Tivicay

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 10 mg film-coated tablets 
Tivicay 25 mg film-coated tablets 
Tivicay 50 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Tivicay 10 mg film-coated tablets 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 10 mg dolutegravir. 
 
Tivicay 25 mg film-coated tablets 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 25 mg dolutegravir. 
 
Tivicay 50 mg film-coated tablets 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Tivicay 10 mg film-coated tablets 
 
White, round, biconvex tablets approximately 6 mm in diameter debossed with ‘SV 572’ on one side and 
‘10’ on the other side. 
 
Tivicay 25 mg film-coated tablets 
 
Pale yellow, round, biconvex tablets approximately 7 mm in diameter debossed with ‘SV 572’ on one side 
and ‘25’ on the other side. 
 
Tivicay 50 mg film-coated tablets 
 
Yellow, round, biconvex tablets approximately 9 mm in diameter debossed with ‘SV 572’ on one side and 
‘50’ on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human 
Immunodeficiency Virus (HIV) infected adults, adolescents and children of at least 6 years of age or older 
and weighing at least 14 kg. 
 
4.2 Posology and method of administration  



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Tivicay should be prescribed by physicians experienced in the management of HIV infection. 
 
Posology 
 
Adults 
 
Patients infected with HIV-1 without documented or clinically suspected resistance to the integrase class 
The recommended dose of dolutegravir is 50 mg orally once daily.  
 
Dolutegravir should be administered twice daily in this population when co-administered with some 
medicines (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin).  Please refer to section 4.5. 
 
Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected) 
The recommended dose of dolutegravir is 50 mg twice daily.  
 
In the presence of documented resistance that includes Q148 + ≥2 secondary mutations from G140A/C/S, 
E138A/K/T, L74I, modelling suggests that an increased dose may be considered for patients with limited 
treatment options (less than 2 active agents) due to advanced multi class resistance (see section 5.2).  
 
The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern (see 
section 5.1). 
   
Adolescents aged 12 and above, to less than 18 years, and weighing at least 20 kg 
 
In patients infected with HIV-1 without resistance to the integrase class, the recommended dose of 
dolutegravir is 50 mg once daily. Alternatively, if preferred 25 mg may be taken twice daily (see section 
5.2). In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for 
dolutegravir in adolescents.  
 
Children aged 6 and above, to less than 12 years, and weighing at least 14 kg  
 
In patients infected with HIV-1 without resistance to the integrase class, the recommended dose of 
dolutegravir is determined according to the weight of the child (see Table 1 and section 5.2).  
 
Table 1 Paediatric dose recommendations for film-coated tablets  
Body weight (kg) Dose 
14 to less than 20  40 mg once daily 
20 or greater 50 mg once daily 
 
Alternatively, if preferred the dose may be divided equally into 2 doses, with one dose taken in the morning 
and one dose taken in the evening (see Table 2 and section 5.2).  
 
Table 2 Alternative paediatric dose recommendations for film-coated tablets 
Body weight (kg) Dose 
14 to less than 20  20 mg twice daily 
20 or greater 25 mg twice daily 
 
In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for 
dolutegravir in children. 
 
Dispersible Tablets 
Tivicay is available as film-coated tablets for patients aged 6 years and above and weighing at least 14 kg. 
Tivicay is also available as dispersible tablets for patients aged 4 weeks and above and weighing at least 3 
kg, or for patients in whom film-coated tablets are not appropriate. Patients can change between film-coated 



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tablets and dispersible tablets. However, the bioavailability of film-coated tablets and dispersible tablets is 
not comparable, therefore they are not interchangeable on a milligram per milligram basis (see section 5.2). 
For example, the recommended adult dose for film-coated tablets is 50 mg versus 30 mg for dispersible 
tablets. Patients changing between film-coated and dispersible tablets should follow the dosing 
recommendations that are specific for the formulation. 
 
Missed doses 
If the patient misses a dose of Tivicay, the patient should take Tivicay as soon as possible, providing the next 
dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed 
dose and simply resume the usual dosing schedule.  
 
Elderly 
There are limited data available on the use of dolutegravir 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, moderate or severe (CrCl <30 mL/min, not on 
dialysis) renal impairment.  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 grade A 
or B).  No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore 
dolutegravir should be used with caution in these patients (see section 5.2). 
 
Paediatric population 
Dolutegravir is also available in dispersible tablets for children aged 4 weeks and above and weighing at 
least 3 kg. However, the safety and efficacy of dolutegravir in children aged less than 4 weeks or weighing 
less than 3 kg have not yet been established. In the presence of integrase inhibitor resistance, there are 
insufficient data to recommend a dose for dolutegravir in children and adolescents. Currently available data 
are described in section 4.8, 5.1 and 5.2, but no recommendation on a posology can be made. 
 
Method of administration 
 
Oral use. 
Tivicay can be taken with or without food (see section 5.2). In the presence of integrase class resistance, 
Tivicay should preferably be taken with food to enhance exposure (particularly in patients with Q148 
mutations) (see section 5.2).  
 
To reduce the risk of choking, patients should not swallow more than one tablet at a time, and where 
possible, children weighing 14 to less than 20 kg should preferentially take the dispersible tablet formulation. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Medicinal products with narrow therapeutic windows that are substrates of organic cation transporter 2 
(OCT2), including but not limited to fampridine (also known as dalfampridine; see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
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.  
 
Integrase class resistance of particular concern 
 



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The decision to use dolutegravir in the presence of integrase class resistance should take into account that the 
activity of dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondary 
mutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent dolutegravir provides added 
efficacy in the presence of such integrase class resistance is uncertain (see section 5.2). 
 
Hypersensitivity reactions 
 
Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, 
constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and 
other suspect medicinal products 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 dolutegravir or other suspect active substances after 
the onset of hypersensitivity may result in a life-threatening allergic reaction.  
 
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.  
 
Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some 
hepatitis B and/or C co-infected patients at the start of dolutegravir therapy.  Monitoring of liver 
biochemistries is recommended in patients with hepatitis B and/or C co-infection.  Particular diligence 
should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) 
when starting dolutegravir-based therapy in hepatitis B co-infected patients (see section 4.8). 
 
Opportunistic infections 
 
Patients should be advised that dolutegravir or any other antiretroviral therapy 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. 
 
Drug interactions 
 
Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. 
This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g. magnesium/ 
aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, etravirine 
(without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John’s wort and certain anti-
epileptic medicinal products) (see section 4.5). 
 
Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered 
when starting and stopping coadministration of dolutegravir 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 dolutegravir. 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.   
 



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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. 
 
Weight and metabolic parameters 
 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such 
changes may in part be linked to disease control and lifestyle. For lipids, there is in some cases evidence for 
a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. 
For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid 
disorders should be managed as clinically appropriate. 
 
Lamivudine and dolutegravir  
 
The two-drug regimen of dolutegravir 50 mg once daily and lamivudine 300 mg once daily was explored in 
two large randomized and blinded studies, GEMINI 1 and GEMINI 2 (see section 5.1). This regimen is only 
suitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integrase 
inhibitor class, or to lamivudine. 
 
Excipients 
 
Tivicay contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially ‘sodium free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Effect of other agents on the pharmacokinetics of dolutegravir 
 
All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class 
resistance. 
 
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of 
UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may 
decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3). 
Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase 
dolutegravir plasma concentration (see Table 3). 
 
The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 3). 
 
Effect of dolutegravir on the pharmacokinetics of other agents 
 
In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe.  Based on in vivo and/or in vitro 
data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of 
any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2).   
 
In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin 
extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is 
dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase 
plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE-1 
(e.g. fampridine [also known as dalfampridine], metformin) (see Table 3). 
 
In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3.  
Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition 



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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.   
 
Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal 
products are listed in Table 3. 
 
Interaction table 
Interactions between dolutegravir and co-administered medicinal products are listed in Table 3 (increase is 
indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as 
“AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”). 
 
Table 3: Drug Interactions 
Medicinal products 
by therapeutic areas 

Interaction  
Geometric mean change 
(%)  

Recommendations concerning 
co-administration 

HIV-1 Antiviral Agents 
Non-nucleoside Reverse Transcriptase Inhibitors 
Etravirine without 
boosted protease 
inhibitors 

Dolutegravir ↓ 
   AUC ↓ 71% 
   Cmax ↓ 52% 
   Cτ ↓ 88% 
 
Etravirine ↔ 
(induction of UGT1A1 and 
CYP3A enzymes) 

Etravirine without boosted protease inhibitors 
decreased plasma dolutegravir concentration. The 
recommended adult dose of dolutegravir is 50 mg 
twice daily when co-administered with etravirine 
without boosted protease inhibitors. In paediatric 
patients the weight-based once daily dose should 
be administered twice daily.  Dolutegravir should 
not be used with etravirine without co-
administration of atazanavir/ritonavir, 
darunavir/ritonavir or lopinavir/ritonavir in INI-
resistant patients (see further below in table). 

Lopinavir/ritonavir + 
etravirine 

Dolutegravir ↔ 
   AUC ↑ 11% 
   Cmax ↑ 7% 
   Cτ ↑ 28% 
LPV ↔ 
RTV ↔ 

No dose adjustment is necessary. 

Darunavir/ritonavir + 
etravirine  

Dolutegravir ↓ 
   AUC ↓ 25% 
   Cmax ↓ 12% 
   Cτ ↓ 36% 
DRV ↔ 
RTV ↔ 

No dose adjustment is necessary. 

Efavirenz Dolutegravir ↓ 
   AUC ↓ 57% 
   Cmax ↓ 39% 
   Cτ ↓ 75% 
 
Efavirenz ↔ (historical 
controls) 
(induction of UGT1A1 and 
CYP3A enzymes) 

The recommended adult dose of dolutegravir is 
50 mg twice daily when co-administered with 
efavirenz. In paediatric patients the weight-based 
once daily dose should be administered twice 
daily.   
In the presence of integrase class resistance 
alternative combinations that do not include 
efavirenz should be considered (see section 4.4). 

Nevirapine Dolutegravir ↓ 
(Not studied, a similar 
reduction in exposure as 
observed with efavirenz is 
expected, due to induction) 

The recommended adult dose of dolutegravir is 
50 mg twice daily when co-administered with 
nevirapine. In paediatric patients the weight-based 
once daily dose should be administered twice 
daily.   
In the presence of integrase class resistance 



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alternative combinations that do not include 
nevirapine should be considered (see section 4.4). 

Rilpivirine Dolutegravir ↔ 
   AUC ↑ 12% 
   Cmax ↑ 13% 
   Cτ ↑ 22% 
Rilpivirine ↔ 

No dose adjustment is necessary. 

Nucleoside Reverse Transcriptase Inhibitors 
Tenofovir Dolutegravir ↔ 

   AUC ↑ 1% 
   Cmax ↓ 3% 
   Cτ  ↓ 8% 
Tenofovir ↔ 

No dose adjustment is necessary. 

Protease Inhibitors 
Atazanavir Dolutegravir ↑ 

   AUC ↑ 91% 
   Cmax ↑ 50% 
   Cτ ↑ 180% 
 
Atazanavir ↔ (historical 
controls) 
(inhibition of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary. 
 
Tivicay should not be dosed higher than 50 mg 
twice daily in combination with atazanavir (see 
section 5.2) due to lack of data. 

Atazanavir/ritonavir Dolutegravir ↑ 
   AUC ↑ 62% 
   Cmax ↑ 34% 
   Cτ ↑ 121% 
 
Atazanavir ↔ 
Ritonavir ↔ 
(inhibition of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary. 
 
Tivicay should not be dosed higher than 50 mg 
twice daily in combination with atazanavir (see 
section 5.2) due to lack of data.  

Tipranavir/ritonavir 
(TPV+RTV) 

Dolutegravir ↓ 
   AUC ↓ 59% 
   Cmax ↓ 47% 
   Cτ ↓ 76% 
(induction of UGT1A1 and 
CYP3A enzymes) 

The recommended adult dose of dolutegravir is 
50 mg twice daily when co-administered with 
tipranavir/ritonavir. In paediatric patients the 
weight-based once daily dose should be 
administered twice daily.   
In the presence of integrase class resistance this 
combination should be avoided (see section 4.4). 

Fosamprenavir/ 
ritonavir (FPV+RTV) 

Dolutegravir ↓ 
   AUC ↓ 35% 
   Cmax ↓ 24% 
   Cτ ↓ 49% 
(induction of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary in the absence of 
integrase class resistance.   
In the presence of integrase class resistance 
alternative combinations that do not include 
fosamprenavir/ritonavir should be considered. 

Darunavir/ritonavir Dolutegravir ↓ 
   AUC ↓ 22%  
   Cmax ↓ 11% 
   C24 ↓ 38% 
(induction of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary. 

Lopinavir/ritonavir Dolutegravir ↔ 
   AUC ↓ 4%  
   Cmax ↔ 0% 
   C24 ↓ 6% 

No dose adjustment is necessary. 



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Other Antiviral agents 
Daclatasvir Dolutegravir ↔ 

   AUC ↑ 33%  
   Cmax ↑ 29% 
   Cτ ↑ 45% 
Daclatasvir ↔ 

Daclatasvir did not change dolutegravir plasma 
concentration to a clinically relevant extent.  
Dolutegravir did not change daclatasvir plasma 
concentration.  No dose adjustment is necessary. 

Other agents 
Potassium channel blocker 
Fampridine (also 
known as 
dalfampridine) 

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 dolutegravir is 
contraindicated. 

Anticonvulsants 
Carbamazepine 
 

Dolutegravir ↓ 
   AUC ↓ 49% 
   Cmax ↓ 33% 
   Cτ ↓ 73% 
 

The recommended adult dose of dolutegravir is 50 
mg twice daily when co-administered with 
carbamazepine. In paediatric patients the weight-
based once daily dose should be administered 
twice daily.  Alternatives to carbamazepine should 
be used where possible for INI resistant patients. 

Oxcarbazepine 
Phenytoin 
Phenobarbital 
 

Dolutegravir ↓ 
(Not studied, decrease 
expected due to induction of 
UGT1A1 and CYP3A 
enzymes, a similar reduction 
in exposure as observed 
with carbamazepine is 
expected) 

The recommended adult dose of dolutegravir is 50 
mg twice daily when co-administered with these 
metabolic inducers. In paediatric patients the 
weight-based once daily dose should be 
administered twice daily.  Alternative 
combinations that do not include these metabolic 
inducers should be used where possible in INI-
resistant patients.  

Azole anti-fungal agents 
Ketoconazole 
Fluconazole  
Itraconazole  
Posaconazole  
Voriconazole 

Dolutegravir ↔ 
(Not studied) 

No dose adjustment is necessary.  Based on data 
from other CYP3A4 inhibitors, a marked increase 
is not expected.   

Herbal products 
St. John’s wort Dolutegravir ↓ 

(Not studied, decrease 
expected due to induction of 
UGT1A1 and CYP3A 
enzymes, a similar reduction 
in exposure as observed 
with carbamazepine is 
expected) 

The recommended adult dose of dolutegravir is 50 
mg twice daily when co-administered with St. 
John’s wort. In paediatric patients the weight-
based once daily dose should be administered 
twice daily.  Alternative combinations that do not 
include St. John’s wort should be used where 
possible in INI-resistant patients. 

Antacids and supplements 
Magnesium/ 
aluminium-containing 
antacid 

Dolutegravir ↓ 
   AUC ↓ 74%  
   Cmax ↓ 72% 
(Complex binding to 
polyvalent ions) 

Magnesium/ aluminium-containing antacid should 
be taken well separated in time from the 
administration of dolutegravir (minimum 2 hours 
after or 6 hours before). 

Calcium supplements  Dolutegravir ↓ 
   AUC ↓ 39%  
   Cmax ↓ 37% 
   C24 ↓ 39% 
(Complex binding to 

Calcium supplements, iron supplements or 
multivitamins should be taken well separated in 
time from the administration of dolutegravir 
(minimum 2 hours after or 6 hours before).  



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polyvalent ions) 
Iron supplements  Dolutegravir ↓ 

   AUC ↓ 54%  
   Cmax ↓ 57% 
   C24 ↓ 56% 
(Complex binding to 
polyvalent ions) 

Multivitamin Dolutegravir ↓ 
   AUC ↓ 33%  
   Cmax ↓ 35% 
   C24 ↓ 32% 
(Complex binding to 
polyvalent ions) 

Corticosteroids 
Prednisone Dolutegravir ↔ 

   AUC ↑ 11% 
   Cmax ↑ 6% 
   Cτ ↑ 17% 

No dose adjustment is necessary. 

Antidiabetics 
Metformin Metformin ↑ 

When co-administered with 
dolutegravir 50mg once 
daily: 
Metformin 
   AUC ↑ 79%  
   Cmax ↑ 66% 
When co-administered with 
dolutegravir 50mg twice 
daily:  
Metformin 
   AUC ↑ 145 %  
   Cmax ↑ 111% 

A dose adjustment of metformin should be 
considered when starting and stopping 
coadministration of dolutegravir with metformin, 
to maintain glycaemic control. In patients with 
moderate renal impairment a dose adjustment of 
metformin should be considered when 
coadministered with dolutegravir, because of the 
increased risk for lactic acidosis in patients with 
moderate renal impairment due to increased 
metformin concentration (section 4.4). 

Antimycobacterials 
Rifampicin Dolutegravir ↓ 

   AUC ↓ 54% 
   Cmax ↓ 43% 
   Cτ ↓72% 
(induction of UGT1A1 and 
CYP3A enzymes) 

The recommended adult dose of dolutegravir is 
50 mg twice daily when co-administered with 
rifampicin in the absence of integrase class 
resistance. In paediatric patients the weight-based 
once daily dose should be administered twice 
daily.   
In the presence of integrase class resistance this 
combination should be avoided (see section 4.4). 

Rifabutin Dolutegravir ↔ 
   AUC ↓ 5% 
   Cmax ↑ 16% 
   Cτ ↓ 30% 
(induction of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary. 

Oral contraceptives 
Ethinyl estradiol (EE) 
and Norelgestromin 
(NGMN) 

Dolutegravir ↔ 
EE ↔ 
   AUC ↑ 3%  
   Cmax ↓ 1% 
 
NGMN ↔ 
   AUC ↓ 2%  

Dolutegravir had no pharmacodynamic effect on 
Luteinizing Hormone (LH), Follicle Stimulating 
Hormone (FSH) and progesterone. No dose 
adjustment of oral contraceptives is necessary 
when co-administered with dolutegravir.  



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   Cmax ↓ 11% 
Analgesics 
Methadone  Dolutegravir ↔ 

Methadone ↔ 
   AUC ↓ 2%  
   Cmax ↔ 0% 
   Cτ ↓ 1% 

No dose adjustment is necessary of either agent. 

 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
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 (see below), including consideration of effective contraceptive measures. 
 
If a woman plans pregnancy, the benefits and the risks of continuing treatment with dolutegravir should be 
discussed with the patient. 
 
Pregnancy 
 
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). If a pregnancy is confirmed in the 
first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to 
another antiretroviral regimen should be discussed with the patient taking the gestational age and the critical 
time period of neural tube defect development into account. 
 
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 toxicity studies, 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 during second and third trimester of pregnancy indicate no 
evidence of increased risk of foeto/neonatal toxicity. Dolutegravir may be used during the second and third 
trimester of pregnancy when the expected benefit justifies the potential risk to the foetus. 
  
Breast-feeding 
 
Dolutegravir is excreted in human milk in small amounts. There is insufficient information on the effects of 
dolutegravir in neonates/infants. 
 
It is recommended that HIV infected women do not breast-feed their infants under any circumstances in 
order to avoid transmission of HIV. 
 



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Fertility 
 
There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no 
effects of dolutegravir on male or female fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical 
status of the patient and the adverse reaction profile of dolutegravir 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 
 
The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included 
rash and severe liver effects (see section 4.4).  The most commonly seen treatment emergent adverse 
reactions were nausea (13%), diarrhoea (18%) and headache (13%). 
 
Tabulated list of adverse reactions 
 
The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ 
class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), 
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). 
 



13 

Table 4 Adverse Reactions 
Immune system 
disorders 

Uncommon Hypersensitivity (see section 4.4) 
Uncommon Immune Reconstitution Syndrome (see section 4.4)** 

Psychiatric disorders Common Insomnia 
Common Abnormal dreams 
Common Depression 
Common Anxiety 
Uncommon Suicidal ideation*, suicide attempt*  

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

Nervous system 
disorders 

Very common Headache 
Common Dizziness 

Gastrointestinal 
disorders 

Very common Nausea 
Very common Diarrhoea 
Common Vomiting 
Common Flatulence 
Common Upper abdominal pain 
Common Abdominal pain 
Common Abdominal discomfort 

Hepatobiliary 
disorders 

Uncommon Hepatitis 

Rare Acute hepatic failure 

Skin and 
subcutaneous tissue 
disorders 

Common Rash 
Common Pruritus 

Musculoskeletal and 
connective tissue 
disorders 

Uncommon Arthralgia 
Uncommon Myalgia 

General disorders 
and administration 
site conditions 

Common Fatigue 

Investigations Common Alanine aminotransferase (ALT) and/or Aspartate 
aminotransferase (AST) elevations 

Common Creatine phosphokinase (CPK) elevations 
 
**see below under Description of selected adverse reactions. 
 
Description of selected adverse reactions 
 
Changes in laboratory biochemistries 
Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained 
stable through 48 weeks. A mean change from baseline of 9.96 µmol/L was observed after 48 weeks of 
treatment. Creatinine increases were comparable by various background regimens. These changes are not 
considered to be clinically relevant since they do not reflect a change in glomerular filtration rate. 
 
Co-infection with Hepatitis B or C 
In Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided that 
baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety 
profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without 
hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup 
with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with 
immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at 
the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see 
section 4.4). 
 



14 

Immune reactivation syndrome 
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral 
therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; 
however, the reported time to onset is more variable and these events can occur many months after initiation 
of treatment (see section 4.4). 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4). 
 
Paediatric population 
 
Based on available data from the ongoing P1093 (ING112578) and ODYSSEY (201296) studies in 172 
infants, children and adolescents (aged 4 weeks and above, to less than 18 years, and weighing at least 3 kg) 
who received the recommended doses of film-coated tablets or dispersible tablets once daily, there were no 
additional types of adverse reactions beyond those observed in the adult population. 
 
Reporting of suspected adverse reactions 
 
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 
 
There is currently limited experience with overdosage in dolutegravir.  
 
Limited experience of single higher doses (up to 250 mg in healthy subjects) revealed no specific symptoms 
or signs, 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 dolutegravir. If overdose occurs, the 
patient should be treated supportively with appropriate monitoring, as necessary. As dolutegravir is highly 
bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX12 
 
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. 
 
Pharmacodynamic effects 
 
Antiviral activity in cell culture  
The IC50 for dolutegravir in various labstrains 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). 
 
Antiviral activity in combination with other antiviral agents 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


15 

No antagonistic effects in vitro were seen with dolutegravir and other antiretrovirals tested: stavudine, 
abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc and raltegravir.  In addition, no 
antagonistic effects were seen for dolutegravir and adefovir, and ribavirin had no apparent effect on 
dolutegravir activity.  
 
Effect of human serum  
In 100% human serum, the mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 
µg/mL.  
 
Resistance 
 
Resistance in vitro 
 
Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIV-1 IIIB during 
passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F, 
resulting in a maximal fold change in susceptibility of 4 (range 2-4). These mutations were not selected in 
patients treated with dolutegravir in the clinical studies.  Using strain NL432, mutations E92Q (FC 3) and 
G193E (also FC 3) were selected. The E92Q mutation has been selected in patients with pre-existing 
raltegravir resistance who were then treated with dolutegravir (listed as a secondary mutation 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 ART 
experienced, INI naive individual patients with subtypes B and C in the clinical program, 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 and 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 these primary mutations in 
experiments with site directed mutants, dolutegravir susceptibility is still unchanged (FC <2 vs wild type 
virus), except in the case of Q148-mutations, where a FC of 5-10 or higher is seen with combinations of 
certain secondary mutations. The effect by the Q148-mutations (H/R/K) was also verified in passage 
experiments with site directed mutants.  In serial passage with strain NL432, starting with site directed 
mutants harbouring N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). 
In contrast, starting with mutants harbouring mutation Q148H (FC 1), a variety of secondary mutations were 
seen 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. 
 
Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed for 
susceptibility to dolutegravir.  Dolutegravir has a less than or equal to 10 FC against 94% of the 705 clinical 
isolates. 
 
Resistance in vivo 
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=1118 follow-up of 48-96 weeks). In 
previously untreated patients receiving dolutegravir + lamivudine in the GEMINI studies through week 96 
(n=716), no development of resistance to the integrase class, or to the NRTI class was seen. 
 
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 



16 

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 experienced or infected with integrase resistant virus by 
transmission. The R263K mutation was also selected in vitro (see above). 
 
In the presence of integrase class-resistance (VIKING-3 study) the following mutations were selected in 32 
patients with protocol defined virological failure (PDVF) through Week 24 and with paired genotypes (all 
treated with dolutegravir 50 mg twice daily + optimized background agents):  L74L/M (n=1), E92Q (n=2), 
T97A (n=9), E138K/A/T (n=8), G140S (n=2), Y143H (n=1), S147G (n=1), Q148H/K/R (n=4), and N155H 
(n=1) and E157E/Q (n=1).  Treatment emergent integrase resistance typically appeared in patients with a 
history of the Q148-mutation (baseline or historic). Five further subjects experienced PDVF between weeks 
24 and 48, and 2 of these 5 had treatment emergent mutations.  Treatment-emergent mutations or mixtures of 
mutations observed were L74I (n=1), N155H (n=2). 
 
The VIKING-4 study examined dolutegravir (plus optimized background therapy) in subjects with primary 
genotypic resistance to INIs at Screening in 30 subjects.  Treatment-emergent mutations observed were 
consistent with those observed in the VIKING-3 study. 
 
In paediatric patients with prior failed therapies, but naïve to the integrase class, the integrase inhibitor 
substitution G118R was observed in 5/159 patients treated with dolutegravir, given in combination with an 
investigator selected background regimen. Of these five, 4 participants had additional integrase associated 
substitutions as follows: L74M, E138E/K, E92E/Q and T66I. Four of the 5 participants with emergent 
G118R had phenotypic data available. Dolutegravir FC (fold change as compared to wildtype virus) for these 
four participants ranged from 6 to 25-fold. 
 
Effects on electrocardiogram 
 
No relevant effects were seen on the QTc interval, with doses exceeding the clinical dose by approximately 
three fold.  
 
Clinical efficacy and safety  
 
Previously untreated patients  
The efficacy of dolutegravir in HIV-infected, therapy naïve subjects is based on the analyses of 96-week data 
from two randomized, international, double-blind, active-controlled trials, SPRING-2 (ING113086) and 
SINGLE (ING114467). This is supported by 96 week data from an open-label, randomized and active-
controlled study FLAMINGO (ING114915) and additional data from the open-label phase of SINGLE to 
144 weeks. The efficacy of dolutegravir in combination with lamivudine in adults is supported by 96-week 
data from two identical 148-week, randomised, multicentre, double-blind, non-inferiority studies GEMINI-1 
(204861) and GEMINI-2 (205543). 
 
In SPRING-2, 822 adults were randomized and received at least one dose of either dolutegravir 50 mg once 
daily or raltegravir (RAL) 400 mg twice daily, both administered with either ABC/3TC or TDF/FTC.  At 
baseline, median patient age was 36 years, 14% were female, 15% non-white, 11% had hepatitis B and/or C 
co-infection and 2% were CDC Class C, these characteristics were similar between treatment groups. 
 
In SINGLE, 833 subjects were randomized and received at least one dose of either dolutegravir 50 mg once 
daily with fixed-dose abacavir-lamivudine (Dolutegravir + ABC/3TC) or fixed-dose efavirenz-tenofovir-
emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% non-
white, 7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics were similar 
between treatment groups.  
 
The primary endpoint and other week 48 outcomes (including outcomes by key baseline covariates) for 
SPRING-2 and SINGLE are shown in Table 5. 
 
Table 5 Response in SPRING-2 and SINGLE at 48 Weeks (Snapshot algorithm, <50 copies/mL) 



17 

 SPRING-2 SINGLE 
 Dolutegravir 

50 mg Once 
Daily + 2 NRTI 

N=411 

RAL 400 mg 
Twice Daily + 2 

NRTI 
N=411 

Dolutegravir 
50 mg + 

ABC/3TC Once 
Daily 

N=414 

EFV/TDF/FTC 
Once Daily 

N=419 

HIV-1 RNA <50 copies/mL 88% 85% 88% 81% 
  Treatment Difference* 2.5% (95% CI: -2.2%, 7.1%) 7.4% (95% CI: 2.5%, 12.3%) 
Virologic non-response†  5% 8% 5% 6% 

HIV-1 RNA <50 copies/mL by baseline covariates 
Baseline Viral Load 
(cps/mL)     

  ≤100,000  267 / 297 (90%) 264 / 295 (89%) 253 / 280 (90%) 238 / 288 (83%) 
  >100,000  94 / 114 (82%) 87 / 116 (75%) 111 / 134 (83%) 100 / 131 (76%) 
Baseline CD4+ (cells/ mm3)     
  <200 43 / 55 (78%) 34 / 50 (68%) 45 / 57 (79%) 48 / 62 (77%) 
  200 to <350  128 / 144 (89%) 118 / 139 (85%) 143 / 163 (88%) 126 / 159 (79%) 
  ≥350  190 / 212 (90%) 199 / 222 (90%) 176 / 194 (91%) 164 / 198 (83%) 
NRTI backbone     
  ABC/3TC 145 / 169 (86%) 142 / 164 (87%) N/A N/A 
  TDF/FTC 216 / 242 (89%) 209 / 247 (85%) N/A N/A 
Gender     
  Male  308 / 348 (89%) 305 / 355 (86%) 307 / 347 (88%) 291 / 356 (82%) 
  Female 53 / 63 (84%) 46 / 56 (82%) 57 / 67 (85%) 47 / 63 (75%) 
Race      
  White  306 / 346 (88%) 301 / 352 (86%) 255 / 284 (90%) 238 /285 (84%) 
  African-America/African 
Heritage/Other 55 / 65 (85%) 50 / 59 (85%) 109 / 130 (84%) 99 / 133 (74%) 

Age (years)     
  <50 324/370 (88%) 312/365 (85%) 319/361 (88%) 302/375 (81%) 
  ≥50 37/41 (90%) 39/46 (85%) 45/53 (85%) 36/44 (82%) 
Median CD4 change from 
baseline 230 230 246‡ 187‡ 

* Adjusted for baseline stratification factors. 
† Includes subjects who changed BR to new class or changed BR not permitted per protocol or due to lack 
of efficacy prior to Week 48 (for SPRING-2 only), subjects who discontinued prior to Week 48 for lack or 
loss of efficacy and subjects who are ≥50 copies in the 48 week window.  
‡ Adjusted mean treatment difference was statistically significant (p<0.001) 
 
At week 48, dolutegravir was non-inferior to raltegravir in the SPRING-2 study, and in the SINGLE study 
dolutegravir + ABC/3TC was superior to efavirenz/TDF/FTC (p=0.003), table 5 above. In SINGLE, the 
median time to viral suppression was shorter in the dolutegravir treated patients (28 vs 84 days, (p<0.0001, 
analysis pre-specified and adjusted for multiplicity).  
 
At week 96, results were consistent with those seen at week 48.  In SPRING-2, dolutegravir was still non-
inferior to raltegravir (viral suppression in 81% vs 76% of patients), and with a median change in CD4 count 
of 276 vs 264 cells/mm3, respectively.  In SINGLE, dolutegravir + ABC/3TC was still superior to 
EFV/TDF/FTC (viral suppression in 80% vs 72%, treatment difference 8.0% (2.3, 13.8), p=0.006, and with 
an adjusted mean change in CD4 count of 325 vs 281 cells/ mm3, respectively.  At 144 weeks in the open-
label phase of SINGLE, virologic suppression was maintained, the dolutegravir + ABC/3TC arm (71%) was 
superior to the EFV/TDF/FTC arm (63%), treatment difference was 8.3% (2.0, 14.6). 
 
In FLAMINGO (ING114915), an open-label, randomised and active-controlled study, 484 HIV-1 infected 
antiretroviral naïve adults received one dose of either dolutegravir 50 mg once daily (n=242) or 
darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily (n=242), both administered with either ABC/3TC or 



18 

TDF/FTC.  At baseline, median patient age was 34 years, 15% were female, 28% non-white, 10% had 
hepatitis B and/or C co-infection, and 3% were CDC Class C; these characteristics were similar between 
treatment groups.  Virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir group (90%) was 
superior to the DRV/r group (83%) at 48 weeks. The adjusted difference in proportion and 95% CI were 
7.1% (0.9, 13.2), p=0.025. At 96 weeks, virologic suppression in the dolutegravir group (80%) was superior 
to the DRV/r group (68%), (adjusted treatment difference [Dolutegravir-(DRV+RTV)]: 12.4%; 95% CI: 
[4.7, 20.2]. 
 
In GEMINI-1 (204861) and GEMINI-2 (205543), identical 148-week, randomised, double-blind studies, 
1433 adult HIV-1 infected antiretroviral naïve subjects were randomised to either a two-drug regimen of 
dolutegravir 50 mg plus lamivudine 300 mg once daily, or to a three-drug regimen of dolutegravir 50 mg 
once daily with fixed dose TDF/FTC. Subjects were enrolled with a screening plasma HIV-1 RNA of 1000 
c/mL to ≤500,000 c/mL. At baseline, in the pooled analysis, median patient age was 33 years, 15% were 
female, 31% non-white, 6% had hepatitis C co-infection and 9% were CDC Stage 3. Approximately one 
third of the patients were infected with an HIV non-B subtype; these characteristics were similar between 
treatment groups. Virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir plus lamivudine 
group was non-inferior to the dolutegravir plus TDF/FTC group at 48 weeks, as shown in Table 6. The 
results of the pooled analysis were in line with those of the individual studies, for which the primary 
endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at week 48 based on the Snapshot 
algorithm) was met. The adjusted difference was -2.6% (95% CI: -6.7; 1.5) for GEMINI-1 and -0.7% (95% 
CI: -4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 10%. 
 
Table 6 Response (<50 cps/ml, snapshot) in GEMINI 1 + 2, pooled data.  

 Dolutegravir + 3TC 
(N=716) 
n/N (%) 

Dolutegravir + 
TDF/FTC 
(N=717) 
n/N (%) 

All patients 655/716 (91) 669/717 (93) 
 adjusted diff -1.7% (CI95-4.4, 1.1) a 

By BL HIV-1 RNA 
≤100,000 cps/mL 526/576 (91) 531/564 (94) 
>100,000 cps/mL 129/140 (92) 138/153 (90) 
By CD4+ 
≤200 c/ mm3 50/63 (79) 51/55 (93) 
>200 c/ mm3 605/653 (93) 618/662 (93) 
By HIV-1 subtype  
B 424/467 (91) 452/488 (93) 
Non-B 231/249 (93) 217/229 (95) 

 
Rebound up to week 48 b 6 (<1) 4 (<1) 

 
Mean change in CD4 count from 
baseline at Week 48, c/ mm3 224 217 

a adjusted for BL stratification factors: Plasma HIV-1 RNA (≤100,000 cps/mL vs. >100,000 cps/mL) and CD4+ 
cell count (≤200 cells/mm3 vs. >200 cells/mm3). 
b Confirmed plasma HIV-1 RNA levels to ≥200 cps/mL after prior confirmed suppression to <200 cps/mL. 

  
At 96 weeks the dolutegravir plus lamivudine group (86% with plasma HIV-1 RNA < 50 copies/mL [pooled 
data]) remained non-inferior to the dolutegravir plus tenofovir/emtricitabine FDC group (90% with plasma 
HIV-1 RNA < 50 copies/mL [pooled data]). The adjusted difference in proportions and 95% CI was -3.4% (-
6.7, 0.0). The results of the pooled analysis were in line with those of the individual studies, for which the 
secondary endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at Week 96 based on the 
Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir/emtricitabine FDC) 
was met. The adjusted differences of -4.9 (95% CI: -9.8; 0.0) for GEMINI-1 and -1.8 (95% CI: -6.4; 2.7) for 
GEMINI-2 were within the prespecified non-inferiority margin of -10%. The mean increase in CD4+ T-cell 
counts was 269 in the DTG+3TC arm and 259 in the DTG+FTC/TDF arm, at week 96. 



19 

Treatment emergent resistance in previously untreated patients failing therapy 
Through 96 weeks in SPRING-2 and FLAMINGO and 144 weeks in SINGLE, no cases of treatment 
emergent primary resistance to the integrase- or NRTI-class were seen in the dolutegravir-containing arms. 
For the comparator arms, the same lack of treatment emergent resistance was also the case for patients 
treated with darunavir/r in FLAMINGO. In SPRING-2, four patients in the RAL-arm failed with major 
NRTI mutations and one with raltegravir resistance; in SINGLE, six patients in the EFV/TDF/FTC-arm 
failed with mutations associated with NNRTI resistance, and one developed a major NRTI mutation. 
Through 96 weeks in the GEMINI-1 and GEMINI-2 studies, no cases of emergent resistance to the 
integrase- or NRTI-class were seen in either the Dolutegravir+3TC or comparator Dolutegravir+TDF/FTC 
arms. 
 
Patients with prior treatment failure, but not exposed to the integrase class  
In the international multicentre, double-blind SAILING study (ING111762), 719 HIV-1 infected, 
antiretroviral therapy (ART)-experienced adults were randomized and received either dolutegravir 50 mg 
once daily or raltegravir 400 mg twice daily with investigator selected background regimen consisting of up 
to 2 agents (including at least one fully active agent).  At baseline, median patient age was 43 years, 32% 
were female, 50% non-white, 16% had hepatitis B and/or C co-infection, and 46% were CDC Class C.  All 
patients had at least two class ART resistance, and 49% of subjects had at least 3-class ART resistance at 
baseline.  
 
Week 48 outcomes (including outcomes by key baseline covariates) for SAILING are shown in Table 7. 
 
Table 7 Response in SAILING at 48 Weeks (Snapshot algorithm, <50 copies/mL) 
 Dolutegravir 50 mg 

Once Daily + BR 
N=354§ 

RAL 400 mg Twice 
Daily + BR 

N=361§ 
HIV-1 RNA <50 copies/mL 71% 64% 
  Adjusted treatment difference‡ 7.4% (95% CI: 0.7%, 14.2%) 
Virologic non-response 20% 28% 

HIV-1 RNA <50 copies/mL by baseline covariates 
Baseline Viral Load (copies/mL)   
  ≤50,000 copies/mL 186 / 249 (75%) 180 / 254 (71%) 
  >50,000 copies/mL 65 / 105 (62%) 50 / 107 (47%) 
Baseline CD4+ (cells/ mm3)   
  <50 33 / 62 (53%) 30 / 59 (51%) 
  50 to <200  77 / 111 (69%) 76 / 125 (61%) 
  200 to <350  64 / 82 (78%) 53 / 79 (67%) 
  ≥350 77 / 99 (78%) 71 / 98 (72%) 
Background Regimen   
  Genotypic Susceptibility Score* <2 155 / 216 (72%) 129 / 192 (67%) 
  Genotypic Susceptibility Score* =2 96 / 138 (70%) 101 / 169 (60%) 
  Use of DRV in background regimen   
    No DRV use  143 / 214 (67%) 126 / 209 (60%) 
    DRV use with primary PI mutations 58 / 68 (85%) 50 / 75 (67%) 
    DRV use without primary PI mutations 50 / 72 (69%) 54 / 77 (70%) 
Gender   
  Male  172 / 247 (70%) 156 / 238 (66%) 
  Female 79 / 107 (74%) 74 / 123 (60%) 
Race    
  White  133 / 178 (75%) 125 / 175 (71%) 
  African-America/African Heritage/Other 118 / 175 (67%) 105 / 185 (57%) 
Age (years)   
  <50 196 / 269 (73%) 172 / 277 (62%) 
  ≥50 55 / 85 (65%) 58 / 84 (69%) 
HIV sub type   



20 

  Clade B 173 / 241 (72%) 159 / 246 (65%) 
  Clade C 34 / 55 (62%) 29 / 48 (60%) 
  Other† 43 / 57 (75%) 42 / 67 (63%) 
Mean increase in CD4+ T cell (cells/mm3) 162 153 
‡ Adjusted for baseline stratification factors. 
§ 4 subjects were excluded from the efficacy analysis due to data integrity at one study site  
*The Genotypic Susceptibility Score (GSS) was defined as the total number of ARTs in BR to which 
a subject’s viral isolate showed susceptibility at baseline based upon genotypic resistance tests.   
†Other clades included: Complex (43), F1 (32), A1 (18), BF (14), all others <10. 
 
 
In the SAILING study, virologic suppression (HIV-1 RNA <50 copies/mL) in the Tivicay arm (71%) was 
statistically superior to the raltegravir arm (64%), at Week 48 (p=0.03). 
 
Statistically fewer subjects failed therapy with treatment-emergent integrase resistance on Tivicay (4/354, 
1%) than on raltegravir (17/361, 5%) (p=0.003) (refer to section ‘Resistance in vivo’ above for details).   
 
Patients with prior treatment failure that included an integrase inhibitor (and integrase class resistance)  
In the multicentre, open-label, single arm VIKING-3 study (ING112574), HIV-1 infected, ART-experienced 
adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance 
received Tivicay 50 mg twice daily with the current failing background regimen for 7 days but with 
optimised background ART from Day 8.  The study enrolled 183 patients, 133 with INI-resistance at 
Screening and 50 with only historical evidence of resistance (and not at Screening).  Raltegravir/elvitegravir 
was part of the current failing regimen in 98/183 patients (part of prior failing therapies in the others).  At 
baseline, median patient age was 48 years, 23% were female, 29% non-white, and 20% had hepatitis B 
and/or C co-infection.  Median baseline CD4+ was 140 cells/mm3, median duration of prior ART was 14 
years, and 56% were CDC Class C.  Subjects showed multiple class ART resistance at baseline: 79% had ≥2 
NRTI, 75% ≥1 NNRTI, and 71% ≥2 PI major mutations; 62% had non-R5 virus.  
 
Mean change from baseline in HIV RNA at day 8 (primary endpoint) was -1.4log10 copies/mL (95% CI -1.3 
– -1.5log10, p<0.001).  Response was associated with baseline INI mutation pathway, as shown in Table 8.   
 
Table 8 Virologic response (day 8) after 7 days of functional monotherapy, in patients with RAL/EVG 
as part of current failing regimen, VIKING 3 
Baseline parameters Dolutegravir 50 mg BID 

N=88* 
n Mean (SD) Plasma HIV-1 

RNA log10 c/mL 
Median  

Derived IN mutation group at 
Baseline with ongoing RAL/EVG 

   

Primary mutation other than 
Q148H/K/Ra 

48 -1.59 (0.47) -1.64 

Q148+1 secondary mutationb 26 -1.14 (0.61) -1.08 
Q148+≥2 secondary mutationsb 14 -0.75 (0.84) -0.45 
*Of 98 on RAL/EVG as part of current failing regimen, 88 had detectable primary INI mutations at 
Baseline and a Day 8 Plasma HIV-1 RNA outcome for evaluation 

a Included primary IN resistance mutations N155H, Y143C/H/R, T66A, E92Q  
b Secondary mutations from G140A/C/S, E138A/K/T, L74I. 
 
In patients without a primary mutation detected at baseline (N=60) (i.e. RAL/EVG not part of current failing 
therapy) there was a 1.63 log10 reduction in viral load at day 8. 
 
After the functional monotherapy phase, subjects had the opportunity to re-optimize their background 
regimen when possible.  The overall response rate through 24 weeks of therapy, 69% (126/183), was 
generally sustained through 48 weeks with 116/183 (63%) of patients with HIV-1 RNA <50c/mL (ITT-E, 



21 

Snapshot algorithm). When excluding patients who stopped therapy for non-efficacy reasons, and those with 
major protocol deviations (incorrect dolutegravir dosing, intake of prohibited co-medication), namely, “the 
Virological Outcome (VO)-population)”, the corresponding response rates were 75% (120/161, week 24) 
and 69% (111/160, week 48).  
 
The response was lower when the Q148-mutation was present at baseline, and in particular in the presence of 
≥2 secondary mutations, Table 9.  The overall susceptibility score (OSS) of the optimised background 
regimen (OBR) was not associated with Week 24 response, nor with the week 48 response.   
 
Table 9 Response by baseline Resistance, VIKING-3. VO Population (HIV-1 RNA <50 c/mL, Snapshot 
algorithm) 

 Week 24 (N=161) Week 48 
(N=160) 

Derived IN Mutation 
Group OSS=0 OSS=1 OSS=2 OSS>2 Total 

Total 

No primary IN mutation1 
2/2 (100%) 15/20 (75%) 19/21 (90%) 9/12 (75%) 

45/55 
(82%) 

38/55 
(69%) 

Primary mutation other 
than Q148H/K/R2 2/2 (100%) 20/20 (100%) 21/27 (78%) 8/10 (80%) 

51/59 
(86%) 

50/58 
(86%) 

Q148 + 1 secondary 
mutation3 2/2 (100%) 8/12 (67%) 10/17 (59%) - 

20/31 
(65%) 

19/31 
(61%) 

Q148 +≥2 secondary 
mutations 3 1/2 (50%) 2/11 (18%) 1/3 (33%) - 4/16 (25%) 4/16 (25%) 
1 Historical or phenotypic evidence of INI resistance only.  
2 N155H, Y143C/H/R, T66A, E92Q 
3 G140A/C/S, E138A/K/T, L74I 
OSS: combined genotypic and phenotypic resistance (Monogram Biosciences Net Assessment) 

 
The median change in CD4+ T cell count from baseline for VIKING-3 based on observed data was 
61 cells/mm3 at Week 24 and 110 cells/mm3 at Week 48.   
 
In the double blind, placebo controlled VIKING-4 study (ING116529), 30 HIV-1 infected, ART-experienced 
adults with primary genotypic resistance to INIs at Screening, were randomised to receive either dolutegravir 
50 mg twice daily or placebo with the current failing regimen for 7 days followed by an open label phase 
with all subjects receiving dolutegravir.  At baseline, median patient age was 49 years, 20% were female, 
58% non-white, and 23% had hepatitis B and/or C co-infection.  Median baseline CD4+ was 160 cells/mm3, 
median duration of prior ART was 13 years, and 63% were CDC Class C.  Subjects showed multiple class 
ART resistance at baseline: 80% had ≥2 NRTI, 73% ≥1 NNRTI, and 67% ≥2 PI major mutations; 83% had 
non-R5 virus.  Sixteen of 30 subjects (53%) harboured Q148 virus at baseline.  The primary endpoint at Day 
8 showed that dolutegravir 50 mg twice daily was superior to placebo, with an adjusted mean treatment 
difference for the change from Baseline in Plasma HIV-1 RNA of -1.2 log10 copies/mL (95% CI -1.5 - -
0.8log10 copies/mL, p<0.001). The day 8 responses in this placebo controlled study were fully in line with 
those seen in VIKING-3 (not placebo controlled), including by baseline integrase resistance categories. At 
week 48, 12/30 (40%) subjects had HIV-1 RNA <50 copies/mL (ITT-E, Snapshot algorithm).  
 
In a combined analysis of VIKING-3 and VIKING-4 (n=186, VO population), the proportion of subjects 
with HIV RNA <50 copies/mL at Week 48 was 123/186 (66%).  The proportion of subjects with HIV RNA 
<50 copies/mL was 96/126 (76%) for No Q148 mutations, 22/41 (54%) for Q148+1 and 5/19 (26%) for 
Q148+≥2 secondary mutations.  
 
Paediatric population 
 
In an ongoing Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic 
parameters, safety, tolerability and efficacy of dolutegravir film-coated tablets and dispersible tablets 



22 

following once daily dosing were evaluated in combination regimens in HIV-1 infected infants, children and 
adolescents aged ≥ 4 weeks to < 18 years, the majority of whom were treatment-experienced.  
 
The efficacy results (Table 10) include participants who received the recommended once daily doses of 
either film-coated tablets or dispersible tablets. 
 
Table 10 Antiviral and Immunological Activity Through Week 24 and Week 48 in Paediatric Patients  

 Week 24 
N=75 

Week 48 
N=66 

 n/N % (95% CI) n/N % (95% CI) 
Proportion of participants with HIV 
RNA <50 c/mLa, b 42/75 56  

(44.1, 67.5) 43/66 65.2  
(52.4, 76.5) 

Proportion of participants with HIV 
RNA <400 c/mLb 62/75 82.7 

(72.2, 90.4) 53/66 80.3  
(68.7, 89.1) 

 Median (n) (Q1, Q3) Median (n) (Q1, Q3) 
Change from baseline in CD4+ cell 
count (cells/mm3)  145 (72) (-64, 489) 184 (62) (-179, 665) 

Change from baseline in CD4+ 
percent 6 (72) (2.5, 10) 8 (62) (0.4, 11) 

Q1, Q3= First and third quartiles, respectively. 
a Results of <200 c/mL from HIV-1 RNA testing using an LLOD of 200 c/mL were censored to >50 c/mL in this 

analysis 
b Snapshot algorithm was used in the analyses 
 

In participants experiencing virologic failure, 5/36 acquired integrase inhibitor substitution G118R. Of these 
five, 4 participants had additional integrase associated substitutions as follows: L74M, E138E/K, E92E/Q 
and T66I. Four of the 5 participants with emergent G118R had phenotypic data available. Dolutegravir FC 
(fold change as compared to wildtype virus) for these four participants ranged from 6 to 25-fold. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with Tivicay in 
paediatric patients aged 4 weeks to below 6 years with HIV infection (see section 4.2 for information on 
paediatric use). 
 
There are no data available on the use of dolutegravir plus lamivudine as a two-drug regimen in paediatric 
patients. 
 
5.2 Pharmacokinetic properties 
 
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 Cτ 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. 
 
Film-coated tablets and dispersible tablets do not have the same bioavailability. The relative bioavailability 
of dispersible tablets is approximately 1.6-fold higher as compared to film-coated tablets. Thus, a 50 mg 
dolutegravir dose administered as film-coated tablet(s) will have similar exposure to a 30 mg dolutegravir 
dose administered as six 5 mg dispersible tablets. Similarly, a 40 mg dolutegravir dose administered as four 
10 mg film-coated tablets will provide comparable exposure to a 25 mg dolutegravir dose administered as 
five 5 mg dispersible tablets.  
 
Absorption 
  



23 

Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for 
tablet formulation.  
 
Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir 
depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, 
and 66%, increased Cmax by 46%, 52%, and 67%, prolonged Tmax to 3, 4, and 5 hours from 2 hours under 
fasted conditions, respectively for the film-coated tablet. These increases may be clinically relevant in the 
presence of certain integrase class resistance. Therefore, Tivicay is recommended to be taken with food by 
patients infected with HIV with integrase class resistance (see section 4.2). 
 
The absolute bioavailability of dolutegravir 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).   
 
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. 
 
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, 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). 
 
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. 
 



24 

Linearity/non-linearity 
  
The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral 
administration of film-coated tablet formulations, in general, dolutegravir exhibited nonlinear 
pharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; however 
increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg for the film-coated tablet 
formulation. With 50 mg film-coated tablet twice daily, the exposure over 24 hours was approximately 
doubled compared to 50 mg film-coated tablet once daily. 
 
Pharmacokinetic/pharmacodynamic relationship(s) 
 
In a randomized, dose-ranging trial, HIV-1–infected subjects treated with dolutegravir monotherapy 
(ING111521) demonstrated rapid and dose-dependent antiviral activity, with mean decline in HIV-1 RNA of 
2.5 log10 at day 11 for 50 mg dose. This antiviral response was maintained for 3 to 4 days after the last dose 
in the 50 mg film-coated tablet group.   
 
PK/PD modelling using pooled data from clinical studies in integrase resistant patients suggest that 
increasing the dose from 50 mg film-coated tablet twice daily to 100 mg film-coated tablet twice daily may 
increase the effectiveness of dolutegravir in patients with integrase resistance and limited treatment options 
due to advanced multi class resistance. The proportion of responders (HIV-1 RNA <50 c/mL) at week 24 
was predicted to increase around 4-18% in the subjects with Q148 + ≥2 secondary mutations from 
G140A/C/S, E138A/K/T, L74I. Although these simulated results have not been confirmed in clinical trials, 
this high dose may be considered in the presence of the Q148 + ≥2 secondary mutations from G140A/C/S, 
E138A/K/T, L74I in patients with overall limited treatment options due to advanced multi class resistance. 
There is no clinical data on the safety or efficacy of the 100 mg film-coated tablet twice daily dose. Co-
treatment with atazanavir increases the exposure of dolutegravir markedly, and should not be used in 
combination with this high dose, since safety with the resulting dolutegravir exposure has not been 
established. 
 
Special patient populations 
 
Children  
The pharmacokinetics of dolutegravir given once daily as film-coated and dispersible tablets in HIV-1 
infected infants, children and adolescents aged ≥ 4 weeks to < 18 years were evaluated in two on-going 
studies (P1093/ING112578 and ODYSSEY/201296). Steady state simulated plasma exposure at once daily 
weight band doses is summarized in Table 11.  



25 

Table 11 Summary of Simulated Dolutegravir PK Parameters at Once Daily Doses by Weight Band in 
Paediatric HIV-1 Infected Subjects 

Weight Band 
(kg) 

Dolutegravir 
Dosage 
Forma 

Once Daily 
Dose (mg) 

PK Parameter 
Geometric Mean (90% CI) 

Cmax 
(µg/mL) 

AUC0-24h 
(µg*h/mL) 

C24h 
(ng/mL) 

3 to <6 DT 5 
4.02  

(2.12, 7.96) 
49.4 

 (21.6, 115) 
1070  

(247, 3830) 

6 to <10b DT 10 
5.90  

(3.23, 10.9) 
67.4  

(30.4, 151) 
1240 

 (257, 4580) 

6 to <10c  DT 15 
6.67  

(3.75, 12.1) 
68.4  

(30.6, 154) 
964 

(158, 4150) 

10 to <14 DT 20 
6.61  

(3.80, 11.5) 
63.1  

(28.9, 136) 
719  

(102, 3340) 

14 to <20 
DT 

 
FCT 

25 
 

40 

7.17 
(4.10, 12.6) 

6.96  
(3.83, 12.5) 

69.5  
(32.1, 151) 

72.6  
(33.7, 156) 

824  
(122, 3780) 

972  
(150, 4260) 

20 to <25 
DT 

 
FCT 

30 
 

50 

7.37  
(4.24, 12.9) 

7.43  
(4.13, 13.3) 

72.0  
(33.3, 156)  

78.6  
(36.8, 171) 

881  
(137, 3960) 

1080  
(178, 4690) 

25 to <30 FCT 50 
6.74  

(3.73, 12.1) 
71.4  

(33.2, 154) 
997  

(162, 4250) 

30 to <35 FCT 50 
6.20  

(3.45, 11.1) 
66.6  

(30.5, 141) 
944  

(154, 4020) 

≥35 FCT 50 
4.93  

(2.66, 9.08) 
54.0  

(24.4, 118) 
814  

(142, 3310) 

Target: Geometric Mean  46 (37-134) 995 (697-2260) 

DT=dispersible tablet 
FCT=film-coated tablet 
a. The bioavailability of dolutegravir DT is ~1.6-fold dolutegravir FCT. 
b. <6 months of age 
c. ≥6 months of age 

 



26 

 
Steady state simulated plasma exposure at alternative twice daily weight band doses are summarized in Table 
12. In contrast to once daily dosing, simulated data for alternative twice daily dosing have not been 
confirmed in clinical trials. 
 
Table 12 Summary of Simulated Dolutegravir PK Parameters at Alternative Twice Daily Doses by 

Weight Band in Paediatric HIV-1 Infected Subjects 
 
 
 
 
 

Weight Band 
(kg) 

Dolutegravir 
Dosage 
Forma 

Twice 
Daily Dose 

(mg) 

PK Parameter 
 Geometric Mean (90% CI) 

Cmax 
(µg/mL) 

AUC0-12h 
(µg*h/mL) 

C12h 
(ng/mL) 

6 to <10b DT 5 
4.28 

(2.10, 9.01) 
31.6 

(14.6, 71.4) 
1760 

 (509, 5330) 

6 to <10c  DT 10 
6.19  

(3.15, 12.6) 
43.6 

(19.4, 96.9) 
2190 

(565, 6960) 

10 to <14 DT 10 
4.40 

(2.27, 8.68) 
30.0 

(13.5, 66.0) 
1400 

(351, 4480) 

14 to <20 
DT 

 
FCT 

15 
 

20 

5.78 
(2.97, 11.4) 

4.98 
(2.55, 9.96) 

39.6 
(17.6, 86.3) 

35.9 
(16.5, 77.4) 

1890 
(482, 6070) 

1840 
(496, 5650) 

20 to <25 
DT 

 
FCT 

15 
 

25 

5.01 
(2.61, 9.99) 

5.38 
(2.73, 10.8) 

34.7 
(15.8, 76.5)    

39.2 
(18.1, 85.4)  

1690  
(455, 5360) 

2040  
(567, 6250) 

25 to <30 
DT 

 
FCT 

15 
 

25 

4.57 
(2.37, 9.05) 

4.93 
(2.50, 9.85) 

32.0 
(14.6, 69.1) 

35.9 
(16.4, 77.4) 

1580 
(414, 4930) 

1910 
(530, 5760) 

30 to <35 FCT 25 
4.54 

(2.31, 9.10) 
33.3 

(15.3, 72.4) 
1770 

(494, 5400) 

≥35 FCT 25 
3.59 

(1.76, 7.36) 
26.8 

(12.1, 58.3) 
1470 

(425, 4400) 

DT=dispersible tablet 
FCT=film-coated tablet 

a. The bioavailability of dolutegravir DT is ~1.6-fold dolutegravir FCT. 
b. <6 months of age 
c. ≥6 months of age 



27 

 
 Elderly 
Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there 
was no clinically relevant effect of age on dolutegravir exposure. 
 
Pharmacokinetic data for dolutegravir in subjects >65 years of age are limited. 
 
Renal impairment 
Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study 
of the pharmacokinetics of a single 50 mg dose of dolutegravir film-coated tablets 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. No dosage adjustment is considered necessary for patients with renal 
impairment. Tivicay has not been studied in patients on dialysis. 
 
Hepatic impairment 
Dolutegravir is primarily metabolized and eliminated by the liver. A single 50 mg dose of dolutegravir film-
coated tablets was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 
8 matched healthy adult controls. While the total dolutegravir concentration in plasma 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. No dosage adjustment is considered necessary for patients with 
mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of 
Tivicay has not been studied. 
 
Polymorphisms in drug metabolising enzymes 
There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir 
pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples 
collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor 
dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with 
subjects with genotypes associated with normal metabolism via UGT1A1 (n=41).  
 
Gender 
Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed 
no clinically relevant effect of gender on the exposure of dolutegravir.  
 
Race  
Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed 
no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir 
following single dose oral administration to Japanese subjects appear similar to observed parameters in 
Western (US) subjects.  
 
Co-infection with Hepatitis B or C  
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant 
effect on the exposure to dolutegravir. There are limited data on subjects with hepatitis B co-infection. 
 
5.3 Preclinical safety data 
 
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. 
 
Dolutegravir did not affect male or female fertility in rats at doses up to 1000 mg/kg/day, the highest dose 
tested (24 times the 50 mg twice daily human clinical exposure based on AUC).   
 



28 

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 (27 times the 50 mg twice 
daily 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 (0.40 times the 50 mg twice daily 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 (0.40 times the 50 mg twice daily 
human clinical exposure based on AUC).   
 
In a juvenile toxicity study in rats, dolutegravir administration resulted in two preweanling deaths at 
75 mg/kg/day.  Over the preweaning treatment period, mean body weight gain was decreased in this group 
and the decrease persisted throughout the entire study for females during the postweaning period.  The 
systemic exposure at this dose (based on AUC) to dolutegravir was ~17-20-fold higher than humans at the 
recommended pediatric exposure.  There were no new target organs identified in juveniles compared to 
adults.  In the rat pre/post-natal development study, decreased body weight of the developing offspring was 
observed during lactation at a maternally toxic dose (approximately 27 times human exposure at the 
maximum recommended human dose). 
 
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 21 and 0.82 times the 50 mg twice daily 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 15 times the human mg/kg equivalent dose (based on a 50 kg human), 
and 5 times the human mg/m2 equivalent dose for a clinical dose of 50 mg twice daily.   
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Mannitol (E421) 
Microcrystalline cellulose 
Povidone  
Sodium starch glycolate 
Sodium stearyl fumarate  
 
Tablet coating 
 
Poly(vinyl alcohol) partially hydrolyzed 
Titanium dioxide (E171) 
Macrogol 
Talc  
Iron oxide yellow (E172) (for 25 mg and 50 mg tablets) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Tivicay 10 mg film-coated tablets 



29 

 
5 years 
 
Tivicay 25 mg film-coated tablets 
 
4 years 
 
Tivicay 50 mg film-coated tablets 
 
5 years 
 
6.4 Special precautions for storage 
 
Tivicay 10 mg film-coated tablets 
 
Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not remove 
the desiccant. Do not swallow the desiccant. 
 
Tivicay 25 mg and 50 mg film-coated tablets 
 
This medicinal product does not require any special storage conditions. 
 
This medicinal product does not require any special temperature storage conditions. 
 
6.5 Nature and contents of container  
 
HDPE (high density polyethylene) bottles closed with child resistant polypropylene screw closures, with a 
polyethylene faced induction heat seal liner.  The bottles contain 30 or 90 film-coated tablets. 
 
Tivicay 10 mg film-coated tablets 
Each bottle contains a desiccant. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/892/001 
EU/1/13/892/002 
EU/1/13/892/003 
EU/1/13/892/004 
EU/1/13/892/005 
EU/1/13/892/006 



30 

 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 January 2014 
Date of latest renewal: 21 September 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. 
 

http://www.ema.europa.eu/


31 

1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 5 mg dispersible tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each dispersible tablet contains dolutegravir sodium equivalent to 5 mg dolutegravir. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Dispersible tablet. 
White, round, biconvex tablets approximately 6 mm in diameter debossed with ‘SV H7S’ on one side and ‘5’ 
on the other side.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human 
Immunodeficiency Virus (HIV) infected adults, adolescents and children of at least 4 weeks of age or older 
and weighing at least 3 kg.  
 
4.2 Posology and method of administration  
 
Tivicay should be prescribed by physicians experienced in the management of HIV infection. 
 
Posology 
 
Adults 
 
Patients infected with HIV-1 without documented or clinically suspected resistance to the integrase class 
The recommended dose of dolutegravir is 30 mg (six 5 mg dispersible tablets) orally once daily.  
 
Dolutegravir should be administered twice daily in this population when co-administered with some 
medicines (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin).  Please refer to section 4.5. 
 
Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected) 
The recommended dose of dolutegravir is 30 mg (six 5 mg dispersible tablets) twice daily.  
 
In the presence of documented resistance that includes Q148 + ≥2 secondary mutations from G140A/C/S, 
E138A/K/T, L74I, modelling suggests that an increased dose may be considered for patients with limited 
treatment options (less than 2 active agents) due to advanced multi class resistance (see section 5.2).  
 
The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern (see 
section 5.1). 
 

Adolescents, children and infants aged 4 weeks and above and weighing at least 3 kg  

Patients infected with HIV-1 without resistance to the integrase class 



32 

The recommended dose of dolutegravir is determined according to weight and age (see Table 1 and section 
5.2).  
 
Table 1 Paediatric dose recommendations for dispersible tablets 

Body weight (kg) Dose 
3 to less than 6  5 mg once daily 

6 to less than 10 
                          < 6 months                          
 
                          ≥ 6 months 
 

 
10 mg once daily  
 
15 mg once daily 
 

10 to less than 14  20 mg once daily 
 

14 to less than 20 25 mg once daily 

20 or greater 30 mg once daily 

 
Alternatively, if preferred the dose may be divided equally into 2 doses, with one dose taken in the morning 
and one dose taken in the evening (see Table 2 and section 5.2). 
 
Table 2 Alternative paediatric dose recommendations for dispersible tablets 

Body weight (kg) Dose 
3 to less than 6           --- 

6 to less than 10 
                          < 6 months                          
 
                          ≥ 6 months 
 

 
5 mg twice daily  
 
10 mg twice daily 
 

10 to less than 14  10 mg twice daily 
 

14 to less than 20  15 mg twice daily 

20 or greater  15 mg twice daily 

 
Patients infected with HIV-1 with resistance to the integrase class 
There are insufficient data to recommend a dose for dolutegravir in integrase inhibitor resistant adolescents, 
children and infants. 
 
Film-coated tablets 
Tivicay is available as dispersible tablets for patients aged 4 weeks and above and weighing at least 3 kg, or 
for patients in whom film-coated tablets are not appropriate. Tivicay is available as film-coated tablets for 
patients aged 6 years and above and weighing at least 14 kg. Patients can change between dispersible tablets 
and film-coated tablets. However, the bioavailability of dispersible tablets and film-coated tablets is not 
comparable, therefore they are not interchangeable on a milligram per milligram basis (see section 5.2). For 
example, the recommended adult dose for dispersible tablets is 30 mg versus 50 mg for film-coated tablets. 
Patients changing between dispersible and film-coated tablets should follow the dosing recommendations 
that are specific for the formulation. 
 
Missed doses 



33 

If the patient misses a dose of Tivicay, the patient should take Tivicay as soon as possible, providing the next 
dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed 
dose and simply resume the usual dosing schedule.  
 
Elderly 
There are limited data available on the use of dolutegravir 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, moderate or severe (CrCl <30 mL/min, not on 
dialysis) renal impairment.  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 grade A 
or B).  No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore 
dolutegravir should be used with caution in these patients (see section 5.2). 
 
Paediatric population 
The safety and efficacy of dolutegravir in children aged less than 4 weeks or weighing less than 3 kg have 
not yet been established. There are insufficient data to recommend a dose for dolutegravir in integrase 
inhibitor resistant adolescents, children and infants. Currently available data are described in section 4.8, 5.1 
and 5.2, but no recommendation on a posology can be made. 
 
Method of administration 
 
Oral use. 
Tivicay can be taken with or without food (see section 5.2). In the presence of integrase class resistance, 
Tivicay should preferably be taken with food to enhance exposure (particularly in patients with Q148 
mutations) (see section 5.2). The dispersible tablets may be dispersed in drinking water, or swallowed whole 
with drinking water.  
 
When dispersed, the amount of water will depend on the number of tablets prescribed. The tablet(s) should 
be fully dispersed before swallowing. However, tablets should not be chewed, cut or crushed. The dose of 
medicine must be given within 30 minutes of preparation. If it has been more than 30 minutes the dose 
should be washed away and a new dose should be prepared. Comprehensive instructions for dispersing the 
tablet are provided in the package leaflet (see Step-by-step instructions for use). 
 
If swallowing tablets whole, patients should not swallow more than one tablet at a time, to reduce the risk of 
choking. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Medicinal products with narrow therapeutic windows that are substrates of organic cation transporter 2 
(OCT2), including but not limited to fampridine (also known as dalfampridine; see section 4.5). 
 
4.4 Special warnings and precautions for use 
 
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.  
 
Integrase class resistance of particular concern 
 



34 

The decision to use dolutegravir in the presence of integrase class resistance should take into account that the 
activity of dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondary 
mutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent dolutegravir provides added 
efficacy in the presence of such integrase class resistance is uncertain (see section 5.2). 
 
Hypersensitivity reactions 
 
Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, 
constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and 
other suspect medicinal products 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 dolutegravir or other suspect active substances after 
the onset of hypersensitivity may result in a life-threatening allergic reaction.  
 
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.  
 
Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some 
hepatitis B and/or C co-infected patients at the start of dolutegravir therapy.  Monitoring of liver 
biochemistries is recommended in patients with hepatitis B and/or C co-infection.  Particular diligence 
should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) 
when starting dolutegravir-based therapy in hepatitis B co-infected patients (see section 4.8). 
 
Opportunistic infections 
 
Patients should be advised that dolutegravir or any other antiretroviral therapy 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. 
 
Drug interactions 
 
Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. 
This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g. magnesium/ 
aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, etravirine 
(without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John’s wort and certain anti-
epileptic medicinal products) (see section 4.5). 
 
Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered 
when starting and stopping coadministration of dolutegravir 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 dolutegravir. 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.   
 



35 

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. 
 
Weight and metabolic parameters 
 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such 
changes may in part be linked to disease control and lifestyle. For lipids, there is in some cases evidence for 
a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. 
For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid 
disorders should be managed as clinically appropriate. 
 
Lamivudine and dolutegravir  
 
The two-drug regimen of dolutegravir 50 mg film-coated tablets once daily and lamivudine 300 mg once 
daily was explored in two large randomized and blinded studies, GEMINI 1 and GEMINI 2 (see section 5.1). 
This regimen is only suitable for the treatment of HIV-1 infection where there is no known or suspected 
resistance to the integrase inhibitor class, or to lamivudine. 
 
Excipients 
 
Tivicay contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially ‘sodium free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Effect of other agents on the pharmacokinetics of dolutegravir 
 
All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class 
resistance. 
 
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of 
UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may 
decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3). 
Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase 
dolutegravir plasma concentration (see Table 3). 
 
The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 3). 
 
Effect of dolutegravir on the pharmacokinetics of other agents 
 
In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe.  Based on in vivo and/or in vitro 
data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of 
any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2).   
 
In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin 
extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is 
dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase 
plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE-1 
(e.g. fampridine [also known as dalfampridine], metformin) (see Table 3). 
 
In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3.  
Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition 



36 

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.   
 
Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal 
products are listed in Table 3. 
 
Interaction table 
Interactions between dolutegravir and co-administered medicinal products are listed in Table 3 (increase is 
indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as 
“AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”). 
 
Table 3: Drug Interactions 
Medicinal products 
by therapeutic areas 

Interaction  
Geometric mean change 
(%)  

Recommendations concerning 
co-administration 

HIV-1 Antiviral Agents 
Non-nucleoside Reverse Transcriptase Inhibitors 
Etravirine without 
boosted protease 
inhibitors 

Dolutegravir ↓ 
   AUC ↓ 71% 
   Cmax ↓ 52% 
   Cτ ↓ 88% 
 
Etravirine ↔ 
(induction of UGT1A1 and 
CYP3A enzymes) 

Etravirine without boosted protease inhibitors 
decreased plasma dolutegravir concentration. The 
recommended adult dose of dolutegravir should be 
given twice daily when co-administered with 
etravirine without boosted protease inhibitors. In 
paediatric patients the weight-based once daily 
dose should be administered twice daily.  
Dolutegravir should not be used with etravirine 
without co-administration of atazanavir/ritonavir, 
darunavir/ritonavir or lopinavir/ritonavir in INI-
resistant patients (see further below in table). 

Lopinavir/ritonavir + 
etravirine 

Dolutegravir ↔ 
   AUC ↑ 11% 
   Cmax ↑ 7% 
   Cτ ↑ 28% 
LPV ↔ 
RTV ↔ 

No dose adjustment is necessary. 

Darunavir/ritonavir + 
etravirine  

Dolutegravir ↓ 
   AUC ↓ 25% 
   Cmax ↓ 12% 
   Cτ ↓ 36% 
DRV ↔ 
RTV ↔ 

No dose adjustment is necessary. 

Efavirenz Dolutegravir ↓ 
   AUC ↓ 57% 
   Cmax ↓ 39% 
   Cτ ↓ 75% 
 
Efavirenz ↔ (historical 
controls) 
(induction of UGT1A1 and 
CYP3A enzymes) 

The recommended adult dose of dolutegravir 
should be given twice daily when co-administered 
with efavirenz. In paediatric patients the weight-
based once daily dose should be administered 
twice daily.   
In the presence of integrase class resistance 
alternative combinations that do not include 
efavirenz should be considered (see section 4.4). 

Nevirapine Dolutegravir ↓ 
(Not studied, a similar 
reduction in exposure as 
observed with efavirenz is 
expected, due to induction) 

The recommended adult dose of dolutegravir 
should be given twice daily when co-administered 
with nevirapine. In paediatric patients the weight-
based once daily dose should be administered 
twice daily.   
In the presence of integrase class resistance 



37 

alternative combinations that do not include 
nevirapine should be considered (see section 4.4). 

Rilpivirine Dolutegravir ↔ 
   AUC ↑ 12% 
   Cmax ↑ 13% 
   Cτ ↑ 22% 
Rilpivirine ↔ 

No dose adjustment is necessary. 

Nucleoside Reverse Transcriptase Inhibitors 
Tenofovir Dolutegravir ↔ 

   AUC ↑ 1% 
   Cmax ↓ 3% 
   Cτ  ↓ 8% 
Tenofovir ↔ 

No dose adjustment is necessary. 

Protease Inhibitors 
Atazanavir Dolutegravir ↑ 

   AUC ↑ 91% 
   Cmax ↑ 50% 
   Cτ ↑ 180% 
 
Atazanavir ↔ (historical 
controls) 
(inhibition of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary. 
 
Tivicay should not be dosed higher than 30 mg 
twice daily in combination with atazanavir (see 
section 5.2) due to lack of data. 

Atazanavir/ritonavir Dolutegravir ↑ 
   AUC ↑ 62% 
   Cmax ↑ 34% 
   Cτ ↑ 121% 
 
Atazanavir ↔ 
Ritonavir ↔ 
(inhibition of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary. 
 
Tivicay should not be dosed higher than 30 mg 
twice daily in combination with atazanavir (see 
section 5.2) due to lack of data.  

Tipranavir/ritonavir 
(TPV+RTV) 

Dolutegravir ↓ 
   AUC ↓ 59% 
   Cmax ↓ 47% 
   Cτ ↓ 76% 
(induction of UGT1A1 and 
CYP3A enzymes) 

The recommended adult dose of dolutegravir 
should be given twice daily when co-administered 
with tipranavir/ritonavir. In paediatric patients the 
weight-based once daily dose should be 
administered twice daily.   
In the presence of integrase class resistance this 
combination should be avoided (see section 4.4). 

Fosamprenavir/ 
ritonavir (FPV+RTV) 

Dolutegravir ↓ 
   AUC ↓ 35% 
   Cmax ↓ 24% 
   Cτ ↓ 49% 
(induction of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary in the absence of 
integrase class resistance.   
In the presence of integrase class resistance 
alternative combinations that do not include 
fosamprenavir/ritonavir should be considered. 

Darunavir/ritonavir Dolutegravir ↓ 
   AUC ↓ 22%  
   Cmax ↓ 11% 
   C24 ↓ 38% 
(induction of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary. 

Lopinavir/ritonavir Dolutegravir ↔ 
   AUC ↓ 4%  
   Cmax ↔ 0% 
   C24 ↓ 6% 

No dose adjustment is necessary. 



38 

Other Antiviral agents 
Daclatasvir Dolutegravir ↔ 

   AUC ↑ 33%  
   Cmax ↑ 29% 
   Cτ ↑ 45% 
Daclatasvir ↔ 

Daclatasvir did not change dolutegravir plasma 
concentration to a clinically relevant extent.  
Dolutegravir did not change daclatasvir plasma 
concentration.  No dose adjustment is necessary. 

Other agents 
Potassium channel blocker 
Fampridine (also 
known as 
dalfampridine) 

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 dolutegravir is 
contraindicated. 

Anticonvulsants 
Carbamazepine 
 

Dolutegravir ↓ 
   AUC ↓ 49% 
   Cmax ↓ 33% 
   Cτ ↓ 73% 
 

The recommended adult dose of dolutegravir 
should be given twice daily when co-administered 
with carbamazepine. In paediatric patients the 
weight-based once daily dose should be 
administered twice daily. Alternatives to 
carbamazepine should be used where possible for 
INI resistant patients. 

Oxcarbazepine 
Phenytoin 
Phenobarbital 
 

Dolutegravir ↓ 
(Not studied, decrease 
expected due to induction of 
UGT1A1 and CYP3A 
enzymes, a similar reduction 
in exposure as observed 
with carbamazepine is 
expected) 

The recommended adult dose of dolutegravir 
should be given twice daily when co-administered 
with these metabolic inducers. In paediatric 
patients the weight-based once daily dose should 
be administered twice daily.  Alternative 
combinations that do not include these metabolic 
inducers should be used where possible in INI-
resistant patients.  

Azole anti-fungal agents 
Ketoconazole 
Fluconazole  
Itraconazole  
Posaconazole  
Voriconazole 

Dolutegravir ↔ 
(Not studied) 

No dose adjustment is necessary. Based on data 
from other CYP3A4 inhibitors, a marked increase 
is not expected.   

Herbal products 
St. John’s wort Dolutegravir ↓ 

(Not studied, decrease 
expected due to induction of 
UGT1A1 and CYP3A 
enzymes, a similar reduction 
in exposure as observed 
with carbamazepine is 
expected) 

The recommended adult dose of dolutegravir 
should be given twice daily when co-administered 
with St. John’s wort. In paediatric patients the 
weight-based once daily dose should be 
administered twice daily. Alternative combinations 
that do not include St. John’s wort should be used 
where possible in INI-resistant patients. 

Antacids and supplements 
Magnesium/ 
aluminium-containing 
antacid 

Dolutegravir ↓ 
   AUC ↓ 74%  
   Cmax ↓ 72% 
(Complex binding to 
polyvalent ions) 

Magnesium/ aluminium-containing antacid should 
be taken well separated in time from the 
administration of dolutegravir (minimum 2 hours 
after or 6 hours before). 

Calcium supplements  Dolutegravir ↓ 
   AUC ↓ 39%  
   Cmax ↓ 37% 
   C24 ↓ 39% 

Calcium supplements, iron supplements or 
multivitamins should be taken well separated in 
time from the administration of dolutegravir 
(minimum 2 hours after or 6 hours before).  



39 

(Complex binding to 
polyvalent ions) 

Iron supplements  Dolutegravir ↓ 
   AUC ↓ 54%  
   Cmax ↓ 57% 
   C24 ↓ 56% 
(Complex binding to 
polyvalent ions) 

Multivitamin Dolutegravir ↓ 
   AUC ↓ 33%  
   Cmax ↓ 35% 
   C24 ↓ 32% 
(Complex binding to 
polyvalent ions) 

Corticosteroids 
Prednisone Dolutegravir ↔ 

   AUC ↑ 11% 
   Cmax ↑ 6% 
   Cτ ↑ 17% 

No dose adjustment is necessary. 

Antidiabetics 
Metformin Metformin ↑ 

When co-administered with 
dolutegravir 50mg film-
coated tablets once daily: 
Metformin 
   AUC ↑ 79%  
   Cmax ↑ 66% 
When co-administered with 
dolutegravir 50mg film-
coated tablets twice daily:  
Metformin 
   AUC ↑ 145 %  
   Cmax ↑ 111% 

A dose adjustment of metformin should be 
considered when starting and stopping 
coadministration of dolutegravir with metformin, 
to maintain glycaemic control. In patients with 
moderate renal impairment a dose adjustment of 
metformin should be considered when 
coadministered with dolutegravir, because of the 
increased risk for lactic acidosis in patients with 
moderate renal impairment due to increased 
metformin concentration (section 4.4). 

Antimycobacterials 
Rifampicin Dolutegravir ↓ 

   AUC ↓ 54% 
   Cmax ↓ 43% 
   Cτ ↓72% 
(induction of UGT1A1 and 
CYP3A enzymes) 

The recommended adult dose of dolutegravir 
should be given twice daily when co-administered 
with rifampicin in the absence of integrase class 
resistance. In paediatric patients the weight-based 
once daily dose should be administered twice 
daily.   
In the presence of integrase class resistance this 
combination should be avoided (see section 4.4). 

Rifabutin Dolutegravir ↔ 
   AUC ↓ 5% 
   Cmax ↑ 16% 
   Cτ ↓ 30% 
(induction of UGT1A1 and 
CYP3A enzymes) 

No dose adjustment is necessary. 

Oral contraceptives 
Ethinyl estradiol (EE) 
and Norelgestromin 
(NGMN) 

Dolutegravir ↔ 
EE ↔ 
   AUC ↑ 3%  
   Cmax ↓ 1% 
 
NGMN ↔ 

Dolutegravir had no pharmacodynamic effect on 
Luteinizing Hormone (LH), Follicle Stimulating 
Hormone (FSH) and progesterone. No dose 
adjustment of oral contraceptives is necessary 
when co-administered with dolutegravir.  



40 

   AUC ↓ 2%  
   Cmax ↓ 11% 

Analgesics 
Methadone  Dolutegravir ↔ 

Methadone ↔ 
   AUC ↓ 2%  
   Cmax ↔ 0% 
   Cτ ↓ 1% 

No dose adjustment is necessary of either agent. 

 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
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 (see below), including consideration of effective contraceptive measures. 
 
If a woman plans pregnancy, the benefits and the risks of continuing treatment with dolutegravir should be 
discussed with the patient. 
 
Pregnancy 
 
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). If a pregnancy is confirmed in the 
first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to 
another antiretroviral regimen should be discussed with the patient taking the gestational age and the critical 
time period of neural tube defect development into account. 
 
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 toxicity studies, 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 during second and third trimester of pregnancy indicate no 
evidence of increased risk of foeto/neonatal toxicity. Dolutegravir may be used during the second and third 
trimester of pregnancy when the expected benefit justifies the potential risk to the foetus. 
 
Breast-feeding 
 
Dolutegravir is excreted in human milk in small amounts. There is insufficient information on the effects of 
dolutegravir in neonates/infants. 
 
It is recommended that HIV infected women do not breast-feed their infants under any circumstances in 
order to avoid transmission of HIV. 



41 

 
Fertility 
 
There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no 
effects of dolutegravir on male or female fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical 
status of the patient and the adverse reaction profile of dolutegravir 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 
 
The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included 
rash and severe liver effects (see section 4.4).  The most commonly seen treatment emergent adverse 
reactions were nausea (13%), diarrhoea (18%) and headache (13%). 
 
Tabulated list of adverse reactions 
 
The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ 
class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), 
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000). 
 



42 

Table 4 Adverse Reactions 
Immune system 
disorders 

Uncommon Hypersensitivity (see section 4.4) 
Uncommon Immune Reconstitution Syndrome (see section 4.4)** 

Psychiatric disorders Common Insomnia 
Common Abnormal dreams 
Common Depression 
Common Anxiety 
Uncommon Suicidal ideation*, suicide attempt*  

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

Nervous system 
disorders 

Very common Headache 
Common Dizziness 

Gastrointestinal 
disorders 

Very common Nausea 
Very common Diarrhoea 
Common Vomiting 
Common Flatulence 
Common Upper abdominal pain 
Common Abdominal pain 
Common Abdominal discomfort 

Hepatobiliary 
disorders 

Uncommon Hepatitis 

Rare Acute hepatic failure 

Skin and 
subcutaneous tissue 
disorders 

Common Rash 
Common Pruritus 

Musculoskeletal and 
connective tissue 
disorders 

Uncommon Arthralgia 
Uncommon Myalgia 

General disorders 
and administration 
site conditions 

Common Fatigue 

Investigations Common Alanine aminotransferase (ALT) and/or Aspartate 
aminotransferase (AST) elevations 

Common Creatine phosphokinase (CPK) elevations 
 
**see below under Description of selected adverse reactions. 
 
Description of selected adverse reactions 
 
Changes in laboratory biochemistries 
Increases in serum creatinine occurred within the first week of treatment with dolutegravir and remained 
stable through 48 weeks. A mean change from baseline of 9.96 µmol/L was observed after 48 weeks of 
treatment. Creatinine increases were comparable by various background regimens. These changes are not 
considered to be clinically relevant since they do not reflect a change in glomerular filtration rate. 
 
Co-infection with Hepatitis B or C 
In Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided that 
baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety 
profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without 
hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup 
with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with 
immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at 
the start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see 
section 4.4). 
 



43 

Immune reactivation syndrome 
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral 
therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; 
however, the reported time to onset is more variable and these events can occur many months after initiation 
of treatment (see section 4.4). 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4). 
 
Paediatric population 
 
Based on available data from the ongoing P1093 (ING112578) and ODYSSEY (201296) studies in 172 
infants, children and adolescents (aged 4 weeks and above, to less than 18 years, and weighing at least 3 kg), 
who received the recommended doses of dispersible tablets or film-coated tablets once daily, there were no 
additional types of adverse reactions beyond those observed in the adult population. 
 
Reporting of suspected adverse reactions 
 
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 
 
There is currently limited experience with overdosage in dolutegravir.  
 
Limited experience of single higher doses (up to 250 mg film-coated tablets in healthy subjects) revealed no 
specific symptoms or signs, 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 dolutegravir. If overdose occurs, the 
patient should be treated supportively with appropriate monitoring, as necessary. As dolutegravir is highly 
bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX12 
 
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. 
 
Pharmacodynamic effects 
 
Antiviral activity in cell culture  
The IC50 for dolutegravir in various labstrains 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). 
 
Antiviral activity in combination with other antiviral agents 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


44 

No antagonistic effects in vitro were seen with dolutegravir and other antiretrovirals tested: stavudine, 
abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc and raltegravir.  In addition, no 
antagonistic effects were seen for dolutegravir and adefovir, and ribavirin had no apparent effect on 
dolutegravir activity.  
 
Effect of human serum  
In 100% human serum, the mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 
µg/mL.  
 
Resistance 
 
Resistance in vitro 
 
Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIV-1 IIIB during 
passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F, 
resulting in a maximal fold change in susceptibility of 4 (range 2-4). These mutations were not selected in 
patients treated with dolutegravir in the clinical studies.  Using strain NL432, mutations E92Q (FC 3) and 
G193E (also FC 3) were selected. The E92Q mutation has been selected in patients with pre-existing 
raltegravir resistance who were then treated with dolutegravir (listed as a secondary mutation 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 ART 
experienced, INI naive individual patients with subtypes B and C in the clinical program, 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 and 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 these primary mutations in 
experiments with site directed mutants, dolutegravir susceptibility is still unchanged (FC <2 vs wild type 
virus), except in the case of Q148-mutations, where a FC of 5-10 or higher is seen with combinations of 
certain secondary mutations. The effect by the Q148-mutations (H/R/K) was also verified in passage 
experiments with site directed mutants.  In serial passage with strain NL432, starting with site directed 
mutants harbouring N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). 
In contrast, starting with mutants harbouring mutation Q148H (FC 1), a variety of secondary mutations were 
seen 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. 
 
Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed for 
susceptibility to dolutegravir.  Dolutegravir has a less than or equal to 10 FC against 94% of the 705 clinical 
isolates. 
 
Resistance in vivo 
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=1118 follow-up of 48-96 weeks). In 
previously untreated patients receiving dolutegravir + lamivudine in the GEMINI studies through week 96 
(n=716), no development of resistance to the integrase class, or to the NRTI class was seen. 
 
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 



45 

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 experienced or infected with integrase resistant virus by 
transmission. The R263K mutation was also selected in vitro (see above). 
 
In the presence of integrase class-resistance (VIKING-3 study) the following mutations were selected in 32 
patients with protocol defined virological failure (PDVF) through Week 24 and with paired genotypes (all 
treated with a 50 mg dose of dolutegravir film-coated tablets twice daily + optimized background agents):  
L74L/M (n=1), E92Q (n=2), T97A (n=9), E138K/A/T (n=8), G140S (n=2), Y143H (n=1), S147G (n=1), 
Q148H/K/R (n=4), and N155H (n=1) and E157E/Q (n=1).  Treatment emergent integrase resistance typically 
appeared in patients with a history of the Q148-mutation (baseline or historic). Five further subjects 
experienced PDVF between weeks 24 and 48, and 2 of these 5 had treatment emergent mutations.  
Treatment-emergent mutations or mixtures of mutations observed were L74I (n=1), N155H (n=2). 
 
The VIKING-4 study examined dolutegravir (plus optimized background therapy) in subjects with primary 
genotypic resistance to INIs at Screening in 30 subjects.  Treatment-emergent mutations observed were 
consistent with those observed in the VIKING-3 study. 
 
In paediatric patients with prior failed therapies, but naïve to the integrase class, the integrase inhibitor 
substitution G118R was observed in 5/159 patients treated with dolutegravir, given in combination with an 
investigator selected background regimen. Of these five, 4 participants had additional integrase associated 
substitutions as follows: L74M, E138E/K, E92E/Q and T66I. Four of the 5 participants with emergent 
G118R had phenotypic data available. Dolutegravir FC (fold change as compared to wildtype virus) for these 
four participants ranged from 6 to 25-fold. 
 
Effects on electrocardiogram 
 
No relevant effects were seen on the QTc interval with doses exceeding the clinical dose by approximately 
three fold.  
 
Clinical efficacy and safety  
 
Previously untreated patients  
The efficacy of dolutegravir in HIV-infected, therapy naïve subjects is based on the analyses of 96-week data 
from two randomized, international, double-blind, active-controlled trials, SPRING-2 (ING113086) and 
SINGLE (ING114467). This is supported by 96 week data from an open-label, randomized and active-
controlled study FLAMINGO (ING114915) and additional data from the open-label phase of SINGLE to 
144 weeks. The efficacy of dolutegravir in combination with lamivudine in adults is supported by 96-week 
data from two identical 148-week, randomised, multicentre, double-blind, non-inferiority studies GEMINI-1 
(204861) and GEMINI-2 (205543). 
 
In SPRING-2, 822 adults were randomized and received at least one dose of either dolutegravir 50 mg film-
coated tablets once daily or raltegravir (RAL) 400 mg twice daily, both administered with either ABC/3TC 
or TDF/FTC.  At baseline, median patient age was 36 years, 14% were female, 15% non-white, 11% had 
hepatitis B and/or C co-infection and 2% were CDC Class C, these characteristics were similar between 
treatment groups. 
 
In SINGLE, 833 subjects were randomized and received at least one dose of either dolutegravir 50 mg film-
coated tablets once daily with fixed-dose abacavir-lamivudine (Dolutegravir + ABC/3TC) or fixed-dose 
efavirenz-tenofovir-emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were 
female, 32% non-white, 7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics 
were similar between treatment groups.  
 
The primary endpoint and other week 48 outcomes (including outcomes by key baseline covariates) for 
SPRING-2 and SINGLE are shown in Table 5. 
 
Table 5 Response in SPRING-2 and SINGLE at 48 Weeks (Snapshot algorithm, <50 copies/mL) 



46 

 SPRING-2 SINGLE 
 Dolutegravir 

50 mg Once 
Daily + 2 NRTI 

N=411 

RAL 400 mg 
Twice Daily + 2 

NRTI 
N=411 

Dolutegravir 
50 mg + 

ABC/3TC Once 
Daily 

N=414 

EFV/TDF/FTC 
Once Daily 

N=419 

HIV-1 RNA <50 copies/mL 88% 85% 88% 81% 
  Treatment Difference* 2.5% (95% CI: -2.2%, 7.1%) 7.4% (95% CI: 2.5%, 12.3%) 
Virologic non-response†  5% 8% 5% 6% 

HIV-1 RNA <50 copies/mL by baseline covariates 
Baseline Viral Load 
(cps/mL)     

  ≤100,000  267 / 297 (90%) 264 / 295 (89%) 253 / 280 (90%) 238 / 288 (83%) 
  >100,000  94 / 114 (82%) 87 / 116 (75%) 111 / 134 (83%) 100 / 131 (76%) 
Baseline CD4+ (cells/ mm3)     
  <200 43 / 55 (78%) 34 / 50 (68%) 45 / 57 (79%) 48 / 62 (77%) 
  200 to <350  128 / 144 (89%) 118 / 139 (85%) 143 / 163 (88%) 126 / 159 (79%) 
  ≥350  190 / 212 (90%) 199 / 222 (90%) 176 / 194 (91%) 164 / 198 (83%) 
NRTI backbone     
  ABC/3TC 145 / 169 (86%) 142 / 164 (87%) N/A N/A 
  TDF/FTC 216 / 242 (89%) 209 / 247 (85%) N/A N/A 
Gender     
  Male  308 / 348 (89%) 305 / 355 (86%) 307 / 347 (88%) 291 / 356 (82%) 
  Female 53 / 63 (84%) 46 / 56 (82%) 57 / 67 (85%) 47 / 63 (75%) 
Race      
  White  306 / 346 (88%) 301 / 352 (86%) 255 / 284 (90%) 238 /285 (84%) 
  African-America/African 
Heritage/Other 55 / 65 (85%) 50 / 59 (85%) 109 / 130 (84%) 99 / 133 (74%) 

Age (years)     
  <50 324/370 (88%) 312/365 (85%) 319/361 (88%) 302/375 (81%) 
  ≥50 37/41 (90%) 39/46 (85%) 45/53 (85%) 36/44 (82%) 
Median CD4 change from 
baseline 230 230 246‡ 187‡ 

* Adjusted for baseline stratification factors. 
† Includes subjects who changed BR to new class or changed BR not permitted per protocol or due to lack 
of efficacy prior to Week 48 (for SPRING-2 only), subjects who discontinued prior to Week 48 for lack or 
loss of efficacy and subjects who are ≥50 copies in the 48 week window.  
‡ Adjusted mean treatment difference was statistically significant (p<0.001) 
 
At week 48, dolutegravir was non-inferior to raltegravir in the SPRING-2 study, and in the SINGLE study 
dolutegravir + ABC/3TC was superior to efavirenz/TDF/FTC (p=0.003), table 5 above. In SINGLE, the 
median time to viral suppression was shorter in the dolutegravir treated patients (28 vs 84 days, (p<0.0001, 
analysis pre-specified and adjusted for multiplicity).  
 
At week 96, results were consistent with those seen at week 48.  In SPRING-2, dolutegravir was still non-
inferior to raltegravir (viral suppression in 81% vs 76% of patients), and with a median change in CD4 count 
of 276 vs 264 cells/mm3, respectively.  In SINGLE, dolutegravir + ABC/3TC was still superior to 
EFV/TDF/FTC (viral suppression in 80% vs 72%, treatment difference 8.0% (2.3, 13.8), p=0.006, and with 
an adjusted mean change in CD4 count of 325 vs 281 cells/ mm3, respectively.  At 144 weeks in the open-
label phase of SINGLE, virologic suppression was maintained, the dolutegravir + ABC/3TC arm (71%) was 
superior to the EFV/TDF/FTC arm (63%), treatment difference was 8.3% (2.0, 14.6). 
 
In FLAMINGO (ING114915), an open-label, randomised and active-controlled study, 484 HIV-1 infected 
antiretroviral naïve adults received one dose of either dolutegravir 50 mg film-coated tablets once daily 
(n=242) or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily (n=242), both administered with either 



47 

ABC/3TC or TDF/FTC.  At baseline, median patient age was 34 years, 15% were female, 28% non-white, 
10% had hepatitis B and/or C co-infection, and 3% were CDC Class C; these characteristics were similar 
between treatment groups.  Virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir group 
(90%) was superior to the DRV/r group (83%) at 48 weeks. The adjusted difference in proportion and 95% 
CI were 7.1% (0.9, 13.2), p=0.025. At 96 weeks, virologic suppression in the dolutegravir group (80%) was 
superior to the DRV/r group (68%), (adjusted treatment difference [Dolutegravir-(DRV+RTV)]: 12.4%; 95% 
CI: [4.7, 20.2]. 
 
In GEMINI-1 (204861) and GEMINI-2 (205543), identical 148-week, randomised, double-blind studies, 
1433 adult HIV-1 infected antiretroviral naïve subjects were randomised to either a two-drug regimen of 
dolutegravir 50 mg film-coated tablets plus lamivudine 300 mg once daily, or to a three-drug regimen of 
dolutegravir 50 mg film-coated tablets once daily with fixed dose TDF/FTC. Subjects were enrolled with a 
screening plasma HIV-1 RNA of 1000 c/mL to ≤500,000 c/mL. At baseline, in the pooled analysis, median 
patient age was 33 years, 15% were female, 31% non-white, 6% had hepatitis C co-infection and 9% were 
CDC Stage 3. Approximately one third of the patients were infected with an HIV non-B subtype; these 
characteristics were similar between treatment groups. Virologic suppression (HIV-1 RNA <50 copies/mL) 
in the dolutegravir plus lamivudine group was non-inferior to the dolutegravir plus TDF/FTC group at 48 
weeks, as shown in Table 6. The results of the pooled analysis were in line with those of the individual 
studies, for which the primary endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at 
week 48 based on the Snapshot algorithm) was met. The adjusted difference was -2.6% (95% CI: -6.7; 1.5) 
for GEMINI-1 and -0.7% (95% CI: -4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 
10%. 
 
Table 6 Response (<50 cps/ml, snapshot) in GEMINI 1 + 2, pooled data.  

 Dolutegravir + 3TC 
(N=716) 
n/N (%) 

Dolutegravir + 
TDF/FTC 
(N=717) 
n/N (%) 

All patients 655/716 (91) 669/717 (93) 
 adjusted diff -1.7% (CI95-4.4, 1.1) a 

By BL HIV-1 RNA 
≤100,000 cps/mL 526/576 (91) 531/564 (94) 
>100,000 cps/mL 129/140 (92) 138/153 (90) 
By CD4+ 
≤200 c/ mm3 50/63 (79) 51/55 (93) 
>200 c/ mm3 605/653 (93) 618/662 (93) 
By HIV-1 subtype  
B 424/467 (91) 452/488 (93) 
Non-B 231/249 (93) 217/229 (95) 

 
Rebound up to week 48 b 6 (<1) 4 (<1) 

 
Mean change in CD4 count from 
baseline at Week 48, c/ mm3 224 217 

a adjusted for BL stratification factors: Plasma HIV-1 RNA (≤100,000 cps/mL vs. >100,000 cps/mL) and CD4+ 
cell count (≤200 cells/mm3 vs. >200 cells/mm3). 
b Confirmed plasma HIV-1 RNA levels to ≥200 cps/mL after prior confirmed suppression to <200 cps/mL. 

  
At 96 weeks the dolutegravir plus lamivudine group (86% with plasma HIV-1 RNA < 50 copies/mL [pooled 
data]) remained non-inferior to the dolutegravir plus tenofovir/emtricitabine FDC group (90% with plasma 
HIV-1 RNA < 50 copies/mL [pooled data]). The adjusted difference in proportions and 95% CI was -3.4% (-
6.7, 0.0). The results of the pooled analysis were in line with those of the individual studies, for which the 
secondary endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at Week 96 based on the 
Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir/emtricitabine FDC) 
was met. The adjusted differences of -4.9 (95% CI: -9.8; 0.0) for GEMINI-1 and -1.8 (95% CI: -6.4; 2.7) for 



48 

GEMINI-2 were within the prespecified non-inferiority margin of -10%. The mean increase in CD4+ T-cell 
counts was 269 in the DTG+3TC arm and 259 in the DTG+FTC/TDF arm, at week 96. 
 
Treatment emergent resistance in previously untreated patients failing therapy 
Through 96 weeks in SPRING-2 and FLAMINGO and 144 weeks in SINGLE, no cases of treatment 
emergent primary resistance to the integrase- or NRTI-class were seen in the dolutegravir-containing arms. 
For the comparator arms, the same lack of treatment emergent resistance was also the case for patients 
treated with darunavir/r in FLAMINGO. In SPRING-2, four patients in the RAL-arm failed with major 
NRTI mutations and one with raltegravir resistance; in SINGLE, six patients in the EFV/TDF/FTC-arm 
failed with mutations associated with NNRTI resistance, and one developed a major NRTI mutation. 
Through 96 weeks in the GEMINI-1 and GEMINI-2 studies, no cases of emergent resistance to the 
integrase- or NRTI-class were seen in either the Dolutegravir+3TC or comparator Dolutegravir+TDF/FTC 
arms. 
 
Patients with prior treatment failure, but not exposed to the integrase class  
In the international multicentre, double-blind SAILING study (ING111762), 719 HIV-1 infected, 
antiretroviral therapy (ART)-experienced adults were randomized and received either dolutegravir 50 mg 
film-coated tablets once daily or raltegravir 400 mg twice daily with investigator selected background 
regimen consisting of up to 2 agents (including at least one fully active agent).  At baseline, median patient 
age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or C co-infection, and 46% 
were CDC Class C.  All patients had at least two class ART resistance, and 49% of subjects had at least 3-
class ART resistance at baseline.  
 
Week 48 outcomes (including outcomes by key baseline covariates) for SAILING are shown in Table 7. 
 
Table 7 Response in SAILING at 48 Weeks (Snapshot algorithm, <50 copies/mL) 
 Dolutegravir 50 mg 

Once Daily + BR 
N=354§ 

RAL 400 mg Twice 
Daily + BR 

N=361§ 
HIV-1 RNA <50 copies/mL 71% 64% 
  Adjusted treatment difference‡ 7.4% (95% CI: 0.7%, 14.2%) 
Virologic non-response 20% 28% 

HIV-1 RNA <50 copies/mL by baseline covariates 
Baseline Viral Load (copies/mL)   
  ≤50,000 copies/mL 186 / 249 (75%) 180 / 254 (71%) 
  >50,000 copies/mL 65 / 105 (62%) 50 / 107 (47%) 
Baseline CD4+ (cells/ mm3)   
  <50 33 / 62 (53%) 30 / 59 (51%) 
  50 to <200  77 / 111 (69%) 76 / 125 (61%) 
  200 to <350  64 / 82 (78%) 53 / 79 (67%) 
  ≥350 77 / 99 (78%) 71 / 98 (72%) 
Background Regimen   
  Genotypic Susceptibility Score* <2 155 / 216 (72%) 129 / 192 (67%) 
  Genotypic Susceptibility Score* =2 96 / 138 (70%) 101 / 169 (60%) 
  Use of DRV in background regimen   
    No DRV use  143 / 214 (67%) 126 / 209 (60%) 
    DRV use with primary PI mutations 58 / 68 (85%) 50 / 75 (67%) 
    DRV use without primary PI mutations 50 / 72 (69%) 54 / 77 (70%) 
Gender   
  Male  172 / 247 (70%) 156 / 238 (66%) 
  Female 79 / 107 (74%) 74 / 123 (60%) 
Race    
  White  133 / 178 (75%) 125 / 175 (71%) 
  African-America/African Heritage/Other 118 / 175 (67%) 105 / 185 (57%) 
Age (years)   



49 

  <50 196 / 269 (73%) 172 / 277 (62%) 
  ≥50 55 / 85 (65%) 58 / 84 (69%) 
HIV sub type   
  Clade B 173 / 241 (72%) 159 / 246 (65%) 
  Clade C 34 / 55 (62%) 29 / 48 (60%) 
  Other† 43 / 57 (75%) 42 / 67 (63%) 
Mean increase in CD4+ T cell (cells/mm3) 162 153 
‡ Adjusted for baseline stratification factors. 
§ 4 subjects were excluded from the efficacy analysis due to data integrity at one study site  
*The Genotypic Susceptibility Score (GSS) was defined as the total number of ARTs in BR to which 
a subject’s viral isolate showed susceptibility at baseline based upon genotypic resistance tests.   
†Other clades included: Complex (43), F1 (32), A1 (18), BF (14), all others <10. 
 
 
In the SAILING study, virologic suppression (HIV-1 RNA <50 copies/mL) in the Tivicay arm (71%) was 
statistically superior to the raltegravir arm (64%), at Week 48 (p=0.03). 
 
Statistically fewer subjects failed therapy with treatment-emergent integrase resistance on Tivicay (4/354, 
1%) than on raltegravir (17/361, 5%) (p=0.003) (refer to section ‘Resistance in vivo’ above for details).   
 
Patients with prior treatment failure that included an integrase inhibitor (and integrase class resistance)  
In the multicentre, open-label, single arm VIKING-3 study (ING112574), HIV-1 infected, ART-experienced 
adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance 
received a 50 mg dose of Tivicay film-coated tablets twice daily with the current failing background regimen 
for 7 days but with optimised background ART from Day 8.  The study enrolled 183 patients, 133 with INI-
resistance at Screening and 50 with only historical evidence of resistance (and not at Screening).  
Raltegravir/elvitegravir was part of the current failing regimen in 98/183 patients (part of prior failing 
therapies in the others).  At baseline, median patient age was 48 years, 23% were female, 29% non-white, 
and 20% had hepatitis B and/or C co-infection.  Median baseline CD4+ was 140 cells/mm3, median duration 
of prior ART was 14 years, and 56% were CDC Class C.  Subjects showed multiple class ART resistance at 
baseline: 79% had ≥2 NRTI, 75% ≥1 NNRTI, and 71% ≥2 PI major mutations; 62% had non-R5 virus.  
 
Mean change from baseline in HIV RNA at day 8 (primary endpoint) was -1.4log10 copies/mL (95% CI -1.3 
– -1.5log10, p<0.001).  Response was associated with baseline INI mutation pathway, as shown in Table 8.   
 
Table 8 Virologic response (day 8) after 7 days of functional monotherapy, in patients with RAL/EVG 
as part of current failing regimen, VIKING 3 
Baseline parameters Dolutegravir 50 mg BID 

N=88* 
n Mean (SD) Plasma HIV-1 

RNA log10 c/mL 
Median  

Derived IN mutation group at 
Baseline with ongoing RAL/EVG 

   

Primary mutation other than 
Q148H/K/Ra 

48 -1.59 (0.47) -1.64 

Q148+1 secondary mutationb 26 -1.14 (0.61) -1.08 
Q148+≥2 secondary mutationsb 14 -0.75 (0.84) -0.45 
*Of 98 on RAL/EVG as part of current failing regimen, 88 had detectable primary INI mutations at 
Baseline and a Day 8 Plasma HIV-1 RNA outcome for evaluation 

a Included primary IN resistance mutations N155H, Y143C/H/R, T66A, E92Q  
b Secondary mutations from G140A/C/S, E138A/K/T, L74I. 
 
In patients without a primary mutation detected at baseline (N=60) (i.e. RAL/EVG not part of current failing 
therapy) there was a 1.63 log10 reduction in viral load at day 8. 
 



50 

After the functional monotherapy phase, subjects had the opportunity to re-optimize their background 
regimen when possible.  The overall response rate through 24 weeks of therapy, 69% (126/183), was 
generally sustained through 48 weeks with 116/183 (63%) of patients with HIV-1 RNA <50c/mL (ITT-E, 
Snapshot algorithm). When excluding patients who stopped therapy for non-efficacy reasons, and those with 
major protocol deviations (incorrect dolutegravir dosing, intake of prohibited co-medication), namely, “the 
Virological Outcome (VO)-population)”, the corresponding response rates were 75% (120/161, week 24) 
and 69% (111/160, week 48).  
 
The response was lower when the Q148-mutation was present at baseline, and in particular in the presence of 
≥2 secondary mutations, Table 9.  The overall susceptibility score (OSS) of the optimised background 
regimen (OBR) was not associated with Week 24 response, nor with the week 48 response.   
 
Table 9 Response by baseline Resistance, VIKING-3. VO Population (HIV-1 RNA <50 c/mL, Snapshot 
algorithm) 

 Week 24 (N=161) Week 48 
(N=160) 

Derived IN Mutation 
Group OSS=0 OSS=1 OSS=2 OSS>2 Total 

Total 

No primary IN mutation1 
2/2 (100%) 15/20 (75%) 19/21 (90%) 9/12 (75%) 

45/55 
(82%) 

38/55 
(69%) 

Primary mutation other 
than Q148H/K/R2 2/2 (100%) 20/20 (100%) 21/27 (78%) 8/10 (80%) 

51/59 
(86%) 

50/58 
(86%) 

Q148 + 1 secondary 
mutation3 2/2 (100%) 8/12 (67%) 10/17 (59%) - 

20/31 
(65%) 

19/31 
(61%) 

Q148 +≥2 secondary 
mutations 3 1/2 (50%) 2/11 (18%) 1/3 (33%) - 4/16 (25%) 4/16 (25%) 
1 Historical or phenotypic evidence of INI resistance only.  
2 N155H, Y143C/H/R, T66A, E92Q 
3 G140A/C/S, E138A/K/T, L74I 
OSS: combined genotypic and phenotypic resistance (Monogram Biosciences Net Assessment) 

 
The median change in CD4+ T cell count from baseline for VIKING-3 based on observed data was 
61 cells/mm3 at Week 24 and 110 cells/mm3 at Week 48.   
 
In the double blind, placebo controlled VIKING-4 study (ING116529), 30 HIV-1 infected, ART-experienced 
adults with primary genotypic resistance to INIs at Screening, were randomised to receive either dolutegravir 
50 mg film-coated twice daily or placebo with the current failing regimen for 7 days followed by an open 
label phase with all subjects receiving dolutegravir.  At baseline, median patient age was 49 years, 20% were 
female, 58% non-white, and 23% had hepatitis B and/or C co-infection.  Median baseline CD4+ was 160 
cells/mm3, median duration of prior ART was 13 years, and 63% were CDC Class C.  Subjects showed 
multiple class ART resistance at baseline: 80% had ≥2 NRTI, 73% ≥1 NNRTI, and 67% ≥2 PI major 
mutations; 83% had non-R5 virus.  Sixteen of 30 subjects (53%) harboured Q148 virus at baseline.  The 
primary endpoint at Day 8 showed that dolutegravir 50 mg film-coated tablets twice daily was superior to 
placebo, with an adjusted mean treatment difference for the change from Baseline in Plasma HIV-1 RNA of 
-1.2 log10 copies/mL (95% CI -1.5 - -0.8log10 copies/mL, p<0.001). The day 8 responses in this placebo 
controlled study were fully in line with those seen in VIKING-3 (not placebo controlled), including by 
baseline integrase resistance categories. At week 48, 12/30 (40%) subjects had HIV-1 RNA <50 copies/mL 
(ITT-E, Snapshot algorithm).  
 
In a combined analysis of VIKING-3 and VIKING-4 (n=186, VO population), the proportion of subjects 
with HIV RNA <50 copies/mL at Week 48 was 123/186 (66%).  The proportion of subjects with HIV RNA 
<50 copies/mL was 96/126 (76%) for No Q148 mutations, 22/41 (54%) for Q148+1 and 5/19 (26%) for 
Q148+≥2 secondary mutations.  
 
Paediatric population 



51 

 
In an ongoing Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic 
parameters, safety, tolerability and efficacy of dolutegravir following once daily dosing were evaluated in 
combination regimens in HIV-1 infected infants, children and adolescents aged ≥ 4 weeks to < 18 years, the 
majority of whom were treatment-experienced.  
 
The efficacy results (Table 10) include participants who received the recommended once daily doses of 
either dispersible tablets or film-coated tablets. 
 
Table 10 Antiviral and Immunological Activity Through Week 24 and Week 48 in Paediatric Patients 

 Week 24 
N=75 

Week 48 
N=66 

 n/N % (95% CI) n/N % (95% CI) 
Proportion of participants with HIV 
RNA <50 c/mLa, b 42/75 56  

(44.1, 67.5) 43/66 65.2  
(52.4, 76.5) 

Proportion of participants with HIV 
RNA <400 c/mLb 62/75 82.7 

(72.2, 90.4) 53/66 80.3  
(68.7, 89.1) 

 Median (n) (Q1, Q3) Median (n) (Q1, Q3) 
Change from baseline in CD4+ cell 
count (cells/mm3)  145 (72) (-64, 489) 184 (62) (-179, 665) 

Change from baseline in CD4+ 
percent 6 (72) (2.5, 10) 8 (62) (0.4, 11) 

Q1, Q3= First and third quartiles, respectively. 
a Results of <200 c/mL from HIV-1 RNA testing using an LLOD of 200 c/mL were censored to >50 c/mL in this 

analysis 
b Snapshot algorithm was used in the analyses 
 

In participants experiencing virologic failure, 5/36 acquired integrase inhibitor substitution G118R. Of these 
five, 4 participants had additional integrase associated substitutions as follows: L74M, E138E/K, E92E/Q 
and T66I. Four of the 5 participants with emergent G118R had phenotypic data available. Dolutegravir FC 
(fold change as compared to wildtype virus) for these four participants ranged from 6 to 25-fold. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with Tivicay in 
paediatric patients aged 4 weeks to below 6 years with HIV infection (see section 4.2 for information on 
paediatric use). 
 
There are no data available on the use of dolutegravir plus lamivudine as a two-drug regimen in paediatric 
patients. 
 
5.2 Pharmacokinetic properties 
 
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 Cτ 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. 
 
Dispersible tablets and film-coated tablets do not have the same bioavailability. The relative bioavailability 
of dispersible tablets is approximately 1.6-fold higher as compared to film-coated tablets. Thus, a 30 mg 
dolutegravir dose administered as six 5 mg dispersible tablets will have similar exposure to a 50 mg 
dolutegravir dose administered as film-coated tablet(s). Similarly, a 25 mg dolutegravir dose administered as 
five 5 mg dispersible tablets, will provide comparable exposure to a 40 mg dolutegravir dose administered as 
four 10 mg film-coated tablets. 



52 

 
Absorption 
  
Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for 
tablet formulation.  
 
Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir 
depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, 
and 66%, increased Cmax by 46%, 52%, and 67%, prolonged Tmax to 3, 4, and 5 hours from 2 hours under 
fasted conditions, respectively for the film-coated tablet. These increases may be clinically relevant in the 
presence of certain integrase class resistance. Therefore, Tivicay is recommended to be taken with food by 
patients infected with HIV with integrase class resistance (see section 4.2). No formal food effect studies 
were conducted for dispersible tablets. However, based on the available data, a higher food effect is not 
expected for the dispersible tablet compared to the film-coated tablet. 
 
The absolute bioavailability of dolutegravir 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).   
 
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. 
 
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, 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). 
 
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. 
 



53 

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. 
 
Linearity/non-linearity 
  
The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral 
administration of film-coated tablet formulations, in general, dolutegravir exhibited nonlinear 
pharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; however 
increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg for the film-coated tablet 
formulation. With 50 mg film-coated tablet twice daily, the exposure over 24 hours was approximately 
doubled compared to 50 mg film-coated tablet once daily. 
 
Pharmacokinetic/pharmacodynamic relationship(s) 
 
In a randomized, dose-ranging trial, HIV-1–infected subjects treated with dolutegravir monotherapy 
(ING111521) demonstrated rapid and dose-dependent antiviral activity, with mean decline in HIV-1 RNA of 
2.5 log10 at day 11 for 50 mg film-coated tablet dose. This antiviral response was maintained for 3 to 4 days 
after the last dose in the 50 mg film-coated tablet group.   
 
PK/PD modelling using pooled data from clinical studies in integrase resistant patients suggest that 
increasing the dose from 50 mg film-coated tablet twice daily to 100 mg film-coated tablet twice daily may 
increase the effectiveness of dolutegravir in patients with integrase resistance and limited treatment options 
due to advanced multi class resistance. The proportion of responders (HIV-1 RNA <50 c/mL) at week 24 
was predicted to increase around 4-18% in the subjects with Q148 + ≥2 secondary mutations from 
G140A/C/S, E138A/K/T, L74I. Although these simulated results have not been confirmed in clinical trials, 
this high dose may be considered in the presence of the Q148 + ≥2 secondary mutations from G140A/C/S, 
E138A/K/T, L74I in patients with overall limited treatment options due to advanced multi class resistance. 
There is no clinical data on the safety or efficacy of the 100 mg film-coated tablet twice daily dose. Co-
treatment with atazanavir increases the exposure of dolutegravir markedly, and should not be used in 
combination with this high dose, since safety with the resulting dolutegravir exposure has not been 
established. 
 
Special patient populations 
 
Children 
The pharmacokinetics of dolutegravir given once daily as dispersible and film-coated tablets in HIV-1 
infected infants, children and adolescents aged ≥ 4 weeks to < 18 years were evaluated in two on-going 
studies (P1093/ING112578 and ODYSSEY/201296). Steady state simulated plasma exposure at once daily 
weight band doses is summarized in Table 11.  



54 

Table 11 Summary of Simulated Dolutegravir PK Parameters at Once Daily Doses by Weight Band in 
Paediatric HIV-1 Infected Subjects 

Weight Band 
(kg) 

Dolutegravir 
Dosage 
Forma 

Once Daily 
Dose (mg) 

PK Parameter 
Geometric Mean (90% CI) 

Cmax 
(µg/mL) 

AUC0-24h 
(µg*h/mL) 

C24h 
(ng/mL) 

3 to <6 DT 5 
4.02  

(2.12, 7.96) 
49.4 

 (21.6, 115) 
1070  

(247, 3830) 

6 to <10b DT 10 
5.90  

(3.23, 10.9) 
67.4  

(30.4, 151) 
1240 

 (257, 4580) 

6 to <10c  DT 15 
6.67  

(3.75, 12.1) 
68.4  

(30.6, 154) 
964 

(158, 4150) 

10 to <14 DT 20 
6.61  

(3.80, 11.5) 
63.1  

(28.9, 136) 
719  

(102, 3340) 

14 to <20 
DT 

 
FCT 

25 
 

40 

7.17 
(4.10, 12.6) 

6.96  
(3.83, 12.5) 

69.5  
(32.1, 151) 

72.6  
(33.7, 156) 

824  
(122, 3780) 

972  
(150, 4260) 

20 to <25 
DT 

 
FCT 

30 
 

50 

7.37  
(4.24, 12.9) 

7.43  
(4.13, 13.3) 

72.0  
(33.3, 156)  

78.6  
(36.8, 171) 

881  
(137, 3960) 

1080  
(178, 4690) 

25 to <30 FCT 50 
6.74  

(3.73, 12.1) 
71.4  

(33.2, 154) 
997  

(162, 4250) 

30 to <35 FCT 50 
6.20  

(3.45, 11.1) 
66.6  

(30.5, 141) 
944  

(154, 4020) 

≥35 FCT 50 
4.93  

(2.66, 9.08) 
54.0  

(24.4, 118) 
814  

(142, 3310) 

Target: Geometric Mean  46 (37-134) 995 (697-2260) 
DT=dispersible tablet 
FCT=film-coated tablet 
a. The bioavailability of dolutegravir DT is ~1.6-fold dolutegravir FCT. 
b. <6 months of age 
c. ≥6 months of age 

 
 
 
 
 



55 

Steady state simulated plasma exposure at alternative twice daily weight band doses is summarized in Table 
12. In contrast to once daily dosing, simulated data for alternative twice daily dosing have not been 
confirmed in clinical trials. 
 
Table 12 Summary of Simulated Dolutegravir PK Parameters at Alternative Twice Daily Doses by 

Weight Band in Paediatric HIV-1 Infected Subjects 
 

Weight Band 
(kg) 

Dolutegravir 
Dosage 
Forma 

Twice 
Daily Dose 

(mg) 

PK Parameter 
 Geometric Mean (90% CI) 

Cmax 
(µg/mL) 

AUC0-12h 
(µg*h/mL) 

C12h 
(ng/mL) 

6 to <10b DT 5 
4.28 

(2.10, 9.01) 
31.6 

(14.6, 71.4) 
1760 

 (509, 5330) 

6 to <10c  DT 10 
6.19  

(3.15, 12.6) 
43.6 

(19.4, 96.9) 
2190 

(565, 6960) 

10 to <14 DT 10 
4.40 

(2.27, 8.68) 
30.0 

(13.5, 66.0) 
1400 

(351, 4480) 

14 to <20 
DT 

 
FCT 

15 
 

20 

5.78 
(2.97, 11.4) 

4.98 
(2.55, 9.96) 

39.6 
(17.6, 86.3) 

35.9 
(16.5, 77.4) 

1890 
(482, 6070) 

1840 
(496, 5650) 

20 to <25 
DT 

 
FCT 

15 
 

25 

5.01 
(2.61, 9.99) 

5.38 
(2.73, 10.8) 

34.7 
(15.8, 76.5)    

39.2 
(18.1, 85.4)  

1690  
(455, 5360) 

2040  
(567, 6250) 

25 to <30 
DT 

 
FCT 

15 
 

25 

4.57 
(2.37, 9.05) 

4.93 
(2.50, 9.85) 

32.0 
(14.6, 69.1) 

35.9 
(16.4, 77.4) 

1580 
(414, 4930) 

1910 
(530, 5760) 

30 to <35 FCT 25 
4.54 

(2.31, 9.10) 
33.3 

(15.3, 72.4) 
1770 

(494, 5400) 

≥35 FCT 25 
3.59 

(1.76, 7.36) 
26.8 

(12.1, 58.3) 
1470 

(425, 4400) 

DT=dispersible tablet 
FCT=film-coated tablet 

a. The bioavailability of dolutegravir DT is ~1.6-fold dolutegravir FCT. 
b. <6 months of age 
c. ≥6 months of age 



56 

 
Elderly 
Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there 
was no clinically relevant effect of age on dolutegravir exposure. 
 
Pharmacokinetic data for dolutegravir in subjects >65 years of age are limited. 
 
Renal impairment 
Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study 
of the pharmacokinetics of a single 50 mg dose of dolutegravir film-coated tablets 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. No dosage adjustment is considered necessary for patients with renal 
impairment. Tivicay has not been studied in patients on dialysis. 
 
Hepatic impairment 
Dolutegravir is primarily metabolized and eliminated by the liver. A single 50 mg dose of dolutegravir film-
coated tablets was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 
8 matched healthy adult controls. While the total dolutegravir concentration in plasma 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. No dosage adjustment is considered necessary for patients with 
mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of 
Tivicay has not been studied. 
 
Polymorphisms in drug metabolising enzymes 
There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir 
pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples 
collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor 
dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with 
subjects with genotypes associated with normal metabolism via UGT1A1 (n=41).  
 
Gender 
Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed 
no clinically relevant effect of gender on the exposure of dolutegravir.  
 
Race  
Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed 
no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir 
following single dose oral administration to Japanese subjects appear similar to observed parameters in 
Western (US) subjects.  
 
Co-infection with Hepatitis B or C  
Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant 
effect on the exposure to dolutegravir. There are limited data on subjects with hepatitis B co-infection. 
 
5.3 Preclinical safety data 
 
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. 
 
Dolutegravir did not affect male or female fertility in rats at doses up to 1000 mg/kg/day, the highest dose 
tested (24 times the twice daily 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 (27 times the twice daily 



57 

human clinical exposure based on AUC). In the rat pre/post-natal development study, decreased body weight 
of the developing offspring was observed during lactation at a maternally toxic dose (approximately 27 times 
human exposure at the maximum recommended human dose). 
 
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 (0.40 times the twice daily 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 (0.40 times the twice daily human clinical 
exposure based on AUC).   
 
In a juvenile toxicity study in rats, dolutegravir administration resulted in two preweanling deaths at 
75 mg/kg/day.  Over the preweaning treatment period, mean body weight gain was decreased in this group 
and the decrease persisted throughout the entire study for females during the postweaning period.  The 
systemic exposure at this dose (based on AUC) to dolutegravir was ~17 to 20-fold higher than humans at the 
recommended pediatric exposure. There were no new target organs identified in juveniles compared to 
adults. At the NOAEL dose of 2 mg/kg/day, the AUC values in juvenile rats on Day 13 post-partum was ∼3 
to 6-fold higher than paediatric patients weighing 3 to <10 kg (ages 4 weeks to >6 months). 
 
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 21 and 0.82 times the twice daily 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 15 times the human mg/kg equivalent dose (based on a 50 kg human), 
and 5 times the human mg/m2 equivalent twice daily dose.   
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Mannitol (E421) 
Microcrystalline cellulose 
Povidone  
Sodium starch glycolate 
Silicified microcrystalline cellulose  
Crospovidone 
Sodium stearyl fumarate 
Calcium sulfate dihydrate 
Sucralose 
Strawberry cream flavour 
 
Tablet coating 
 
Titanium dioxide (E171) 
Hypromellose 
Macrogol 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 



58 

 
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. Do not swallow the desiccant. This medicinal product does not require any special temperature 
storage conditions. 
 
6.5 Nature and contents of container  
 
HDPE (high density polyethylene) bottles closed with child resistant polypropylene screw closures, with a 
polyethylene faced induction heat seal liner.  The bottles contain 60 dispersible tablets and a desiccant. 
 
A dosing cup and oral syringe, both made from polypropylene with graduation marks, are supplied with the 
pack. The syringe’s plunger is made from HDPE. 
 
6.6 Special precautions for disposal and other handling 
 
Comprehensive instructions for dispersing the tablet are provided in the package leaflet (see Step-by-step 
instructions for use). 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/892/007 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 16 January 2014 
Date of latest renewal: 21 September 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. 
 

http://www.ema.europa.eu/


59 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER 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 

 



60 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Film-coated Tablets: 
GLAXO WELLCOME, S.A., Avda. Extremadura 3, 09400 Aranda de Duero, Burgos, Spain 
OR 
GlaxoSmithKline Pharmaceuticals S.A., ul., Grunwaldzka 189, 60-322 Poznan, Poland. 
 
5 mg Dispersible Tablets: 
GLAXO WELLCOME, S.A., Avda. Extremadura 3, 09400 Aranda de Duero, Burgos, Spain 
 
The printed package leaflet of the medicinal product must state the name and address of the manufacturer 
responsible for the release of the concerned batch. 
 
 
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. 
 
 
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. 

 



61 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



62 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



63 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 10mg film-coated tablets 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 10 mg film-coated tablets 
dolutegravir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 10 mg dolutegravir 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 film-coated 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 {MM/YYYY} 
 
 
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. Do not swallow the desiccant. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 



64 

 
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/1/13/892/003 
EU/1/13/892/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
tivicay 10 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



65 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 10 mg film-coated tablets 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 10 mg tablets 
dolutegravir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 10 mg dolutegravir 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 film-coated 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 {MM/YYYY} 
 
 
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. Do not swallow the desiccant. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 



66 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/892/003 
EU/1/13/892/004 
 
 
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 
 



67 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 25mg film-coated tablets 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 25 mg film-coated tablets 
dolutegravir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 25 mg dolutegravir 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 film-coated 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 {MM/YYYY} 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 



68 

ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/892/005 
EU/1/13/892/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
tivicay 25 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



69 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 25 mg film-coated tablets 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 25 mg tablets 
dolutegravir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 25 mg dolutegravir 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 film-coated 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 {MM/YYYY} 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 



70 

ViiV Healthcare BV 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/892/005 
EU/1/13/892/006 
 
 
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 
 
 



71 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 50mg film-coated tablets 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 50 mg film-coated tablets 
dolutegravir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 film-coated 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 {MM/YYYY} 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 



72 

ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/892/001 
EU/1/13/892/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
tivicay 50 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



73 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 50 mg film-coated tablets 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 50 mg tablets 
dolutegravir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
90 film-coated 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 {MM/YYYY} 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
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 
 



74 

ViiV Healthcare BV 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/892/001 
EU/1/13/892/002 
 
 
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 
 
 



75 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 5 mg dispersible tablets 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 5 mg dispersible tablets 
dolutegravir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each dispersible tablet contains dolutegravir sodium equivalent to 5 mg dolutegravir 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 dispersible tablets 
 
This pack contains a dosing cup and oral syringe 
 
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 {MM/YYYY} 
 
 
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. Do not swallow the desiccant. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 



76 

 
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/1/13/892/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
tivicay 5 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



77 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 5 mg dispersible tablets 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Tivicay 5 mg dispersible tablets 
dolutegravir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each dispersible tablet contains dolutegravir sodium equivalent to 5 mg dolutegravir 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 dispersible 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 {MM/YYYY} 
 
 
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. Do not swallow the desiccant. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 



78 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
ViiV Healthcare BV 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/892/007 
 
 
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 
 
 
 



79 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



80 

Package leaflet: Information for the patient 
 

Tivicay 10 mg film-coated tablets 
Tivicay 25 mg film-coated tablets 
Tivicay 50 mg film-coated tablets 

dolutegravir 
 
 
Read all of this leaflet carefully before you (or your child, if they are the patient) 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 (or your child, if they are the patient) 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 Tivicay is and what it is used for  
2. What you need to know before you take Tivicay  
3. How to take Tivicay 
4. Possible side effects  
5. How to store Tivicay 
6. Contents of the pack and other information 
 
 
1. What Tivicay is and what it is used for 
 
Tivicay contains the active ingredient dolutegravir. Dolutegravir belongs to a group of anti-retroviral 
medicines called integrase inhibitors (INIs). 
 
Tivicay is used to treat HIV (human immunodeficiency virus) infection in adults, adolescents and children 
of at least 6 years of age or older, and who weigh at least 14 kg. 
 
Tivicay does not cure HIV infection; it reduces the amount of virus in your body, and keeps it at a low level. 
As a result of that, it also increases the CD4 cell count in your blood. CD4 cells are a type of white blood 
cells that are important in helping your body to fight infection. 
 
Not everyone responds to treatment with Tivicay in the same way. Your doctor will monitor the effectiveness 
of your treatment. 
 
Tivicay is always used in combination with other anti-retroviral medicines (combination therapy).  
To control your HIV infection, and to stop your illness from getting worse, you must keep taking all your 
medicines, unless your doctor tells you to stop taking any. 
 
 
2. What you need to know before you take Tivicay  
 
Don’t take Tivicay: 

• if you (or your child, if they are the patient) are allergic to dolutegravir or any of the other 
ingredients of this medicine (listed in section 6). 

• if you (or your child) are taking another medicine called fampridine (also known as dalfampridine; 
used in multiple sclerosis). 

→ If you think any of these apply to you (or your child), tell your doctor. 
 



81 

Warnings and precautions 
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 (or your child, if they are 
the patient) are taking Tivicay. 

→ Read the information 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 
Do not give this medicine to children under 6 years of age, weighing less than 14 kg or with HIV infection 
that is resistant to other medicines similar to Tivicay. The use of Tivicay film-coated tablets in children under 
6 or weighing less than 14 kg has not yet been studied. 
 
Children must keep planned doctor’s appointments (see ‘Use in children and adolescents’ in Section 3 for 
more information). 
 
Other medicines and Tivicay 
Tell your doctor if you (or your child) are taking, have recently taken or are planning to take any other 
medicines. 
 
Don't take Tivicay with the following medicine: 

• fampridine (also known as dalfampridine), used in multiple sclerosis. 
 
Some medicines can affect how Tivicay works, or make it more likely that you will have side effects. 
Tivicay can also affect how some other medicines work.  
Tell your doctor if you (or your child) are taking any of the medicines in the following list: 

• metformin, to treat diabetes 
• medicines called antacids, to treat indigestion and heartburn. Do not take an antacid during the 6 

hours before you take Tivicay, or for at least 2 hours after you take it. (See also Section 3). 
• calcium supplements, iron supplements and multivitamins.  Do not take a calcium supplement, 

iron supplement or multivitamin during the 6 hours before you take Tivicay, or for at least 2 hours 
after you take it (see also Section 3). 

• etravirine, efavirenz, fosamprenavir/ritonavir, nevirapine or tipranavir/ritonavir, to treat HIV 
infection 

• rifampicin, to treat tuberculosis (TB) and other bacterial infections 
• phenytoin and phenobarbital, to treat epilepsy 
• oxcarbazepine and carbamazepine, to treat epilepsy or bipolar disorder 
• St. John’s wort (Hypericum perforatum), a herbal remedy to treat depression 

 → Tell your doctor or pharmacist if you (or your child) are taking any of these. Your doctor may 
decide to adjust your dose or 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: 
 → Talk to your doctor about the risks and benefits of taking Tivicay. 
 
Taking Tivicay at the time of becoming pregnant or during the first six weeks of pregnancy, may increase the 
risk of a type of birth defect, called neural tube defect, such as spina bifida (malformed spinal cord). 



82 

If you could get pregnant while receiving Tivicay: 
 → 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 Tivicay 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.  
 
A small amount of the ingredient in Tivicay 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 
Tivicay can make you dizzy and have other side effects that make you less alert. 
 → Don’t drive or operate machinery unless you are sure you’re not affected.  
 
Tivicay contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially ‘sodium-free.’ 
 
3. How to take Tivicay 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure. 
 

• The usual dose is 50 mg once a day.  
• If you are taking certain other medicines, the dose is 50 mg twice a day. 
• For HIV that is resistant to other medicines similar to Tivicay, the usual dose is 50 mg, twice a 

day. 
 
Your doctor will decide on the correct dose of Tivicay for you. 
 
Swallow the tablet(s) with some liquid.  
 
Tivicay can be taken with or without food. When Tivicay is taken twice a day, your doctor may advise you 
to take with food.  
 
Tivicay is also available as dispersible tablets. Film-coated tablets and dispersible tablets are not the same, 
therefore do not switch between film-coated tablets and dispersible tablets without first talking to your 
doctor.  
 
Use in children and adolescents 

• Children’s dose of Tivicay needs to be adjusted as they get older or gain weight. 
  → It is important therefore that children keep planned doctor’s appointments. 

• Children and adolescents weighing at least 20 kg can take the adult dose of 50 mg, once a day or 25 
mg twice daily. Your doctor will decide how Tivicay should be given. 

• For children aged between 6 and 12 years your doctor will decide on the correct dose of Tivicay, 
depending on the weight of your child.  

• To reduce the risk of choking, children must not swallow more than one tablet at a time. 
• Tivicay should not be used in children and adolescents with HIV infection that is resistant to other 

medicines similar to Tivicay. 
 
Antacid medicines 



83 

Antacids, to treat indigestion and heartburn, can stop Tivicay being absorbed into your body and make it 
less effective. 
Do not take an antacid during the 6 hours before you take Tivicay, or for at least 2 hours after you take it.  
Other acid-lowering medicines like ranitidine and omeprazole can be taken at the same time as Tivicay.   
 → Talk to your doctor for further advice on taking acid-lowering medicines with Tivicay. 
 
Calcium supplements, iron supplements or multivitamins 
Calcium supplements, iron supplements or multivitamins can stop Tivicay being absorbed into your body 
and make it less effective. 
Do not take a calcium supplement, iron supplement or multivitamin during the 6 hours before you take 
Tivicay, or for at least 2 hours after you take it.   
 → Talk to your doctor for further advice on taking calcium supplements, iron supplements or 
multivitamins with Tivicay. 
 
If you take more Tivicay than you should 
If you (or your child) take too many tablets of Tivicay, contact your doctor or pharmacist for advice. If 
possible, show them the Tivicay pack. 
 
If you forget to take Tivicay 
If you (or your child) miss a dose, take it as soon as you remember.  But if your next dose is due within 4 
hours, skip the dose you missed and take the next one at the usual time. Then continue your treatment as 
before.  
 Don't take a double dose to make up for a missed dose. 
 
Don’t stop taking Tivicay without advice from your doctor 
Take Tivicay for as long as your doctor recommends.  Don’t stop unless your doctor advises you to.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, but not everybody gets them.  
 
Allergic reactions 
These are uncommon in people taking Tivicay. Signs include: 

• 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 on your liver, kidneys or 
blood, and may tell you to stop taking Tivicay. 

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

• headache 
• diarrhoea 
• feeling sick (nausea). 

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

• rash 
• itching (pruritus) 
• being sick (vomiting) 
• stomach pain (abdominal pain) 



84 

• stomach (abdominal) discomfort 
• insomnia 
• dizziness 
• abnormal dreams 
• depression (feelings of deep sadness and unworthiness) 
• anxiety 
• lack of energy (fatigue) 
• wind (flatulence) 
• increase in the level of liver enzymes 
• increase in the level of enzymes produced in the muscles (creatine phosphokinase). 
 

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

• inflammation of the liver (hepatitis) 
• suicide attempt* 
• suicidal thoughts*  
• joint pain 
• muscle pain 

 
* particularly in patients who have had depression or mental health problems before. 
 
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). 

 
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). Such infections may have been “silent” and not detected by the 
weak immune system before treatment was started. After starting treatment, the immune system becomes 
stronger, and may attack the infections, which can cause symptoms of infection or inflammation. 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 (or your child) get any symptoms of infection and inflammation 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 



85 

• if their immune systems are very weak 
• if they are overweight. 

Signs of osteonecrosis include: 
• 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. 
 
Weight, blood lipid and blood glucose effects 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This is 
partly linked to restored health and lifestyle, and in the case of blood lipids sometimes to the HIV medicines 
themselves. Your doctor will test for these changes.  

 
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 Tivicay 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated after EXP on the carton and bottle. 
 
Tivicay 10 mg film-coated tablets 
Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not remove 
the desiccant. Do not swallow the desiccant. This medicine does not require any special temperature storage 
conditions.  
 
Tivicay 25 mg and 50 mg film-coated tablets 
This medicine does not require any special 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 Tivicay contains  
- The active substance is dolutegravir. Each tablet contains dolutegravir sodium equivalent to 10 mg, 

25 mg or 50 mg dolutegravir. 
- The other ingredients are mannitol (E421), microcrystalline cellulose, povidone, sodium starch 

glycolate, sodium stearyl fumarate, poly(vinyl alcohol) partially hydrolyzed, titanium dioxide (E171), 
macrogol, talc and for 25 mg and 50 mg tablets, iron oxide yellow (E172). 

 
What Tivicay looks like and contents of the pack 
Tivicay 10 mg film-coated tablets are white, round, biconvex tablets marked with the code ‘SV 572’ on one 
side and ‘10’ on the other side.  The bottle contains a desiccant to reduce moisture. Once the bottle has been 
opened keep the desiccant in the bottle, do not remove it.  
 
Tivicay 25 mg film-coated tablets are pale yellow, round, biconvex tablets marked with the code ‘SV 572’ 
on one side and ‘25’ on the other side.   
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


86 

Tivicay 50 mg film-coated tablets are yellow, round, biconvex tablets marked with the code ‘SV 572’ on one 
side and ‘50’ on the other side.   
 
The film-coated tablets are provided in bottles containing 30 or 90 tablets.  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, 09400 Aranda De Duero, Burgos, Spain 
OR 
GlaxoSmithKline Pharmaceuticals S.A., ul., Grunwaldzka 189, 60-322 Poznan, Poland. 
 
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 Polska 



87 

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

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 

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 7741600 

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

Κύπρος 
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 39 70 00 
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 {month YYYY}. 
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

http://www.ema.europa.eu/


88 

Package leaflet: Information for the patient 
 

Tivicay 5 mg dispersible tablets 
dolutegravir 

 
 
Read all of this leaflet carefully before you (or your child, if they are the patient) 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 (or your child, if they are the patient) 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 Tivicay is and what it is used for  
2. What you need to know before you take Tivicay  
3. How to take Tivicay 
4. Possible side effects  
5. How to store Tivicay 
6. Contents of the pack and other information 
Step-by-step instructions for use are also provided 
 
 
1. What Tivicay is and what it is used for 
 
Tivicay contains the active ingredient dolutegravir. Dolutegravir belongs to a group of anti-retroviral 
medicines called integrase inhibitors (INIs). 
 
Tivicay is used to treat HIV (human immunodeficiency virus) infection in adults, adolescents and children 
of at least 4 weeks of age or older, and who weigh at least 3 kg. 
 
Tivicay does not cure HIV infection; it reduces the amount of virus in your body, and keeps it at a low level. 
As a result of that, it also increases the CD4 cell count in your blood. CD4 cells are a type of white blood 
cells that are important in helping your body to fight infection. 
 
Not everyone responds to treatment with Tivicay in the same way. Your doctor will monitor the effectiveness 
of your treatment. 
 
Tivicay is always used in combination with other anti-retroviral medicines (combination therapy). To control 
your HIV infection, and to stop your illness from getting worse, you must keep taking all your medicines, 
unless your doctor tells you to stop taking any. 
 
 
2. What you need to know before you take Tivicay  
 
Don’t take Tivicay: 

• if you (or your child, if they are the patient) are allergic to dolutegravir or any of the other 
ingredients of this medicine (listed in section 6). 

• if you (or your child) are taking another medicine called fampridine (also known as dalfampridine; 
used in multiple sclerosis). 

→ If you think any of these apply to you (or your child), tell your doctor. 
 
Warnings and precautions 



89 

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 (or your child, if they are 
the patient) are taking Tivicay. 

→ Read the information 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 
Do not give this medicine to children under 4 weeks of age, weighing less than 3 kg or with HIV infection 
that is resistant to other medicines similar to Tivicay. The use of Tivicay dispersible tablets in children under 
4 weeks or weighing less than 3 kg has not yet been studied. 
 
Children must keep planned doctor’s appointments (see ‘Children and adolescents’ in Section 3 for more 
information). 
 
Other medicines and Tivicay 
Tell your doctor if you (or your child) are taking, have recently taken or are planning to take any other 
medicines. 
 
Don't take Tivicay with the following medicine: 

• fampridine (also known as dalfampridine), used in multiple sclerosis. 
 
Some medicines can affect how Tivicay works, or make it more likely that you will have side effects. 
Tivicay can also affect how some other medicines work.  
Tell your doctor if you (or your child) are taking any of the medicines in the following list: 

• metformin, to treat diabetes 
• medicines called antacids, to treat indigestion and heartburn. Do not take an antacid during the 6 

hours before you take Tivicay, or for at least 2 hours after you take it. (See also Section 3). 
• calcium supplements, iron supplements and multivitamins.  Do not take a calcium supplement, 

iron supplement or multivitamin during the 6 hours before you take Tivicay, or for at least 2 hours 
after you take it (see also Section 3). 

• etravirine, efavirenz, fosamprenavir/ritonavir, nevirapine or tipranavir/ritonavir, to treat HIV 
infection 

• rifampicin, to treat tuberculosis (TB) and other bacterial infections 
• phenytoin and phenobarbital, to treat epilepsy 
• oxcarbazepine and carbamazepine, to treat epilepsy or bipolar disorder 
• St. John’s wort (Hypericum perforatum), a herbal remedy to treat depression 

 → Tell your doctor or pharmacist if you (or your child) are taking any of these. Your doctor may 
decide to adjust your dose or 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: 
 → Talk to your doctor about the risks and benefits of taking Tivicay. 
 
Taking Tivicay at the time of becoming pregnant or during the first six weeks of pregnancy, may increase the 
risk of a type of birth defect, called neural tube defect, such as spina bifida (malformed spinal cord). 
 



90 

If you could get pregnant while receiving Tivicay: 
 → 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 Tivicay 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.  
 
A small amount of the ingredient in Tivicay 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 
Tivicay can make you dizzy and have other side effects that make you less alert. 
 → Don’t drive or operate machinery unless you are sure you’re not affected.  
 
Tivicay contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially ‘sodium-free.’ 
 
 
3. How to take Tivicay 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you 
are not sure. 
 
Adults 

• The usual adult dose is 30 mg (taken as six 5 mg dispersible tablets) once a day.  
• If you are taking certain other medicines, the dose is 30 mg (taken as six 5 mg dispersible tablets) 

twice a day. 
• For HIV that is resistant to other medicines similar to Tivicay, the usual dose is 30 mg (taken as 

six 5 mg dispersible tablets), twice a day. 
 
Your doctor will decide on the correct dose of Tivicay for you. 
 
Children and adolescents 

• Children’s dose of Tivicay needs to be adjusted as they get older or gain weight. 
→ It is important therefore that children keep planned doctor’s appointments. 

• Children and adolescents weighing at least 20 kg can take the adult dose of 30 mg, once a day or 15 
mg twice a day. Your doctor will decide how Tivicay should be given. 

• For children aged at least 4 weeks and weighing between 3 and 20 kg, your doctor will decide on the 
correct dose of Tivicay, depending on the weight and age of your child. 

• If swallowing tablets whole with water, children must not swallow more than one tablet at a time 
to reduce the risk of choking. 

• Tivicay should not be used in children and adolescents with HIV infection that is resistant to other 
medicines similar to Tivicay. 

 
How to take the dispersible tablets 

• The dispersible tablets may be dispersed in drinking water or swallowed whole with drinking water. 
When dispersed, the amount of water will depend on the number of tablets prescribed. The tablet(s) 
should be fully dispersed before swallowing.  
See the separate instructions for use regarding how to disperse and administer the tablets using the 
dosing cup and oral syringe provided in this pack. 

• Do not chew, cut or crush the tablets.  



91 

• Tivicay can be taken with or without food. When Tivicay is taken twice a day, your doctor may 
advise you to take with food. 

 
Tivicay is also available as film-coated tablets. Film-coated tablets and dispersible tablets are not the same, 
therefore do not switch between film-coated tablets and dispersible tablets without first talking to your 
doctor. 
 
Antacid medicines 
Antacids, to treat indigestion and heartburn, can stop Tivicay being absorbed into your body and make it 
less effective. 
Do not take an antacid during the 6 hours before you take Tivicay, or for at least 2 hours after you take it.  
Other acid-lowering medicines like ranitidine and omeprazole can be taken at the same time as Tivicay.   
 → Talk to your doctor for further advice on taking acid-lowering medicines with Tivicay. 
 
Calcium supplements, iron supplements or multivitamins 
Calcium supplements, iron supplements or multivitamins can stop Tivicay being absorbed into your body 
and make it less effective. 
Do not take a calcium supplement, iron supplement or multivitamin during the 6 hours before you take 
Tivicay, or for at least 2 hours after you take it.   
 → Talk to your doctor for further advice on taking calcium supplements, iron supplements or 
multivitamins with Tivicay. 
 
If you take more Tivicay than you should 
If you (or your child) take too many tablets of Tivicay, contact your doctor or pharmacist for advice. If 
possible, show them the Tivicay pack. 
 
If you forget to take Tivicay 
If you (or your child) miss a dose, take it as soon as you remember.  But if your next dose is due within 4 
hours, skip the dose you missed and take the next one at the usual time. Then continue your treatment as 
before.  
 Don't take a double dose to make up for a missed dose. 
 
Don’t stop taking Tivicay without advice from your doctor 
Take Tivicay for as long as your doctor recommends.  Don’t stop unless your doctor advises you to.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, but not everybody gets them.  
 
Allergic reactions 
These are uncommon in people taking Tivicay. Signs include: 

• 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 on your liver, kidneys or 
blood, and may tell you to stop taking Tivicay. 

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

• headache 



92 

• diarrhoea 
• feeling sick (nausea). 

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

• rash 
• itching (pruritus) 
• being sick (vomiting) 
• stomach pain (abdominal pain) 
• stomach (abdominal) discomfort 
• insomnia 
• dizziness 
• abnormal dreams 
• depression (feelings of deep sadness and unworthiness) 
• anxiety 
• lack of energy (fatigue) 
• wind (flatulence) 
• increase in the level of liver enzymes 
• increase in the level of enzymes produced in the muscles (creatine phosphokinase). 
 

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

• inflammation of the liver (hepatitis) 
• suicide attempt* 
• suicidal thoughts*  
• joint pain 
• muscle pain 

 
* particularly in patients who have had depression or mental health problems before 
 
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). 

 
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). Such infections may have been “silent” and not detected by the 
weak immune system before treatment was started. After starting treatment, the immune system becomes 
stronger, and may attack the infections, which can cause symptoms of infection or inflammation. 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 (or your child) get any symptoms of infection and inflammation or if you notice any of the 
symptoms above: 



93 

 → 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: 
• 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. 
 
Weight, blood lipid and blood glucose effects 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This is 
partly linked to restored health and lifestyle, and in the case of blood lipids sometimes to the HIV medicines 
themselves. Your doctor will test for these changes.  

 
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 Tivicay 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated after EXP on the carton and bottle. 
 
Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not remove 
the desiccant. Do not swallow 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 Tivicay contains  

The active substance is dolutegravir. Each tablet contains dolutegravir sodium equivalent to 5 mg 
dolutegravir. 
The other ingredients are mannitol (E421), microcrystalline cellulose, povidone, sodium starch 
glycolate, silicified microcrystalline cellulose, crospovidone, sodium stearyl fumarate, calcium sulfate 
dihydrate, sucralose, strawberry cream flavour, titanium dioxide (E171), hypromellose and macrogol. 

 
What Tivicay looks like and contents of the pack 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


94 

Tivicay 5 mg dispersible tablets are white, round, biconvex tablets marked with the code ‘SV H7S’ on one 
side and ‘5’ on the other side. The bottle contains a desiccant to reduce moisture. Once the bottle has been 
opened keep the desiccant in the bottle, do not remove it.  
 
The dispersible tablets are provided in bottles containing 60 tablets. 
 
A dosing cup and oral syringe are supplied with the pack. 
 
 
Marketing Authorisation Holder 
ViiV Healthcare BV 
Van Asch van Wijckstraat 55H 
3811 LP Amersfoort 
Netherlands. 
 
Manufacturer  
Glaxo Wellcome, S.A., Avda. Extremadura 3, 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 



95 

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 

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 7741600 

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

Κύπρος 
GlaxoSmithKline (Cyprus) Ltd 
Τηλ: + 357 22 39 70 00 
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 {month YYYY}. 
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu/


96 

Step-by-step instructions for use 
 

Read this Instructions for use before giving a dose of medicine. 
Follow the steps, using clean drinking water to prepare and give a dose to an infant or a child who cannot swallow the 
tablets. 

Important information 

Always give this medicine exactly as your healthcare provider tells you. Talk to your healthcare provider if you are not 
sure. 

Do not chew, cut, or crush the tablets. 

If you forget to give a dose of medicine, give it as soon as you remember. But if your next dose is due within 4 hours, 
skip the dose you missed and take the next one at the usual time. Then continue your treatment as before. Do not give 2 
doses at the same time or give more than your healthcare provider has prescribed. 

If you give too much medicine, get emergency medical help right away. 

If your child is able and prefers to swallow the tablets then you may skip the following steps. 

.   

 
• A bottle containing 60 tablets. 

• Dosing kit: 

- Cup: use this to prepare and give the medicine to children. 

- Oral syringe: use this to give the medicine to infants. 

 

Bottle 

Cup 

Oral syringe Tip 

Plunger 

Your pack contains:  



97 

 
• Clean drinking water. 

1 
.  

 

 

 

 

 

 

 

 

 

 
• Pour clean drinking water into the cup.  

The Water Volume Guide above shows the amount of water needed for the prescribed dose. 

Water Volume Guide 

Number of 
tablets 1 2 3 4 5 6 

Volume of 
water 5 mL 10 mL 

Use drinking water only. 
Do not use any other drink or food to prepare the dose. 

 

 
2. Prepare the medicine 

You will also need: 

Getting ready 

1. Pour water 



98 

 
 

• Add the prescribed number of tablet(s) to the water. 

 

• Swirl the cup gently for 1 to 2 minutes to disperse the tablet(s). The medicine will become cloudy. Take care not 
to spill any of the medicine. 

 

• Check that the medicine is ready. If there are any lumps of tablet swirl the cup until they are gone. 

 

If you spill any medicine, clean up the spill.  
Throw away the rest of the prepared medicine and make a new dose. 
 

You must give the dose of medicine within 30 minutes of preparing the dose. If it has been more than 30 minutes 
wash the dose away and prepare a new dose of medicine. 

 

 

 

Giving the medicine 

3. Give the medicine 

Swirl 1 to 2 
minutes 



99 

  

 

 

 

 

 

 

 

 

 

• Make sure that the child is upright. Give all the prepared medicine to the child. 

• Add another 5 mL of drinking water to the cup, swirl and give it all to the child.  

• Repeat if any medicine remains to make sure the child gets the full dose. 

 

 

• Place the tip of the oral syringe into the prepared medicine and draw up all the medicine into the oral syringe by 
pulling up on the plunger. 

• Place the tip of the oral syringe against the inside of the infant’s cheek. Gently push down the plunger to give the 
dose slowly. 

• Add another 5 mL of drinking water to the cup and swirl. Draw up the remaining medicine into the oral syringe and 
give it all to the infant. 

• Repeat if any medicine remains to make sure the infant gets the full dose. 

Allow time for the medicine to be swallowed. 

Give the medicine to a Child 

Give the medicine to an Infant 



100 

 

 

 

 

• Wash the cup with water. 

• Pull the plunger out of the oral syringe and wash the oral syringe parts separately in water. Allow parts to dry 
completely before reassembling and storing. 

• All used parts will need to be clean before preparing the next dose. 

 

Keep the tablets in the bottle. Keep the bottle tightly closed. 
 
The bottle contains a desiccant canister which helps to keep the tablets dry. Do not eat the desiccant. Do not remove 
the desiccant. 
 
Keep all medicines out of reach of children. 

 

When all the tablets in the bottle have been taken or are no longer needed, throw away the bottle, cup and oral syringe. 
Dispose of them using your local household waste guidelines. 
 
You will get a new cup and oral syringe in your next pack. 

 

4. Clean the dosing items 

Cleaning 

Storage information  

Disposal information  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER 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
	A. LABELLING
	B. PACKAGE LEAFLET