have had depression or mental health 

problems before) 
 joint pain 
 muscle pain. 

 
Rare side effects  
These may affect up to 1 in 1000 people: 

 liver failure (signs may include yellowing of the skin and the whites of the eyes or unusually dark 
urine). 

 
Not known  
Frequency cannot be estimated from the available data: 

 signs or symptoms of inflammation or infection, for example fever, chills, sweats (immune 
reactivation syndrome). 

 

 
Other possible side effects 

People taking combination therapy for HIV may get other side effects. 

Symptoms of infection and inflammation  

 
People with advanced HIV infection (AIDS) have weak immune systems, and are more likely to develop 
serious infections (opportunistic infections).  Symptoms of infection may develop, caused by old, hidden 
infections flaring up again as the body fights them.  Symptoms usually include fever, plus some of the 
following: 

 headache 
 stomach ache 
 difficulty breathing. 

In rare cases, as the immune system becomes stronger, it can also attack healthy body tissue (autoimmune 
disorders). The symptoms of autoimmune disorders may develop many months after you start taking 
medicine to treat your HIV infection. Symptoms may include: 

 palpitations (rapid or irregular heartbeat) or tremor 
 hyperactivity (excessive restlessness and movement) 
 weakness beginning in the hands and feet and moving up towards the trunk of the body. 

 
If you get any symptoms of infection or if you notice any of the symptoms above: 
  Tell your doctor immediately. Don’t take other medicines for the infection without your doctor’s 
advice. 
 
Joint pain, stiffness and bone problems 
 
Some people taking combination therapy for HIV develop a condition called osteonecrosis. With this 
condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be more 
likely to get this condition: 

 if they have been taking combination therapy for a long time 
 if they are also taking anti-inflammatory medicines called corticosteroids 
 if they drink alcohol 
 if their immune systems are very weak 
 if they are overweight. 

 
Signs of osteonecrosis include: 



 

50 

 stiffness in the joints 
 aches and pains in the joints (especially in the hip, knee or shoulder) 
 difficulty moving. 

If you notice any of these symptoms: 
  Tell your doctor. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side effects not 
listed in this leaflet.  You can also report side effects directly via the national reporting system listed in 
Appendix V.  By reporting side effects you can help provide more information on the safety of this medicine. 
 
5. How to store Juluca 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and bottle after EXP.  The expiry 
date refers to the last day of that month. 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed.  Do not 
remove the desiccant. 
 
This medicine does not require any special temperature storage conditions. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to throw 
away medicines you no longer use.  These measures will help protect the environment. 
 
6. Contents of the pack and other information 
 
What Juluca contains  
- The active substances are dolutegravir and rilpivirine.  Each tablet contains dolutegravir sodium 

equivalent to 50 mg dolutegravir and rilpivirine hydrochloride equivalent to 25 mg rilpivirine.  
- The other ingredients are 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). 

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

 
What Juluca looks like and contents of the pack 
 
Juluca film-coated tablets are pink, oval, biconvex tablets debossed with ‘SV J3T’ on one side. 
 
The film-coated tablets are provided in bottles closed with child-resistant closures.  
Each bottle contains 30 film-coated tablets and a desiccant to reduce moisture.  Once the bottle has been 
opened keep the desiccant in the bottle, do not remove it. 
Multipacks containing 90 film-coated tablets (3 packs of 30 film-coated tablets) are also available.  
Not all pack sizes may be available in your country. 
 
Marketing Authorisation Holder  
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
Manufacturer 
Glaxo Wellcome, S.A.  
Avda. Extremadura, 3 



 

51 

09400 Aranda De Duero 
Burgos 
Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
ViiV Healthcare srl/bv  
Tél/Tel: + 32 (0) 10 85 65 00 

Lietuva 
GlaxoSmithKline Lietuva UAB 
Tel: + 370 5 264 90 00 
info.lt@gsk.com 

България 
ГлаксоСмитКлайн ЕООД 
Teл.: + 359 2 953 10 34 
 

Luxembourg/Luxemburg 
ViiV Healthcare srl/bv  
Belgique/Belgien 
Tél/Tel: + 32 (0) 10 85 65 00 

 
Česká republika 
GlaxoSmithKline, s.r.o. 
Tel: + 420 222 001 111 
cz.info@gsk.com 

 
Magyarország 
GlaxoSmithKline Kft. 
Tel.: + 36 1 225 5300 

 
Danmark 
GlaxoSmithKline Pharma A/S 
Tlf: + 45 36 35 91 00 
dk-info@gsk.com 

 
Malta 
GlaxoSmithKline (Malta) Limited 
Tel: + 356 21 238131 

 
Deutschland 
ViiV Healthcare GmbH  
Tel.: + 49 (0)89 203 0038-10  
viiv.med.info@viivhealthcare.com  

 
Nederland 
ViiV Healthcare BV  
Tel: + 31 (0)33 2081199 
 

 
Eesti 
GlaxoSmithKline Eesti OÜ 
Tel: + 372 6676 900 
estonia@gsk.com 

 
Norge 
GlaxoSmithKline AS 
Tlf: + 47 22 70 20 00 
 

 
Ελλάδα 
GlaxoSmithKline Μονοπρόσωπη A.E.B.E. 
Τηλ: + 30 210 68 82 100 

 
Österreich 
GlaxoSmithKline Pharma GmbH 
Tel: + 43 (0)1 97075 0 
at.info@gsk.com 

 
España 
Laboratorios ViiV Healthcare, S.L.  
Tel: + 34 900 923 501  
es-ci@viivhealthcare.com 

 
Polska 
GSK Services Sp. z o.o. 
Tel.: + 48 (0)22 576 9000 
 

 
France 
ViiV Healthcare SAS  
Tél.: + 33 (0)1 39 17 69 69 
Infomed@viivhealthcare.com 

 
Portugal 
VIIVHIV HEALTHCARE, UNIPESSOAL, LDA  
Tel: + 351 21 094 08 01  
viiv.fi.pt@viivhealthcare.com 

 
Hrvatska 
GlaxoSmithKline d.o.o. 
Tel: + 385 1  6051 999 

 
România 
GlaxoSmithKline (GSK) S.R.L.  
Tel: + 4021 3028 208 



 

52 

 
Ireland 
GlaxoSmithKline (Ireland) Limited 
Tel: + 353 (0)1 4955000 

 
Slovenija 
GlaxoSmithKline d.o.o. 
Tel: + 386 (0)1 280 25 00 
medical.x.si@gsk.com 

 
Ísland 
Vistor hf. 
Sími: +354 535 7000 

 
Slovenská republika 
GlaxoSmithKline Slovakia s. r. o. 
Tel: + 421 (0)2 48 26 11 11 
recepcia.sk@gsk.com 

 
Italia 
ViiV Healthcare S.r.l  
Tel: + 39 (0)45 9212611 

 
Suomi/Finland 
GlaxoSmithKline Oy 
Puh/Tel: + 358 (0)10 30 30 30 
Finland.tuoteinfo@gsk.com 

 
Κύπρος 
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 397000 
gskcyprus@gsk.com 

 
Sverige 
GlaxoSmithKline AB 
Tel: + 46 (0)8 638 93 00 
info.produkt@gsk.com 

 
Latvija 
GlaxoSmithKline Latvia SIA 
Tel: + 371 67312687 
lv-epasts@gsk.com 

 
United Kingdom 
ViiV Healthcare UK Limited 
Tel: + 44 (0)800 221441 
customercontactuk@gsk.com  

 
This leaflet was last revised in. 
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVEUSE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET