Genvoya

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

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This medicinal product is subject to additional monitoring.  This will allow quick identification of 
new safety information.  Healthcare professionals are asked to report any suspected adverse reactions.  
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Genvoya 150 mg/150 mg/200 mg/10 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine and 
tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. 
 
Excipients with known effect 
 
Each tablet contains 61 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Green, capsule-shaped, film-coated tablet of dimensions 19 mm x 8.5 mm, debossed with “GSI” on 
one side of the tablet and “510” on the other side of the tablet. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Genvoya is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection without 
any known mutations associated with resistance to the integrase inhibitor class, emtricitabine or 
tenofovir as follows: 
• In adults and adolescents aged from 12 years and with body weight at least 35 kg 
• In children aged from 6 years and with body weight at least 25 kg for whom alternative 

regimens are unsuitable due to toxicities. 
See sections 4.2, 4.4 and 5.1. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the management of HIV infection. 
 
Posology 
 
Adults and paediatric patients aged 6 years and older, weighing at least 25 kg 
One tablet to be taken once daily with food. 
 
If the patient misses a dose of Genvoya within 18 hours of the time it is usually taken, the patient 
should take Genvoya with food as soon as possible and resume the normal dosing schedule.  If a 
patient misses a dose of Genvoya by more than 18 hours, the patient should not take the missed dose 
and simply resume the usual dosing schedule. 
 
If the patient vomits within 1 hour of taking Genvoya another tablet should be taken. 



 

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Elderly 
No dose adjustment of Genvoya is required in elderly patients (see sections 5.1 and 5.2). 
 
Renal impairment 
No dose adjustment of Genvoya is required in adults or adolescents (aged at least 12 years and of at 
least 35 kg body weight) with estimated creatinine clearance (CrCl) ≥ 30 mL/min.  Genvoya should be 
discontinued in patients with estimated CrCl that declines below 30 mL/min during treatment (see 
section 5.2). 
 
No dose adjustment of Genvoya is required in adults with end stage renal disease (estimated 
CrCl < 15 mL/min) on chronic haemodialysis; however, Genvoya should generally be avoided but 
may be used in these patients if the potential benefits are considered to outweigh the potential risks 
(see sections 4.4 and 5.2).  On days of haemodialysis, Genvoya should be administered after 
completion of haemodialysis treatment. 
 
Genvoya should be avoided in patients with estimated CrCl ≥ 15 mL/min and < 30 mL/min, or 
< 15 mL/min who are not on chronic haemodialysis, as the safety of Genvoya has not been established 
in these populations. 
 
No data are available to make dose recommendations in children aged less than 12 years with renal 
impairment or in children less than 18 years with end stage renal disease. 
 
Hepatic impairment 
No dose adjustment of Genvoya is required in patients with mild (Child-Pugh Class A) or moderate 
(Child-Pugh Class B) hepatic impairment.  Genvoya has not been studied in patients with severe 
hepatic impairment (Child-Pugh Class C); therefore, Genvoya is not recommended for use in patients 
with severe hepatic impairment (see sections 4.4 and 5.2). 
 
Paediatric population 
The safety and efficacy of Genvoya in children younger than 6 years of age, or weighing < 25 kg, have 
not yet been established.  No data are available. 
 
Pregnancy 
Treatment with cobicistat and elvitegravir during pregnancy results in lower elvitegravir exposure (see 
sections 4.4 and 5.2).  Therefore, therapy with Genvoya should not be initiated during pregnancy, and 
women who become pregnant during therapy with Genvoya should be switched to an alternative 
regimen (see sections 4.4 and 4.6). 
 
Method of administration 
 
Genvoya should be taken orally, once daily with food (see section 5.2).  The film-coated tablet should 
not be chewed or crushed.  For patients who are unable to swallow the tablet whole, the tablet may be 
split in half and both halves taken one after the other, ensuring that the full dose is taken. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
Co-administration is contraindicated with medicinal products that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious or life-threatening 
adverse reactions.  Therefore, Genvoya should not be co-administered with medicinal products that 
include, but are not limited to, the following (see sections 4.4 and 4.5): 
 
• alpha 1-adrenoreceptor antagonists: alfuzosin 
• antiarrhythmics: amiodarone, quinidine 
• ergot derivatives: dihydroergotamine, ergometrine, ergotamine 



 

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• gastrointestinal motility agents: cisapride 
• HMG Co-A reductase inhibitors: lovastatin, simvastatin 
• neuroleptics/antipsychotics: pimozide, lurasidone 
• PDE-5 inhibitors: sildenafil for the treatment of pulmonary arterial hypertension 
• sedatives/hypnotics: orally administered midazolam, triazolam 
 
Co-administration is contraindicated with medicinal products that are strong inducers of CYP3A due 
to the potential for loss of virologic response and possible resistance to Genvoya.  Therefore, Genvoya 
should not be co-administered with medicinal products that include, but are not limited to, the 
following (see sections 4.4 and 4.5): 
 
• anticonvulsants: carbamazepine, phenobarbital, phenytoin 
• antimycobacterials: rifampicin 
• herbal products: St. John’s wort (Hypericum perforatum) 
 
Co-administration with dabigatran etexilate, a P-glycoprotein (P-gp) substrate, is contraindicated (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. 
 
Patients co-infected with HIV and hepatitis B or C virus 
 
Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for 
severe and potentially fatal hepatic adverse reactions. 
 
The safety and efficacy of Genvoya in patients co-infected with HIV-1 and hepatitis C virus (HCV) 
have not been established. 
 
Tenofovir alafenamide is active against hepatitis B virus (HBV).  Discontinuation of Genvoya therapy 
in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of 
hepatitis.  Patients co-infected with HIV and HBV who discontinue Genvoya should be closely 
monitored with both clinical and laboratory follow-up for at least several months after stopping 
treatment. 
 
Liver disease 
 
The safety and efficacy of Genvoya in patients with significant underlying liver disorders have not 
been established. 
 
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy (CART) and 
should be monitored according to standard practice.  If there is evidence of worsening liver disease in 
such patients, interruption or discontinuation of treatment must be considered. 
 
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 life style.  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. 
 



 

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Mitochondrial dysfunction following exposure in utero 
 
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most 
pronounced with stavudine, didanosine and zidovudine.  There have been reports of mitochondrial 
dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these 
have predominantly concerned treatment with regimens containing zidovudine.  The main adverse 
reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders 
(hyperlactataemia, hyperlipasaemia).  These events have often been transitory.  Late onset 
neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).  
Whether such neurological disorders are transient or permanent is currently unknown.  These findings 
should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with 
severe clinical findings of unknown aetiology, particularly neurologic findings.  These findings do not 
affect current national recommendations to use antiretroviral therapy in pregnant women to prevent 
vertical transmission of HIV. 
 
Immune Reactivation Syndrome 
 
In HIV infected patients with severe immune deficiency at the time of institution of 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 include 
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 reactivation; however, the reported time to onset is more variable, and 
these events can occur many months after initiation of treatment. 
 
Opportunistic infections 
 
Patients receiving Genvoya or any other antiretroviral therapy may continue to develop opportunistic 
infections and other complications of HIV infection, and therefore should remain under close clinical 
observation by physicians experienced in the treatment of patients with HIV associated diseases. 
 
Osteonecrosis 
 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported particularly 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. 
 
Nephrotoxicity 
 
A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to 
dosing with tenofovir alafenamide cannot be excluded (see section 5.3). 
 
Patients with end stage renal disease on chronic haemodialysis 
 
Genvoya should generally be avoided but may be used in adults with end stage renal disease 
(estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits outweigh the 
potential risks (see section 4.2).  In a study of Genvoya in HIV-1 infected adults with end stage renal 
disease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy was maintained through 
48 weeks but emtricitabine exposure was significantly higher than in patients with normal renal 
function.  Although there were no new safety issues identified, the implications of increased 
emtricitabine exposure remain uncertain (see sections 4.8 and 5.2). 



 

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Co-administration of other medicinal products 
 
Some medicinal products should not be co-administered with Genvoya (see sections 4.3 and 4.5). 
 
Genvoya should not be co-administered with other antiretroviral medicinal products (see section 4.5). 
 
Genvoya should not be administered concomitantly with medicinal products containing tenofovir 
alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of 
HBV infection (see section 4.5). 
 
Contraception requirements 
Female patients of childbearing potential should use either a hormonal contraceptive containing at 
least 30 µg ethinyloestradiol and containing drospirenone or norgestimate as the progestogen or should 
use an alternative reliable method of contraception (see sections 4.5 and 4.6).  The use of Genvoya 
with oral contraceptives containing other progestogens should be avoided (see section 4.5).  Plasma 
concentrations of drospirenone are expected to be increased following co-administration with 
Genvoya and clinical monitoring is recommended due to the potential for hyperkalaemia (see 
section 4.5). 
 
Paediatric population 
 
In a clinical study (GS-US-292-0106) in which Genvoya was administered to 23 HIV-1 infected 
paediatric patients with a mean age of 10 years (range 8 to 11 years), the mean exposures of 
elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofovir alafenamide were higher (20 to 80%) 
than the mean exposures achieved in adults (see sections 4.1 and 5.2). 
 
Pregnancy 
 
Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy has 
been shown to result in lower elvitegravir exposures (see section 5.2).  Cobicistat levels decrease and 
may not provide sufficient boosting.  The substantial reduction in elvitegravir exposure may result in 
virological failure and an increased risk of mother-to-child transmission of HIV infection.  Therefore, 
therapy with Genvoya should not be initiated during pregnancy, and women who become pregnant 
during therapy with Genvoya should be switched to an alternative regimen (see sections 4.2 and 4.6). 
 
Excipients 
 
Genvoya contains lactose monohydrate.  Patients with rare hereditary problems of galactose 
intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal 
product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Genvoya should not be co-administered with other antiretroviral medicinal products.  Therefore, 
information regarding drug-drug interactions with other antiretroviral products (including protease 
inhibitors [PIs] and non-nucleoside reverse transcriptase inhibitors [NNRTIs]) is not provided (see 
section 4.4).  Interaction studies have only been performed in adults. 
 
Genvoya should not be administered concomitantly with medicinal products containing tenofovir 
alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of 
HBV infection. 
 
Elvitegravir 
 
Elvitegravir is primarily metabolised by CYP3A, and medicinal products that induce or inhibit 
CYP3A may affect the exposure of elvitegravir.  Co-administration of Genvoya with medicinal 



 

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products that induce CYP3A may result in decreased plasma concentrations of elvitegravir and 
reduced therapeutic effect of Genvoya (see “Concomitant use contraindicated” and section 4.3).  
Elvitegravir may have the potential to induce CYP2C9 and/or inducible uridine diphosphate 
glucuronosyltransferase (UGT) enzymes; as such it may decrease the plasma concentration of 
substrates of these enzymes. 
 
Cobicistat 
 
Cobicistat is a strong mechanism-based inhibitor of CYP3A and is also a CYP3A substrate.  Cobicistat 
is also a weak CYP2D6 inhibitor and is metabolised, to a minor extent, by CYP2D6.  Medicinal 
products that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased plasma 
concentrations of cobicistat. 
 
Medicinal products that are highly dependent on CYP3A metabolism and have high first pass 
metabolism are the most susceptible to large increases in exposure when co-administered with 
cobicistat (see “Concomitant use contraindicated” and section 4.3). 
 
Cobicistat is an inhibitor of the following transporters: P-gp, breast cancer resistance protein (BCRP), 
organic anion transporting polypeptide (OATP) 1B1 and OATP1B3.  Co-administration with 
medicinal products that are substrates of P-gp, BCRP, OATP1B1 and OATP1B3 may result in 
increased plasma concentrations of these products. 
 
Emtricitabine 
 
In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for 
CYP-mediated interactions involving emtricitabine with other medicinal products is low.  
Co-administration of emtricitabine with medicinal products that are eliminated by active tubular 
secretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product.  
Medicinal products that decrease renal function may increase concentrations of emtricitabine. 
 
Tenofovir alafenamide 
 
Tenofovir alafenamide is transported by P-gp and BCRP.  Medicinal products that strongly affect P-gp 
and BCRP activity may lead to changes in tenofovir alafenamide absorption.  However, upon 
co-administration with cobicistat in Genvoya, near maximal inhibition of P-gp by cobicistat is 
achieved leading to increased availability of tenofovir alafenamide with resulting exposures 
comparable to tenofovir alafenamide 25 mg administered alone.  As such, tenofovir alafenamide 
exposures following administration of Genvoya are not expected to be further increased when used in 
combination with another P-gp and/or BCRP inhibitor (e.g., ketoconazole).  Based on data from an 
in vitro study, co-administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., 
febuxostat) is not expected to increase systemic exposure to tenofovir in vivo.  In vitro and clinical 
pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated 
interactions involving tenofovir alafenamide with other medicinal products is low.  Tenofovir 
alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.  
Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo.  Tenofovir alafenamide is a 
substrate of OATP in vitro.  Inhibitors of OATP and BCRP include ciclosporin. 
 
Concomitant use contraindicated 
 
Co-administration of Genvoya and some medicinal products that are primarily metabolised by CYP3A 
may result in increased plasma concentrations of these products, which are associated with the 
potential for serious or life-threatening adverse reactions such as peripheral vasospasm or ischaemia 
(e.g., dihydroergotamine, ergotamine, ergometrine), or myopathy, including rhabdomyolysis (e.g., 
simvastatin, lovastatin), or prolonged or increased sedation or respiratory depression (e.g., orally 
administered midazolam or triazolam).  Co-administration of Genvoya and other medicinal products 
primarily metabolised by CYP3A such as amiodarone, quinidine, cisapride, pimozide, lurasidone, 
alfuzosin and sildenafil for pulmonary arterial hypertension is contraindicated (see section 4.3). 



 

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Co-administration of Genvoya and some medicinal products that induce CYP3A such as St. John’s 
wort (Hypericum perforatum), rifampicin, carbamazepine, phenobarbital, and phenytoin may result in 
significantly decreased cobicistat and elvitegravir plasma concentrations, which may result in loss of 
therapeutic effect and development of resistance (see section 4.3). 
 
Other interactions 
 
Cobicistat and tenofovir alafenamide are not inhibitors of human UGT1A1 in vitro.  It is not known 
whether cobicistat, emtricitabine, or tenofovir alafenamide are inhibitors of other UGT enzymes. 
 
Interactions between the components of Genvoya and potential co-administered medicinal products 
are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”).  The 
interactions described are based on studies conducted with Genvoya, or the components of Genvoya 
(elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide), as individual agents and/or in 
combination, or are potential drug-drug interactions that may occur with Genvoya. 
 
Table 1: Interactions between the individual components of Genvoya and other medicinal 
products 
 

Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

ANTI-INFECTIVES 
Antifungals 
Ketoconazole (200 mg twice 
daily)/ Elvitegravir (150 mg once 
daily)2 

Elvitegravir: 
AUC: ↑ 48% 
Cmin: ↑ 67% 
Cmax: ↔ 
 
Concentrations of ketoconazole 
and/or cobicistat may increase with 
co-administration of Genvoya. 

When administering with Genvoya, 
the maximum daily dose of 
ketoconazole should not exceed 
200 mg per day.  Caution is 
warranted and clinical monitoring is 
recommended during the 
co-administration. 

Itraconazole3 
Voriconazole3 
Posaconazole3 
Fluconazole 

Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of itraconazole, 
fluconazole and posaconazole may 
be increased when co-administered 
with cobicistat. 
 
Concentrations of voriconazole 
may increase or decrease when 
co-administered with Genvoya. 

Clinical monitoring should be made 
upon co-administration with 
Genvoya.  When administering with 
Genvoya, the maximum daily dose 
of itraconazole should not exceed 
200 mg per day. 
 
An assessment of benefit/risk ratio 
is recommended to justify use of 
voriconazole with Genvoya. 



 

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Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

Antimycobacterials 
Rifabutin (150 mg every other 
day)/ Elvitegravir (150 mg once 
daily)/ Cobicistat (150 mg once 
daily) 

Co-administration of rifabutin, a 
potent CYP3A inducer, may 
significantly decrease cobicistat 
and elvitegravir plasma 
concentrations, which may result in 
loss of therapeutic effect and 
development of resistance. 
 
Rifabutin: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
25-O-desacetyl-rifabutin 
AUC: ↑ 525% 
Cmin: ↑ 394% 
Cmax: ↑ 384% 
 
Elvitegravir: 
AUC: ↓ 21% 
Cmin: ↓ 67% 
Cmax: ↔ 
 
Cobicistat: 
AUC: ↔ 
Cmin: ↓ 66% 
Cmax: ↔ 

Co-administration of Genvoya and 
rifabutin is not recommended. 
 
If the combination is needed, the 
recommended dose of rifabutin is 
150 mg 3 times per week on set 
days (for example Monday-
Wednesday-Friday). 
Increased monitoring for 
rifabutin-associated adverse 
reactions including neutropenia and 
uveitis is warranted due to an 
expected increase in exposure to 
desacetyl-rifabutin.  Further dose 
reduction of rifabutin has not been 
studied.  It should be kept in mind 
that a twice weekly dose of 150 mg 
may not provide an optimal 
exposure to rifabutin thus leading to 
a risk of rifamycin resistance and a 
treatment failure. 



 

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Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

Anti-hepatitis C virus medicinal products 
Ledipasvir (90 mg once daily)/ 
Sofosbuvir (400 mg once daily)/ 
Elvitegravir (150 mg once daily)/ 
Cobicistat (150 mg once daily)/ 
Emtricitabine (200 mg once daily)/ 
Tenofovir alafenamide (10 mg 
once daily)5 

Ledipasvir: 
AUC: ↑ 79% 
Cmin: ↑ 93% 
Cmax: ↑ 65% 
 
Sofosbuvir: 
AUC: ↑ 47% 
Cmin: N/A 
Cmax: ↑ 28% 
 
Sofosbuvir metabolite GS-566500: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Sofosbuvir metabolite GS-331007: 
AUC: ↑ 48% 
Cmin: ↑ 66% 
Cmax: ↔ 
 
Elvitegravir: 
AUC: ↔ 
Cmin: ↑ 46% 
Cmax: ↔ 
 
Cobicistat: 
AUC: ↑ 53% 
Cmin: ↑ 225% 
Cmax: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Tenofovir alafenamide: 
AUC: ↔ 
Cmin: N/A 
Cmax: ↔ 

No dose adjustment of 
ledipasvir/sofosbuvir and Genvoya 
is warranted upon co-administration. 



 

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Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

Sofosbuvir (400 mg once daily)/ 
Velpatasvir (100 mg once daily)/ 
Elvitegravir (150 mg once daily)/ 
Cobicistat (150 mg once daily)/ 
Emtricitabine (200 mg once daily)/ 
Tenofovir alafenamide (10 mg 
once daily)5 

Sofosbuvir: 
AUC: ↑ 37% 
Cmin: N/A 
Cmax: ↔ 
 
Sofosbuvir metabolite GS-331007: 
AUC: ↑ 48% 
Cmin: ↑ 58% 
Cmax: ↔ 
 
Velpatasvir: 
AUC: ↑ 50% 
Cmin: ↑ 60% 
Cmax: ↑ 30% 
 
Elvitegravir: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Cobicistat: 
AUC: ↔ 
Cmin: ↑ 103% 
Cmax: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Tenofovir alafenamide: 
AUC: ↔ 
Cmin: N/A 
Cmax: ↓ 20% 

No dose adjustment of 
sofosbuvir/velpatasvir and Genvoya 
is warranted upon co-administration. 



 

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Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

Sofosbuvir/Velpatasvir/ 
Voxilaprevir 
(400 mg/100 mg/100 mg+100 mg 
once daily)7/  
Elvitegravir (150 mg once daily)/ 
Cobicistat (150 mg once daily)/ 
Emtricitabine (200 mg once daily)/ 
Tenofovir alafenamide (10 mg 
once daily)5 

Sofosbuvir: 
AUC: ↔ 
Cmin: N/A 
Cmax: ↑ 27% 
 
Sofosbuvir metabolite GS-331007: 
AUC: ↑ 43% 
Cmin: N/A 
Cmax: ↔ 
 
Velpatasvir: 
AUC: ↔ 
Cmin: ↑ 46% 
Cmax: ↔ 
 
Voxilaprevir: 
AUC: ↑ 171% 
Cmin: ↑ 350% 
Cmax: ↑ 92% 
 
Elvitegravir: 
AUC: ↔ 
Cmin: ↑ 32% 
Cmax: ↔ 
 
Cobicistat: 
AUC: ↑ 50% 
Cmin: ↑ 250% 
Cmax: ↔ 
 
Emtricitabine: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Tenofovir alafenamide: 
AUC: ↔ 
Cmin: N/A 
Cmax: ↓ 21% 

No dose adjustment of 
sofosbuvir/velpatasvir/voxilaprevir 
and Genvoya is warranted upon 
co-administration. 

Macrolide antibiotics 
Clarithromycin Interaction not studied with any of 

the components of Genvoya. 
 
Concentrations of clarithromycin 
and/or cobicistat may be altered 
with co-administration of Genvoya. 

Clarithromycin dosing should be 
based on the patient’s CrCl, taking 
into consideration the effect of 
cobicistat on CrCl and serum 
creatinine (see section 4.8). 
 
Patients with CrCl greater than or 
equal to 60 mL/min: 
No dose adjustment of 
clarithromycin is required. 
 
Patients with CrCl between 
30 mL/min and 60 mL/min: 
The dose of clarithromycin should 
be reduced by 50%. 



 

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Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

Telithromycin Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of telithromycin 
and/or cobicistat may be altered 
with co-administration of Genvoya. 

Clinical monitoring is recommended 
upon co-administration of Genvoya. 

ANTICONVULSANTS 
Carbamazepine (200 mg twice 
daily)/ Elvitegravir (150 mg once 
daily)/ Cobicistat (150 mg once 
daily) 

Co-administration of 
carbamazepine, a potent CYP3A 
inducer, may significantly decrease 
cobicistat plasma concentrations. 
 
Elvitegravir: 
AUC: ↓ 69% 
Cmin: ↓ 97% 
Cmax: ↓ 45% 
 
Cobicistat: 
AUC: ↓ 84% 
Cmin: ↓ 90% 
Cmax: ↓ 72% 
 
Carbamazepine: 
AUC: ↑ 43% 
Cmin: ↑ 51% 
Cmax: ↑ 40% 
 
Carbamazepine-10,11-epoxide: 
AUC: ↓ 35% 
Cmin: ↓ 41% 
Cmax: ↓ 27% 

Carbamazepine decreases plasma 
concentrations of elvitegravir and 
cobicistat, which may result in loss 
of therapeutic effect and 
development of resistance.  
Co-administration of Genvoya with 
carbamazepine is contraindicated 
(see section 4.3). 

GLUCOCORTICOIDS 
All corticosteroids excluding cutaneous products 
Corticosteroids primarily 
metabolised by CYP3A (including 
betamethasone, budesonide, 
fluticasone, mometasone, 
prednisone, triamcinolone). 

Interaction not studied with any of 
the components of Genvoya. 
 
Plasma concentrations of these 
medicinal products may be 
increased when co-administered 
with Genvoya, resulting in reduced 
serum cortisol concentrations. 

Concomitant use of Genvoya and 
corticosteroids that are metabolised 
by CYP3A (e.g. fluticasone 
propionate or other inhaled or nasal 
corticosteroids) may increase the 
risk of development of systemic 
corticosteroid effects, including 
Cushing’s syndrome and adrenal 
suppression. 
 
Co-administration with 
CYP3A-metabolised corticosteroids 
is not recommended unless the 
potential benefit to the patient 
outweighs the risk, in which case 
patients should be monitored for 
systemic corticosteroid effects.  
Alternative corticosteroids which 
are less dependent on CYP3A 
metabolism e.g. beclomethasone for 
intranasal or inhalational use should 
be considered, particularly for 
long-term use. 



 

14 

Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

ANTACIDS 
Magnesium/aluminium-containing 
antacid suspension (20 mL single 
dose)/ Elvitegravir (50 mg single 
dose)/ Ritonavir (100 mg single 
dose) 

Elvitegravir (antacid suspension 
after ± 2 hours): 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Elvitegravir (simultaneous 
administration): 
AUC: ↓ 45% 
Cmin: ↓ 41% 
Cmax: ↓ 47% 

Elvitegravir plasma concentrations 
are lower with antacids due to local 
complexation in the gastrointestinal 
tract and not to changes in gastric 
pH.  It is recommended to separate 
Genvoya and antacid administration 
by at least 4 hours. 
 
For information on other acid 
reducing agents (e.g., H2-receptor 
antagonists and proton pump 
inhibitors), see “Studies conducted 
with other medicinal products”. 

FOOD SUPPLEMENTS 
Multivitamin supplements Interaction not studied with any of 

the components of Genvoya. 
As the effect of cationic 
complexation of elvitegravir cannot 
be excluded when Genvoya is 
co-administered with multivitamin 
supplements, it is recommended to 
separate Genvoya and multivitamin 
supplements dosing by at least 
4 hours. 

ORAL ANTI-DIABETICS 
Metformin Interaction not studied with any of 

the components of Genvoya. 
 
Cobicistat reversibly inhibits 
MATE1, and concentrations of 
metformin may be increased when 
co-administered with Genvoya. 

Careful patient monitoring and dose 
adjustment of metformin is 
recommended in patients who are 
taking Genvoya. 

NARCOTIC ANALGESICS 
Methadone (80-120 mg)/ 
Elvitegravir (150 mg once daily)/ 
Cobicistat (150 mg once daily) 

Methadone: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Cobicistat: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Elvitegravir: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 

No dose adjustment of methadone is 
required. 



 

15 

Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

Buprenorphine/Naloxone (16/4 to 
24/6 mg)/ Elvitegravir (150 mg 
once daily)/ Cobicistat (150 mg 
once daily) 

Buprenorphine: 
AUC: ↑ 35% 
Cmin: ↑ 66% 
Cmax: ↑ 12% 
 
Naloxone: 
AUC: ↓ 28% 
Cmax: ↓ 28% 
 
Cobicistat: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Elvitegravir: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 

No dose adjustment of 
buprenorphine/naloxone is required. 

ORAL CONTRACEPTIVES 
Drospirenone/Ethinyloestradiol 
(3 mg/0.02 mg single dose)/ 
Cobicistat (150 mg once daily) 

Interaction not studied with 
Genvoya. 
 
Expected 
Drospirenone: 
AUC: ↑ 

Plasma concentrations of 
drospirenone may be increased 
when co-administered with 
cobicistat-containing products.  
Clinical monitoring is recommended 
due to the potential for 
hyperkalaemia. 
 
Caution should be exercised when 
co-administering Genvoya and a 
hormonal contraceptive.  The 
hormonal contraceptive should 
contain at least 30 µg 
ethinyloestradiol and contain 
drospirenone or norgestimate as the 
progestogen or patients should use 
an alternative reliable method of 
contraception (see sections 4.4 and 
4.6). 
 
The long-term effects of substantial 
increases in progestogen exposure 
are unknown. 

Norgestimate 
(0.180/0.215/0.250 mg once daily)/ 
Ethinyloestradiol (0.025 mg once 
daily)/ Emtricitabine/Tenofovir 
alafenamide (200/25 mg once 
daily)6 

Norelgestromin: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Norgestrel: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Ethinyloestradiol: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 

Norgestimate (0.180/0.215 mg 
once daily)/ Ethinyloestradiol 
(0.025 mg once daily)/ Elvitegravir 
(150 mg once daily)/ Cobicistat 
(150 mg once daily)4 

Norgestimate: 
AUC: ↑ 126% 
Cmin: ↑ 167% 
Cmax: ↑ 108% 
 
Ethinyloestradiol: 
AUC: ↓ 25% 
Cmin: ↓ 44% 
Cmax: ↔ 
 
Elvitegravir: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 



 

16 

Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

ANTIARRHYTHMICS 
Digoxin (0.5 mg single dose)/ 
Cobicistat (150 mg multiple doses) 

Digoxin: 
AUC: ↔ 
Cmax: ↑ 41% 

It is recommended that digoxin 
levels be monitored when digoxin is 
combined with Genvoya. 

Disopyramide 
Flecainide 
Systemic lidocaine 
Mexiletine 
Propafenone 

Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of these 
antiarrhythmic drugs may be 
increased when co-administered 
with cobicistat. 

Caution is warranted and clinical 
monitoring is recommended upon 
co-administration with Genvoya. 

ANTI-HYPERTENSIVES 
Metoprolol 
Timolol 

Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of beta-blockers 
may be increased when 
co-administered with cobicistat. 

Clinical monitoring is recommended 
and a dose decrease may be 
necessary when these agents are 
co-administered with Genvoya. 

Amlodipine 
Diltiazem 
Felodipine 
Nicardipine 
Nifedipine 
Verapamil 

Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of calcium channel 
blockers may be increased when 
co-administered with cobicistat. 

Clinical monitoring of therapeutic 
effects and adverse reactions is 
recommended when these medicinal 
products are concomitantly 
administered with Genvoya. 

ENDOTHELIN RECEPTOR ANTAGONISTS 
Bosentan Interaction not studied with any of 

the components of Genvoya. 
 
Co-administration with Genvoya 
may lead to decreased elvitegravir 
and/or cobicistat exposures and 
loss of therapeutic effect and 
development of resistance. 

Alternative endothelin receptor 
antagonists may be considered. 

ANTICOAGULANTS 
Dabigatran Interaction not studied with any of 

the components of Genvoya. 
 
Co-administration with Genvoya 
may increase dabigatran plasma 
concentrations with similar effects 
as seen with other strong P-gp 
inhibitors. 

Co-administration of Genvoya with 
dabigatran is contraindicated. 

Apixaban 
Rivaroxaban 
Edoxaban 

Interaction not studied with any of 
the components of Genvoya. 
 
Co-administration with Genvoya 
may result in increased plasma 
concentrations of the DOAC, 
which may lead to an increased 
bleeding risk. 

Co-administration of apixaban, 
rivaroxaban or edoxaban is not 
recommended with Genvoya. 

Warfarin Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of warfarin may be 
affected upon co-administration 
with Genvoya. 

It is recommended that the 
international normalised ratio (INR) 
be monitored upon 
co-administration of Genvoya.  INR 
should continue to be monitored 
during the first weeks following 
ceasing treatment with Genvoya. 



 

17 

Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

INHALED BETA AGONIST 
Salmeterol Interaction not studied with any of 

the components of Genvoya. 
 
Co-administration with Genvoya 
may result in increased plasma 
concentrations of salmeterol, which 
is associated with the potential for 
serious or life-threatening adverse 
reactions. 

Concurrent administration of 
salmeterol and Genvoya is not 
recommended. 

HMG CO-A REDUCTASE INHIBITORS 
Rosuvastatin (10 mg single dose)/ 
Elvitegravir (150 mg once daily)/ 
Cobicistat (150 mg once daily) 

Elvitegravir: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Rosuvastatin: 
AUC: ↑ 38% 
Cmin: N/A 
Cmax: ↑ 89% 

Concentrations of rosuvastatin are 
transiently increased when 
administered with elvitegravir and 
cobicistat.  Dose modifications are 
not necessary when rosuvastatin is 
administered in combination with 
Genvoya. 

Atorvastatin (10 mg single 
dose)/Elvitegravir (150 mg once 
daily)/Cobicistat (150 mg once 
daily)/Emtricitabine (200 mg once 
daily)/Tenofovir alafenamide 
(10 mg once daily) 

Atorvastatin: 
AUC: ↑ 160% 
Cmin: NC 
Cmax: ↑ 132%  
 
Elvitegravir: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 

Concentrations of atorvastatin are 
increased when co-administered 
with elvitegravir and cobicistat.  
Start with the lowest possible dose 
of atorvastatin with careful 
monitoring upon co-administration 
with Genvoya. 

Pitavastatin Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of pitavastatin may 
be increased when administered 
with elvitegravir and cobicistat. 

Caution should be exercised when 
co-administering Genvoya with 
pitavastatin. 

Pravastatin 
Fluvastatin 

Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of these 
HMG Co-A reductase inhibitors 
are expected to transiently increase 
when administered with 
elvitegravir and cobicistat. 

Dose modifications are not 
necessary when administered in 
combination with Genvoya. 

Lovastatin 
Simvastatin 

Interaction not studied with any of 
the components of Genvoya. 

Co-administration of Genvoya and 
lovastatin and simvastatin is 
contraindicated (see section 4.3). 



 

18 

Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS 
Sildenafil 
Tadalafil 
Vardenafil 

Interaction not studied with any of 
the components of Genvoya. 
 
PDE-5 inhibitors are primarily 
metabolised by CYP3A.  
Co-administration with Genvoya 
may result in increased plasma 
concentrations of sildenafil and 
tadalafil, which may result in 
PDE-5 inhibitor-associated adverse 
reactions. 

Co-administration of Genvoya and 
sildenafil for the treatment of 
pulmonary arterial hypertension is 
contraindicated. 
 
Caution should be exercised, 
including consideration of dose 
reduction, when co-administering 
Genvoya with tadalafil for the 
treatment of pulmonary arterial 
hypertension. 
 
For the treatment of erectile 
dysfunction, it is recommended that 
a single dose of sildenafil no more 
than 25 mg in 48 hours, vardenafil 
no more than 2.5 mg in 72 hours, or 
tadalafil no more than 10 mg in 
72 hours be co-administered with 
Genvoya. 

ANTIDEPRESSANTS 
Sertraline (50 mg single dose)/ 
Elvitegravir (150 mg once daily)/ 
Cobicistat (150 mg once daily)/ 
Emtricitabine (200 mg once daily)/ 
Tenofovir alafenamide (10 mg 
once daily)5  

Elvitegravir: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Tenofovir alafenamide: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 
 
Sertraline: 
AUC: ↔ 
Cmin: ↔ 
Cmax: ↔ 

Concentrations of sertraline are not 
affected upon co-administration 
with Genvoya.  No dose adjustment 
is required upon co-administration. 

Tricyclic antidepressants (TCAs) 
Trazodone 
Selective serotonin reuptake 
inhibitors (SSRIs) 
Escitalopram 

Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of antidepressant 
agents may be increased when 
co-administered with cobicistat. 

Careful dose titration of the 
antidepressant and monitoring for 
antidepressant response is 
recommended. 

IMMUNOSUPPRESSANTS 
Ciclosporin 
Sirolimus 
Tacrolimus 

Interaction not studied with any of 
the components of Genvoya. 
 
Concentrations of these 
immunosuppressant agents may be 
increased when administered with 
cobicistat. 

Therapeutic monitoring is 
recommended upon 
co-administration with Genvoya. 



 

19 

Medicinal product by 
therapeutic areas 

Effects on medicinal product 
levels. 

Mean percent change in AUC, 
Cmax, Cmin1 

Recommendation concerning 
co-administration with Genvoya 

SEDATIVES/HYPNOTICS 
Buspirone 
Clorazepate 
Diazepam 
Estazolam 
Flurazepam 
Lorazepam 
Triazolam 
Zolpidem 

Interaction not studied with any of 
the components of Genvoya. 
 
Triazolam is primarily metabolised 
by CYP3A.  Co-administration 
with Genvoya may result in 
increased plasma concentrations of 
this medicinal product, which is 
associated with the potential for 
serious or life-threatening adverse 
reactions. 
 
Concentrations of other 
benzodiazepines, including 
diazepam, may be increased when 
administered with Genvoya. 
 
Based on non-CYP-mediated 
elimination pathways for 
lorazepam, no effect on plasma 
concentrations is expected upon 
co-administration with Genvoya. 

Co-administration of Genvoya and 
triazolam is contraindicated (see 
section 4.3).  With other 
sedatives/hypnotics, dose reduction 
may be necessary and concentration 
monitoring is recommended. 

Orally administered midazolam 
(2.5 mg single dose)/ Tenofovir 
alafenamide (25 mg once daily)  
 
Intravenously administered 
midazolam (1 mg single dose)/ 
Tenofovir alafenamide (25 mg 
once daily) 

Midazolam: 
AUC: ↔ 
Cmax: ↔ 
 
Midazolam is primarily 
metabolised by CYP3A.  Due to 
the presence of cobicistat, 
co-administration with Genvoya 
may result in increased plasma 
concentrations of this medicinal 
product, which is associated with 
the potential for serious or 
life-threatening adverse reactions. 

Co-administration of Genvoya and 
orally administered midazolam is 
contraindicated (see section 4.3). 

ANTI-GOUT 
Colchicine Interaction not studied with any of 

the components of Genvoya. 
 
Co-administration with Genvoya 
may result in increased plasma 
concentrations of this medicinal 
product. 

Dose reductions of colchicine may 
be required.  Genvoya should not be 
co-administered with colchicine to 
patients with renal or hepatic 
impairment. 

N/A = not applicable 
NC = not calculated 
DOAC = direct oral anticoagulant 
1 When data available from drug-drug interaction studies. 
2 These studies were performed with ritonavir boosted elvitegravir. 
3 These are medicinal products within class where similar interactions could be predicted. 
4 This study was conducted using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate. 
5 This study was conducted using Genvoya. 
6 This study was conducted using emtricitabine/tenofovir alafenamide. 
7 This study was conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in 

HCV infected patients. 
 



 

20 

Studies conducted with other medicinal products 
 
Based on drug-drug interaction studies conducted with Genvoya or the components of Genvoya, no 
clinically significant drug-drug interactions have been either observed or are expected between the 
components of Genvoya and the following medicinal products: entecavir, famciclovir, ribavirin, 
famotidine, and omeprazole. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / contraception in males and females 
 
The use of Genvoya should be accompanied by the use of effective contraception (see sections 4.4 
and 4.5). 
 
Pregnancy 
 
There are no adequate and well-controlled studies of Genvoya or its components in pregnant women.  
There are no or limited data (less than 300 pregnancy outcomes) from the use of Genvoya in pregnant 
women.  However, a large amount of data on pregnant women (more than 1,000 exposed outcomes) 
indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine. 
 
Animal studies do not indicate direct or indirect harmful effects of elvitegravir, cobicistat, or 
emtricitabine, administered separately, with respect to fertility parameters, pregnancy, foetal 
development, parturition or postnatal development.  Studies of tenofovir alafenamide in animals have 
shown no evidence of harmful effects of tenofovir alafenamide on fertility parameters, pregnancy, or 
foetal development (see section 5.3). 
 
Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy has 
been shown to result in lower elvitegravir exposure (see section 5.2).  Cobicistat levels decrease and 
may not provide sufficient boosting.  The substantial reduction in elvitegravir exposure may result in 
virological failure and an increased risk of mother-to-child transmission of HIV infection.   Therefore, 
therapy with Genvoya should not be initiated during pregnancy, and women who become pregnant 
during therapy with Genvoya should be switched to an alternative regimen (see sections 4.2 and 4.4). 
 
Breast-feeding 
 
It is not known whether elvitegravir, cobicistat, or tenofovir alafenamide are excreted in human milk.  
Emtricitabine is excreted in human milk.  In animal studies it has been shown that elvitegravir, 
cobicistat, and tenofovir are excreted in milk. 
 
There is insufficient information on the effects of elvitegravir, cobicistat, emtricitabine and tenofovir 
in newborns/infants.  Therefore, Genvoya should not be used during breast-feeding. 
 
In order to avoid transmission of HIV to the infant it is recommended that HIV infected women do not 
breast-feed their infants under any circumstances. 
 
Fertility 
 
There are no data on fertility from the use of Genvoya in humans.  In animal studies there were no 
effects of elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide on mating or fertility 
parameters (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 Genvoya. 
 



 

21 

4.8 Undesirable effects 
 
Summary of the safety profile 
 
Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies in which 
2,396 patients received Genvoya and from post-marketing experience.  The most frequently reported 
adverse reactions in clinical studies through 144 weeks were nausea (11%), diarrhoea (7%), and 
headache (6%) (pooled data from Phase 3 clinical studies GS-US-292-0104 and GS-US-292-0111 in 
866 treatment-naïve adult patients receiving Genvoya). 
 
Tabulated summary of adverse reactions 
 
The adverse reactions in Table 2 are listed by system organ class and frequency.  Frequencies are 
defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to 
< 1/100). 
 
Table 2: Tabulated list of adverse reactions 
 

Frequency Adverse reaction 
Blood and lymphatic system disorders 
Uncommon: anaemia1 
Psychiatric disorders 
Common: abnormal dreams 

Uncommon: suicidal ideation and suicide attempt (in patients with a pre-existing history of depression or psychiatric illness), depression2 
Nervous system disorders 
Common: headache, dizziness 
Gastrointestinal disorders 
Very common: nausea 
Common: diarrhoea, vomiting, abdominal pain, flatulence 
Uncommon: dyspepsia 
Skin and subcutaneous tissue disorders 
Common: rash 
Uncommon: angioedema3,4, pruritus, urticaria4 
General disorders and administration site conditions 
Common: fatigue 

1 This adverse reaction was not observed in the Phase 3 clinical studies for Genvoya but identified from clinical studies or 
post-marketing experience for emtricitabine when used with other antiretrovirals. 

2 This adverse reaction was not observed in the Phase 3 clinical studies for Genvoya but identified from clinical studies for 
elvitegravir when used with other antiretrovirals. 

3 This adverse reaction was identified through post-marketing surveillance for emtricitabine-containing products. 
4 This adverse reaction was identified through post-marketing surveillance for tenofovir alafenamide-containing products. 
 
Description of selected adverse reactions 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see 
section 4.4). 
 
Immune Reactivation Syndrome 
In HIV infected patients with severe immune deficiency at the time of initiation of 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). 
 



 

22 

Osteonecrosis 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to CART.  The frequency of this is unknown 
(see section 4.4). 
 
Changes in serum creatinine 
Cobicistat increases serum creatinine due to inhibition of tubular secretion of creatinine without 
affecting renal glomerular function.  In clinical studies of Genvoya, increases in serum creatinine 
occurred by Week 2 of treatment and remained stable through 144 weeks.  In treatment-naïve patients, 
a mean change from baseline of 0.04 ± 0.12 mg/dL (3.5 ± 10.6 µmol/L) was observed after 144 weeks 
of treatment.  Mean increases from baseline in the Genvoya group were smaller than in the elvitegravir 
150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg 
(E/C/F/TDF) group at Week 144 (difference -0.04, p < 0.001). 
 
Changes in lipid laboratory tests 
In studies in treatment-naïve patients, increases from baseline were observed in both treatment groups 
for the fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)- and 
high-density lipoprotein (HDL)-cholesterol, and triglycerides at Week 144.  The median increase from 
baseline for those parameters was greater in the Genvoya group compared with the E/C/F/TDF group 
at Week 144 (p < 0.001 for the difference between treatment groups for fasting total cholesterol, direct 
LDL- and HDL-cholesterol, and triglycerides).  The median (Q1, Q3) change from baseline in total 
cholesterol to HDL-cholesterol ratio at Week 144 was 0.2 (-0.3, 0.7) in the Genvoya group and 0.1 
(-0.4, 0.6) in the E/C/F/TDF group (p = 0.006 for the difference between treatment groups). 
 
Paediatric population 
 
The safety of Genvoya was evaluated through 48 weeks in HIV-1 infected adolescent patients between 
the ages of 12 to < 18 years weighing ≥ 35 kg, who were either treatment-naïve (GS-US-292-0106, 
n = 50), or who were virologically suppressed (GS-US-292-1515, n = 50), and in virologically 
suppressed children between the ages of 8 to < 12 years weighing > 25 kg (GS-US-292-0106, n = 23).  
The safety profile in paediatric patients who received treatment with Genvoya was similar to that in 
adults. 
 
Other special populations 
 
Patients with renal impairment 
The safety of Genvoya in 248 HIV-1 infected patients who were either treatment-naïve (n = 6) or 
virologically suppressed (n = 242) with mild to moderate renal impairment (estimated glomerular 
filtration rate by Cockcroft-Gault method [eGFRCG]: 30-69 mL/min) was evaluated through 144 weeks 
in an open-label clinical study (GS-US-292-0112).  The safety profile of Genvoya in patients with 
mild to moderate renal impairment was similar to that in patients with normal renal function (see 
section 5.1). 
 
The safety of Genvoya in 55 virologically suppressed HIV-1 infected patients with end stage renal 
disease (eGFRCG < 15 mL/min) on chronic haemodialysis was evaluated through 48 weeks in a single 
arm, open-label clinical study (GS-US-292-1825).  There were no new safety issues identified in 
patients with end stage renal disease on chronic haemodialysis receiving Genvoya (see section 5.2). 
 
Patients co-infected with HIV and HBV 
The safety of Genvoya was evaluated in 72 HIV/HBV co-infected patients receiving treatment for 
HIV in an open-label clinical study (GS-US-292-1249), through Week 48, in which patients were 
switched from another antiretroviral regimen (which included tenofovir disoproxil in 69 of 
72 patients) to Genvoya.  Based on these limited data, the safety profile of Genvoya in patients with 
HIV/HBV co-infection was similar to that in patients with HIV-1 monoinfection. 
 



 

23 

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 
 
If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8).  Treatment 
of overdose with Genvoya consists of general supportive measures including monitoring of vital signs 
as well as observation of the clinical status of the patient. 
 
As elvitegravir and cobicistat are highly bound to plasma proteins, it is unlikely that they would be 
significantly removed by haemodialysis or peritoneal dialysis.  Emtricitabine can be removed by 
haemodialysis, which removes approximately 30% of the emtricitabine dose over a 3 hour dialysis 
period starting within 1.5 hours of emtricitabine dosing.  Tenofovir is efficiently removed by 
haemodialysis with an extraction coefficient of approximately 54%.  It is not known whether 
emtricitabine or tenofovir can be removed by peritoneal dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antivirals for systemic use; antivirals for treatment of HIV infections, 
combinations.  ATC code: J05AR18. 
 
Mechanism of action 
 
Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI).  Integrase is an HIV-1 encoded 
enzyme that is required for viral replication.  Inhibition of integrase prevents the integration of HIV-1 
deoxyribonucleic acid (DNA) into host genomic DNA, blocking the formation of the HIV-1 provirus 
and propagation of the viral infection. 
 
Cobicistat is a selective, mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the 
CYP3A subfamily.  Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic 
exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is 
shortened by CYP3A-dependent metabolism. 
 
Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and nucleoside analogue of 
2’-deoxycytidine.  Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 
triphosphate.  Emtricitabine triphosphate inhibits HIV replication through incorporation into viral 
DNA by the HIV reverse transcriptase (RT), which results in DNA chain-termination.  Emtricitabine 
has activity against HIV-1, HIV-2, and HBV. 
 
Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonamidate 
prodrug of tenofovir (2’-deoxyadenosine monophosphate analogue).  Tenofovir alafenamide is 
permeable into cells and due to increased plasma stability and intracellular activation through 
hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil in 
concentrating tenofovir in peripheral blood mononuclear cells (PBMCs) (including lymphocytes and 
other HIV target cells) and macrophages.  Intracellular tenofovir is subsequently phosphorylated to the 
pharmacologically active metabolite tenofovir diphosphate.  Tenofovir diphosphate inhibits 
HIV replication through incorporation into viral DNA by the HIV RT, which results in DNA 
chain-termination.  Tenofovir has activity against HIV-1, HIV-2, and HBV. 
 

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Antiviral activity in vitro 
 
Elvitegravir, emtricitabine, and tenofovir alafenamide demonstrated synergistic antiviral activity in 
cell culture.  Antiviral synergy was maintained for elvitegravir, emtricitabine, and tenofovir 
alafenamide when tested in the presence of cobicistat. 
 
The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cells, monocyte/macrophage cells, and peripheral blood lymphocytes and the 
50% effective concentration (EC50) values were in the range of 0.02 to 1.7 nM.  Elvitegravir displayed 
antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged 
from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 of 0.53 nM). 
 
Cobicistat has no detectable antiviral activity against HIV-1 and does not antagonise the antiviral 
effects of elvitegravir, emtricitabine, or tenofovir. 
 
The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in 
lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs.  The EC50 values for emtricitabine 
were in the range of 0.0013 to 0.64 µM.  Emtricitabine displayed antiviral activity in cell culture 
against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 µM) and 
showed strain specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 µM). 
 
The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1 
subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells 
and CD4+-T lymphocytes.  The EC50 values for tenofovir alafenamide were in the range of 2.0 to 
14.7 nM.  Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV-1 groups 
(M, N, and O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) 
and showed strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM). 
 
Resistance 
 
In vitro 
Reduced susceptibility to elvitegravir is most commonly associated with the primary integrase 
mutations T66I, E92Q, and Q148R.  Additional integrase mutations observed in cell culture selection 
included H51Y, F121Y, S147G, S153Y, E157Q, and R263K.  HIV-1 with the raltegravir-selected 
substitutions T66A/K, Q148H/K, and N155H showed cross-resistance to elvitegravir. 
 
No in vitro resistance can be demonstrated with cobicistat due to its lack of antiviral activity. 
 
Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 RT. 
 
HIV-1 isolates with reduced susceptibility to tenofovir alafenamide express a K65R mutation in 
HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed.  HIV-1 isolates 
with the K65R mutation have low-level reduced susceptibility to abacavir, emtricitabine, tenofovir, 
and lamivudine. 
 
In treatment-naïve patients 
In a pooled analysis, genotyping was performed on plasma HIV-1 isolates from antiretroviral-naïve 
patients receiving Genvoya in Phase 3 studies GS-US-292-0104 and GS-US-292-0111 with 
HIV-1 RNA ≥ 400 copies/mL at confirmed virologic failure, Week 144, or time of early study drug 
discontinuation.  Up to Week 144, the development of one or more primary elvitegravir, emtricitabine, 
or tenofovir alafenamide resistance-associated mutations was observed in HIV-1 isolates from 12 of 
22 patients with evaluable genotypic data from paired baseline and Genvoya treatment-failure isolates 
(12 of 866 patients [1.4%]) compared with 12 of 20 treatment-failure isolates from patients with 
evaluable genotypic data in the E/C/F/TDF treatment group (12 of 867 patients [1.4%]).  Of the 
HIV-1 isolates from 12 patients with resistance development in the Genvoya group, the mutations that 
emerged were M184V/I (n = 11) and K65R/N (n = 2) in RT and T66T/A/I/V (n = 2), E92Q (n = 4), 
Q148Q/R (n = 1) and N155H (n = 2) in integrase.  Of the HIV-1 isolates from 12 patients with 



 

25 

resistance development in the E/C/F/TDF group, the mutations that emerged were M184V/I (n = 9), 
K65R/N (n = 4), and L210W (n = 1) in RT and E92Q/V (n = 4), and Q148R (n = 2), and N155H/S 
(n = 3) in integrase.  Most HIV-1 isolates from patients in both treatment groups who developed 
resistance mutations to elvitegravir developed resistance mutations to both emtricitabine and 
elvitegravir. 
 
In phenotypic analyses of patients in the final resistance analysis population, 7 of 22 patients (32%) 
had HIV-1 isolates with reduced susceptibility to elvitegravir in the Genvoya group compared with 
HIV-1 isolates from 7 of 20 patients (35%) in the E/C/F/TDF group, HIV-1 isolates from 8 patients 
(36%) had reduced susceptibility to emtricitabine in the Genvoya group compared with HIV-1 isolates 
from 7 patients (35%) in the E/C/F/TDF group.  One patient in the Genvoya group (1 of 22 [4.5%]) 
and 2 patients in the E/C/F/TDF group (2 of 20 [10%]) had reduced susceptibility to tenofovir. 
 
In virologically suppressed patients 
Three patients with emergent HIV-1 resistance to Genvoya were identified (M184M/I; M184I+E92G; 
M184V+E92Q) up to Week 96 in a clinical study of virologically suppressed patients who switched 
from a regimen containing emtricitabine/tenofovir disoproxil and a third agent (GS-US-292-0109, 
n = 959). 
 
In patients co-infected with HIV and HBV 
In a clinical study of HIV virologically suppressed patients co-infected with chronic hepatitis B, who 
received Genvoya for 48 weeks (GS-US-292-1249, n = 72), 2 patients qualified for resistance analysis.  
In these 2 patients, no amino acid substitutions associated with resistance to any of the components of 
Genvoya were identified in HIV-1 or HBV. 
 
Cross-resistance in HIV-1 infected, treatment-naïve or virologically suppressed patients 
Elvitegravir-resistant viruses show varying degrees of cross-resistance to the INSTI raltegravir 
depending on the type and number of mutations.  Viruses expressing the T66I/A mutations maintain 
susceptibility to raltegravir, while most other patterns showed reduced susceptibility to raltegravir.  
Viruses expressing elvitegravir or raltegravir resistance mutations maintain susceptibility to 
dolutegravir. 
 
Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but 
retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine. 
 
The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine, 
emtricitabine, and tenofovir, but retain sensitivity to zidovudine. 
 
Clinical data 
 
HIV-1 infected, treatment-naïve patients 
In studies GS-US-292-0104 and GS-US-292-0111, patients were randomised in a 1:1 ratio to receive 
either Genvoya (n = 866) once daily or elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 
200 mg/tenofovir disoproxil (as fumarate) 245 mg (E/C/F/TDF) (n = 867) once daily.  The mean age 
was 36 years (range 18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian.  
Nineteen percent of patients were identified as Hispanic/Latino.  The mean baseline plasma 
HIV-1 RNA was 4.5 log10 copies/mL (range 1.3-7.0) and 23% had baseline viral loads 
> 100,000 copies/mL.  The mean baseline CD4+ cell count was 427 cells/mm3 (range 0-1,360) and 
13% had a CD4+ cell count < 200 cells/mm3. 
 
Genvoya demonstrated statistical superiority in achieving HIV-1 RNA < 50 copies/mL when 
compared to E/C/F/TDF at Week 144.  The difference in percentage was 4.2% (95% CI: 0.6% to 
7.8%).  Pooled treatment outcomes at 48 and 144 weeks are shown in Table 3. 
 



 

26 

Table 3: Pooled virologic outcomes of studies GS-US-292-0104 and GS-US-292-0111 at 
Weeks 48 and 144a,b 
 
 Week 48 Week 144 

Genvoya 
(n = 866) 

E/C/F/TDF 
(n = 867) 

Genvoya 
(n = 866) 

E/C/F/TDF 
(n = 867) 

HIV-1 RNA < 50 copies/mL 92% 90% 84% 80% 
Treatment difference 2.0% (95% CI: -0.7% to 4.7%) 4.2% (95% CI: 0.6% to 7.8%) 

HIV-1 RNA ≥ 50 copies/mLc 4% 4% 5% 4% 
No virologic data at Week 48 
or 144 window 

4% 6% 11% 16% 

Discontinued study drug due 
to AE or deathd 

1% 2% 1% 3% 

Discontinued study drug due 
to other reasons and last 
available HIV-1 RNA 
< 50 copies/mLe 

2% 4% 9% 11% 

Missing data during window 
but on study drug 

1% < 1% 1% 1% 

Proportion (%) of patients with 
HIV-1 RNA < 50 copies/mL by 
subgroup 

    

Age 
< 50 years 
≥ 50 years 

 
716/777 (92%) 

84/89 (94%) 

 
680/753 (90%) 
104/114 (91%) 

 
647/777 (83%)  

82/89 (92%)  

 
602/753 (80%)  
92/114 (81%)  

Sex 
Male 
Female 

 
674/733 (92%) 
126/133 (95%) 

 
673/740 (91%) 
111/127 (87%) 

 
616/733 (84%)  
113/133 (85%)  

 
603/740 (81%)  
91/127 (72%)  

Race 
Black 
Non-black 

 
197/223 (88%) 
603/643 (94%) 

 
177/213 (83%) 
607/654 (93%) 

 
168/223 (75%)  
561/643 (87%)  

 
152/213 (71%)  
542/654 (83%)  

Baseline viral load 
≤ 100,000 copies/mL 
> 100,000 copies/mL 

 
629/670 (94%) 
171/196 (87%) 

 
610/672 (91%) 
174/195 (89%) 

 
567/670 (85%)  
162/196 (83%)  

 
537/672 (80%)  
157/195 (81%)  

Baseline CD4+ cell count 
< 200 cells/mm3 
≥ 200 cells/mm3 

 
96/112 (86%) 

703/753 (93%) 

 
104/117 (89%) 
680/750 (91%) 

 
93/112 (83%)  

635/753 (84%)  

 
94/117 (80%)  

600/750 (80%)  
HIV-1 RNA < 20 copies/mL 84.4% 84.0% 81.1% 75.8% 

Treatment difference 0.4% (95% CI: -3.0% to 3.8%) 5.4% (95% CI: 1.5% to 9.2%) 
E/C/F/TDF = elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate 
a Week 48 window was between Day 294 and 377 (inclusive); Week 144 window was between Day 966 and 1,049 

(inclusive). 
b In both studies, patients were stratified by baseline HIV-1 RNA (≤ 100,000 copies/mL, > 100,000 copies/mL to 

≤ 400,000 copies/mL, or > 400,000 copies/mL), by CD4+ cell count (< 50 cells/µL, 50-199 cells/µL, or ≥ 200 cells/µL), 
and by region (US or ex-US). 

c Includes patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack or 
loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy 
and at the time of discontinuation had a viral value of ≥ 50 copies/mL. 

d Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this 
resulted in no virologic data on treatment during the specified window. 

e Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, 
loss to follow-up, etc. 

 
The mean increase from baseline in CD4+ cell count was 230 cells/mm3 in Genvoya-treated patients 
and 211 cells/mm3 in E/C/F/TDF-treated patients (p = 0.024) at Week 48, and 326 cells/mm3 in 
Genvoya-treated patients and 305 cells/mm3 in E/C/F/TDF-treated patients (p = 0.06) at Week 144. 
 
HIV-1 infected virologically suppressed patients 
In Study GS-US-292-0109, the efficacy and safety of switching from either efavirenz 
(EFV)/emtricitabine (FTC)/tenofovir disoproxil, FTC/tenofovir disoproxil plus atazanavir (boosted by 
either cobicistat or ritonavir), or E/C/F/TDF to Genvoya were evaluated in a randomised, open-label 
study of virologically suppressed (HIV-1 RNA < 50 copies/mL) HIV-1 infected adults (n = 1,436).  



 

27 

Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen for 
at least 6 months and had HIV-1 with no resistance mutations to any of the components of Genvoya 
prior to study entry.  Patients were randomised in a 2:1 ratio to either switch to Genvoya at baseline 
(n = 959), or stay on their baseline antiretroviral regimen (n = 477).  Patients had a mean age of 
41 years (range 21-77), 89% were male, 67% were White, and 19% were Black.  The mean baseline 
CD4+ cell count was 697 cells/mm3 (range 79-1,951).  Patients were stratified by prior treatment 
regimen.  At screening, 42% of patients were receiving FTC/tenofovir disoproxil plus atazanavir 
(boosted by either cobicistat or ritonavir), 32% of patients were receiving E/C/F/TDF, and 26% of 
patients were receiving EFV/FTC/tenofovir disoproxil. 
 
Switching from a tenofovir disoproxil-based regimen to Genvoya was superior in maintaining 
HIV-1 RNA < 50 copies/mL compared to staying on the baseline regimen (Table 4). 
 
Table 4: Virologic outcomes of Study GS-US-292-0109 at Weeks 48a and 96b 
 

 Week 48 Week 96 

 Genvoya (n = 959) 
Baseline regimen 

(n = 477) 
Genvoya 
(n = 959) 

Baseline regimen 
(n = 477) 

HIV-1 RNA < 50 copies/mL 97% 93% 93% 89% 
Treatment difference 4.1% (95% CI: 1.6% to 6.7%, 

p < 0.001c) 
3.7% (95% CI: 0.4% to 7.0%,  

p < 0.017c) 
HIV-1 RNA ≥ 50 copies/mLd 1% 1% 2% 2% 
No virologic data at Week 48/ 
Week 96 window 2% 6% 5% 9% 

Discontinued study drug due 
to AE or deathe 1% 1% 1% 3% 

Discontinued study drug due 
to other reasons and last 
available HIV-1 RNA 
< 50 copies/mLf 

1% 4% 3% 6% 

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

Proportion (%) of patients 
with HIV-1 RNA 
< 50 copies/mL by prior 
treatment regimen 

    

EFV/FTC/tenofovir 
disoproxil 96% 90% 90% 86% 

FTC/tenofovir disoproxil 
plus boosted atazanavir 97% 92% 92% 88% 

E/C/F/TDF 98% 97% 96% 93% 
EFV = efavirenz; FTC = emtricitabine; E/C/F/TDF = elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate 
a Week 48 window was between Day 294 and 377 (inclusive). 
b Week 96 window was between Day 630 and 713 (inclusive). 
c P-value for the superiority test comparing the percentages of virologic success was from the CMH test stratified by the 

prior treatment regimen (EFV/FTC/tenofovir disoproxil, FTC/tenofovir disoproxil plus boosted atazanavir, or 
E/C/F/TDF). 

d Includes patients who had ≥ 50 copies/mL in the Week 48 or Week 96 window; patients who discontinued early due to 
lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of 
efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL. 

e Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this 
resulted in no virologic data on treatment during the specified window. 

f Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, 
loss to follow-up, etc. 

 
HIV-1 infected patients with mild to moderate renal impairment 
In Study GS-US-292-0112, the efficacy and safety of Genvoya were evaluated in an open-label 
clinical study of 242 HIV-1 infected patients with mild to moderate renal impairment (eGFRCG: 
30-69 mL/min).  Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 
6 months before switching to Genvoya.  The mean age was 58 years (range 24-82), with 63 patients 
(26%) who were ≥ 65 years of age.  Seventy-nine percent were male, 63% were White, 18% were 



 

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Black, and 14% were Asian.  Thirteen percent of patients were identified as Hispanic/Latino.  At 
baseline, 80 patients (33%) had eGFRCG < 50 mL/min and 162 patients had eGFRCG ≥ 50 mL/min.  At 
baseline, median eGFR was 56 mL/min.  The mean baseline CD4+ cell count was 664 cells/mm3 
(range 126-1,813). 
 
At Week 144, 83.1% (197/237 patients) maintained HIV-1 RNA < 50 copies/mL after switching to 
Genvoya. 
 
In Study GS-US-292-1825, the efficacy and safety of Genvoya were evaluated in a single-arm, 
open-label clinical study in which 55 HIV-1 infected adults with end stage renal disease 
(eGFRCG < 15 mL/min) on chronic haemodialysis for at least 6 months before switching to Genvoya.  
Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months before 
switching to Genvoya. 
 
The mean age was 48 years (range 23-64).  Seventy-six percent were male, 82% were Black and 18% 
were White.  Fifteen percent of patients identified as Hispanic/Latino.  The mean baseline CD4+ cell 
count was 545 cells/mm3 (range 205-1473).  At Week 48, 81.8% (45/55 patients) maintained HIV-1 
RNA < 50 copies/mL after switching to Genvoya.  There were no clinically significant changes in 
fasting lipid laboratory tests in patients who switched to Genvoya. 
 
Patients co-infected with HIV and HBV 
In open-label Study GS-US-292-1249, the efficacy and safety of Genvoya were evaluated in adult 
patients co-infected with HIV-1 and chronic hepatitis B.  Sixty-nine of the 72 patients were on prior 
tenofovir disoproxil-containing antiretroviral therapy.  At the start of treatment with Genvoya, the 
72 patients had been HIV suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months with or 
without suppression of HBV DNA and had compensated liver function.  The mean age was 50 years 
(range 28-67), 92% of patients were male, 69% were White, 18% were Black, and 10% were Asian.  
The mean baseline CD4+ cell count was 636 cells/mm3 (range 263-1,498).  Eighty-six percent of 
patients (62/72) were HBV suppressed (HBV DNA < 29 IU/mL) and 42% (30/72) were 
HBeAg positive at baseline. 
 
Of the patients who were HBeAg positive at baseline, 1/30 (3.3%) achieved seroconversion to 
anti-HBe at Week 48.  Of the patients who were HBsAg positive at baseline, 3/70 (4.3%) achieved 
seroconversion to anti-HBs at Week 48. 
 
At Week 48, 92% of patients (66/72) maintained HIV-1 RNA < 50 copies/mL after switching to 
Genvoya.  The mean change from baseline in CD4+ cell count at Week 48 was -2 cells/mm3.  
Ninety-two percent (66/72 patients) had HBV DNA < 29 IU/mL using missing = failure analysis at 
Week 48.  Of the 62 patients who were HBV suppressed at baseline, 59 remained suppressed and 
3 had missing data.  Of the 10 patients who were not HBV suppressed at baseline 
(HBV DNA ≥ 29 IU/mL), 7 became suppressed, 2 remained detectable, and 1 had missing data. 
 
There are limited clinical data on the use of Genvoya in HIV/HBV co-infected patients who are 
treatment-naïve. 
 
Changes in measures of bone mineral density 
In studies in treatment-naïve patients, Genvoya was associated with smaller reductions in bone mineral 
density (BMD) compared to E/C/F/TDF as measured by DXA analysis of hip (mean change: -0.8% 
versus -3.4%, p < 0.001) and lumbar spine (mean change: -0.9% versus -3.0%, p < 0.001) after 
144 weeks of treatment. 
 
Improvements in BMD were noted at 96 weeks after switching to Genvoya from a tenofovir 
disoproxil-containing regimen compared to maintaining the tenofovir disoproxil-containing regimen. 
 
Changes in measures of renal function 
In studies in treatment-naïve patients, Genvoya was associated with a lower impact on renal safety 
parameters (as measured after 144 weeks treatment by estimated glomerular filtration rate by 



 

29 

Cockcroft-Gault method, and urine protein to creatinine ratio and after 96 weeks treatment by urine 
albumin to creatinine ratio) compared to E/C/F/TDF (see also section 4.4).  Through 144 weeks of 
treatment, no subject discontinued Genvoya due to a treatment-emergent renal adverse event 
compared with 12 subjects who discontinued E/C/F/TDF (p < 0.001). 
 
An improved renal safety profile was maintained through Week 96 in patients who switched to 
Genvoya compared with those who stayed on a tenofovir disoproxil-containing regimen. 
 
Paediatric population 
 
Study GS-US-292-0106 
In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of Genvoya were evaluated in 
an open-label study in HIV-1 infected, treatment-naïve adolescents between the ages of 12 to 
< 18 years, weighing ≥ 35 kg (n = 50) in Cohort 1, and in virologically suppressed children between 
the ages of 8 to < 12 years, weighing > 25 kg (n = 23) in Cohort 2. 
 
Patients in Cohort 1 had a mean age of 15 years (range 12 to 17), were 44% male, 12% Asian, and 
88% Black.  At baseline, mean plasma HIV-1 RNA was 4.6 log10 copies/mL, median CD4+ cell count 
was 456 cells/mm3 (range: 95 to 1,110), and median CD4+% was 23% (range: 7 to 45%).  Overall, 
22% had baseline plasma HIV-1 RNA > 100,000 copies/mL. 
 
At Week 48, the virologic response rate to Genvoya in treatment-naïve HIV-1 infected adolescents 
was similar to response rates in studies of treatment-naïve HIV-1 infected adults.  In patients treated 
with Genvoya, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL.  The mean increase from baseline 
in CD4+ cell count at Week 48 was 224 cells/mm3.  Three patients had virologic failure at Week 48; 
there was no virologic resistance detected to Genvoya. 
 
Patients in Cohort 2 had a mean age of 10 years (range: 8 to 11), a mean baseline weight of 32 kg 
(range: 26 to 58), were 39% male, 13% Asian, and 78% Black.  At baseline, median CD4+ cell count 
was 969 cells/mm3 (range: 603 to 1,421), and median CD4+% was 39% (range: 30 to 51%). 
 
After switching to Genvoya, 100% (23/23) of patients in Cohort 2 remained suppressed (HIV-1 RNA 
< 50 copies/mL) at Week 48.  The mean change from baseline in CD4+ cell count and percentage at 
Week 48 was -90 cells/mm3 and -1.3%, respectively.  No patient qualified for resistance analysis 
through Week 48. 
 
Study GS-US-292-1515 
In Study GS-US-292-1515, the efficacy and safety of Genvoya were evaluated in an open-label study 
in HIV-1 infected, virologically suppressed adolescents between the ages of 12 and 18 years, weighing 
≥ 35 kg (n = 50). 
 
Patients in the study had a median age of 15 years (range: 12 to 17 years), 64% were female and 98% 
were Black.  At baseline, median CD4+ cell count was 742 cells/mm3 (range: 255 to 1,246) and 
median CD4+% was 34% (range: 21 to 53%). 
 
After switching to Genvoya, 90% (45/50) of patients remained suppressed (HIV-1 RNA 
< 50 copies/mL) at Week 48.  The mean change from baseline in CD4+ cell count and percentage at 
Week 48 was -43 cells/mm3 and -0.1%, respectively.  Five subjects had virologic failure through the 
end of the study; no phenotypic or genotypic resistance to Genvoya was detected. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Genvoya in one or more subsets of the paediatric population in the treatment of human 
HIV-1 infection (see section 4.2 for information on paediatric use). 
 



 

30 

5.2 Pharmacokinetic properties 
 
Absorption 
 
Following oral administration with food in HIV-1 infected patients, peak plasma concentrations were 
observed approximately 4 hours post-dose for elvitegravir, 3 hours post-dose for cobicistat, 3 hours 
post-dose for emtricitabine, and 1 hour post-dose for tenofovir alafenamide.  The steady-state mean 
Cmax, AUCtau, and Ctrough (mean ± SD) in HIV-1 infected patients, respectively, were 1.7 ± 0.39 µg/mL, 
23 ± 7.5 µg•h/mL, and 0.45 ± 0.26 µg/mL for elvitegravir, which provides inhibitory quotient of ~10 
(ratio of Ctrough: protein binding-adjusted IC95 for wild-type HIV-1 virus).  Corresponding steady-state 
mean Cmax, AUCtau, and Ctrough (mean ± SD) were 1.1 ± 0.40 µg/mL, 8.3 ± 3.8 µg•h/mL, and 
0.05 ± 0.13 µg/mL for cobicistat; 1.9 ± 0.5 µg/mL, 13 ± 4.5 µg•h/mL, and 0.14 ± 0.25 µg/mL for 
emtricitabine.  Steady-state mean Cmax and AUCtau for tenofovir alafenamide were 0.16 ± 0.08 µg/mL 
and 0.21 ± 0.15 µg•h/mL, respectively. 
 
For elvitegravir, Cmax and AUC increased 22% and 36% with a light meal, and 56% and 91% with a 
high-fat meal, relative to fasting conditions.  Cobicistat exposures were unaffected by a light meal and 
although there was a modest decrease of 24% and 18% in Cmax and AUC respectively with a high-fat 
meal, no difference was observed in its pharmacoenhancing effect on elvitegravir.  Emtricitabine 
exposures were unaffected by a light or high-fat meal.  Relative to fasting conditions, the 
administration of Genvoya with a light meal (~400 kcal, 20% fat) or high-fat meal (~800 kcal, 50% 
fat) did not affect overall exposures of tenofovir alafenamide to a clinically meaningful extent 
(approximately 15% and 18% higher AUC with a light or high-fat meal, respectively, versus fasted). 
 
Distribution 
 
Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drug 
concentration over the range of 1 ng/mL to 1.6 µg/mL.  The mean plasma to blood drug concentration 
ratio was 1.37. 
 
Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drug 
concentration ratio was 2. 
 
In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of 
concentration over the range of 0.02-200 µg/mL.  At peak plasma concentration, the mean plasma to 
blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio 
was ~4.0. 
 
In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentration 
over the range of 0.01-25 µg/mL.  Ex vivo binding of tenofovir alafenamide to human plasma proteins 
in samples collected during clinical studies was approximately 80%. 
 
Biotransformation 
 
Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidated 
via UGT1A1/3 enzymes.  Following oral administration of boosted [14C]-elvitegravir, elvitegravir was 
the predominant species in plasma, representing ~94% of the circulating radioactivity.  Aromatic and 
aliphatic hydroxylation or glucuronidation metabolites are present in very low levels, displaying 
considerably lower antiviral activity against HIV-1 and do not contribute to the overall antiviral 
activity of elvitegravir. 
 
Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does not 
undergo glucuronidation.  Following oral administration of [14C]-cobicistat, 99% of circulating 
radioactivity in plasma was unchanged cobicistat. 
 
In vitro studies indicate that emtricitabine is not an inhibitor of human CYP enzymes.  Following 
administration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved in 



 

31 

urine (~86%) and faeces (~14%).  Thirteen percent of the dose was recovered in the urine as three 
putative metabolites.  The biotransformation of emtricitabine includes oxidation of the thiol moiety to 
form the 3’-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 
2’-O-glucuronide (~4% of dose).  No other metabolites were identifiable. 
 
Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for 
> 80% of an oral dose.  In vitro studies have shown that tenofovir alafenamide is metabolised to 
tenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target 
cells) and macrophages; and by carboxylesterase-1 in hepatocytes.  In vivo, tenofovir alafenamide is 
hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active 
metabolite tenofovir diphosphate.  In human clinical studies, a 10 mg oral dose of tenofovir 
alafenamide in Genvoya resulted in tenofovir diphosphate concentrations > 4-fold higher in PBMCs 
and > 90% lower concentrations of tenofovir in plasma as compared to a 245 mg oral dose of tenofovir 
disoproxil (as fumarate) in E/C/F/TDF. 
 
In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or 
CYP2D6.  Tenofovir alafenamide is minimally metabolised by CYP3A4.  Upon co-administration 
with the moderate CYP3A inducer probe efavirenz, tenofovir alafenamide exposure was not 
significantly affected.  Following administration of tenofovir alafenamide, plasma [14C]-radioactivity 
showed a time-dependent profile with tenofovir alafenamide as the most abundant species in the initial 
few hours and uric acid in the remaining period. 
 
Elimination 
 
Following oral administration of [14C]-elvitegravir/ritonavir, 94.8% of the dose was recovered in 
faeces, consistent with the hepatobiliary excretion of elvitegravir; 6.7% of the administered dose was 
recovered in urine.  The median terminal plasma half-life of elvitegravir following administration of 
E/C/F/TDF is approximately 12.9 hours. 
 
Following oral administration of [14C]-cobicistat, 86% and 8.2% of the dose were recovered in faeces 
and urine, respectively.  The median terminal plasma half-life of cobicistat following administration of 
E/C/F/TDF is approximately 3.5 hours and the associated cobicistat exposures provide elvitegravir 
Ctrough approximately 10-fold above the protein-binding adjusted IC95 for wild-type HIV-1 virus. 
 
Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved in 
urine (approximately 86%) and faeces (approximately 14%).  Thirteen percent of the emtricitabine 
dose was recovered in urine as three metabolites.  The systemic clearance of emtricitabine averaged 
307 mL/min.  Following oral administration, the elimination half-life of emtricitabine is approximately 
10 hours. 
 
Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminated 
in urine.  Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir.  Tenofovir 
alafenamide and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively.  
Tenofovir is eliminated from the body by the kidneys by both glomerular filtration and active tubular 
secretion. 
 
Pharmacokinetics in special populations 
 
Age, gender, and ethnicity 
No clinically relevant pharmacokinetic differences due to gender or ethnicity have been identified for 
cobicistat-boosted elvitegravir, cobicistat, emtricitabine, or tenofovir alafenamide. 
 
Exposures of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofovir alafenamide achieved in 
24 adolescent patients aged 12 to < 18 years who received Genvoya in Study GS-US-292-0106 were 
similar to exposures achieved in treatment-naïve adults following administration of Genvoya 
(Table 5). 
 



 

32 

Table 5: Pharmacokinetics of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofovir 
alafenamide in antiretroviral-naïve adolescents and adults 
 

 

Adolescents aged 12 to < 18 years, ≥ 35 kg Adults 
Genvoya Genvoya 

EVGa COBIa FTCa TAFb TFVb EVGe COBIe FTCe TAFf TFVf 
AUCtau 
(ng•h/mL
) 

23,840.
1 (25.5) 

8,240.8 
(36.1)b 

14,424.
4 (23.9) 

242.8
c 

(57.8) 

275.8 
(18.4

) 

22,797.
0 (34.7) 

9,459.
1 

(33.9) 

11,714.
1 (16.6) 

206.4 
(71.8

) 

292.6 
(27.4

) 
Cmax 
(ng/mL) 2,229.6 (19.2) 

1,202.4 
(35.0) 

2,265.0 
(22.5) 

121.7 
(46.2) 

14.6 
(20.0

) 

2,113.1 
(33.7) 

1,450.
3 

(28.4) 

2,056.3 
(20.2) 

162.2 
(51.1

) 

15.2 
(26.1

) 
Ctau 
(ng/mL) 300.8 (81.0) 

25.0 
(180.0)

d 

102.4 
(38.9)b N/A 

10.0 
(19.6

) 

287.3 
(61.7) 

20.6 
(85.2) 

95.2 
(46.7) N/A 

10.6 
(28.5

) 
EVG = elvitegravir; COBI = cobicistat; FTC = emtricitabine; TAF = tenofovir alafenamide fumarate; TFV = tenofovir 
N/A = not applicable 
Data are presented as mean (%CV). 
a n = 24 adolescents. 
b n = 23 adolescents. 
c AUClast. 
d n = 15 adolescents. 
e n = 19 adults. 
f n = 539 (TAF) or 841 (TFV) adults. 
 
Mean exposures of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofovir alafenamide 
achieved in children aged 8 to < 12 years (> 25 kg; n = 23) who received Genvoya in study 
GS-US-292-0106 were higher (20 to 80%) than the mean exposures achieved in adults (Table 6). 
 
Table 6: Pharmacokinetics of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofovir 
alafenamide in virologically suppressed children and adults 
 

 

Children aged 8 to < 12 years, > 25 kg Adults 
Genvoya Genvoya 

EVGa COBIa FTCa TAFa TFVa EVGe COBIe FTCe TAFf TFVf 
AUCtau 
(ng•h/mL
) 

33,813.
9 

(57.8)b 

15,890.
7 

(51.7)c 

20,629.
2 

(18.9)b 

332.9
d 

(44.8) 

440.2 
(20.9

) 

22,797.
0 (34.7) 

9,459.
1 

(33.9) 

11,714.
1 (16.6) 

206.4 
(71.8

) 

292.6 
(27.4

) 
Cmax 
(ng/mL) 3,055.2 (38.7) 

2,079.4 
(46.7) 

3,397.4 
(27.0) 

313.3 
(61.2) 

26.1 
(20.8

) 

2,113.1 
(33.7) 

1,450.
3 

(28.4) 

2,056.3 
(20.2) 

162.2 
(51.1

) 

15.2 
(26.1

) 
Ctau 
(ng/mL) 370.0 (118.5) 

96.0 
(168.7) 

114.9 
(24.1) N/A 

15.1 
(24.9

) 

287.3 
(61.7) 

20.6 
(85.2) 

95.2 
(46.7) N/A 

10.6 
(28.5

) 
EVG = elvitegravir; COBI = cobicistat; FTC = emtricitabine; TAF = tenofovir alafenamide fumarate; TFV = tenofovir 
N/A = not applicable 
Data are presented as mean (%CV). 
a n = 23 children. 
b n = 22 children. 
c n = 20 children. 
d AUClast. 
e n = 19 adults. 
f n = 539 (TAF) or 841 (TFV) adults. 
 
Renal impairment 
No clinically relevant differences in elvitegravir, cobicistat, tenofovir alafenamide, or tenofovir 
pharmacokinetics were observed between healthy subjects and patients with severe renal impairment 
(estimated CrCl ≥ 15 mL/min and < 30 mL/min) in Phase 1 studies of cobicistat-boosted elvitegravir 
or of tenofovir alafenamide, respectively.  In a separate Phase 1 study of emtricitabine alone, mean 
systemic emtricitabine exposure was higher in patients with severe renal impairment (estimated 
CrCl < 30 mL/min) (33.7 µg•h/mL) than in subjects with normal renal function (11.8 µg•h/mL).  The 



 

33 

safety of Genvoya has not been established in patients with severe renal impairment (estimated 
CrCl ≥ 15 mL/min and < 30 mL/min). 
 
Exposures of emtricitabine and tenofovir in 12 patients with end stage renal disease (estimated 
CrCl < 15 mL/min) on chronic haemodialysis who received Genvoya in Study GS-US-292-1825 were 
significantly higher than in patients with normal renal function.  No clinically relevant differences in 
elvitegravir, cobicistat, or tenofovir alafenamide pharmacokinetics were observed in patients with 
end stage renal disease on chronic haemodialysis as compared to those with normal renal function.  
There were no new safety issues identified in patients with end stage renal disease on chronic 
haemodialysis receiving Genvoya (see section 4.8). 
 
There are no pharmacokinetic data on elvitegravir, cobicistat, emtricitabine or tenofovir alafenamide 
in patients with end stage renal disease (estimated CrCl < 15 mL/min) not on chronic haemodialysis.  
The safety of elvitegravir, cobicistat, emtricitabine or tenofovir alafenamide has not been established 
in these patients. 
 
Hepatic impairment 
Both elvitegravir and cobicistat are primarily metabolised and eliminated by the liver.  A study of the 
pharmacokinetics of cobicistat-boosted elvitegravir was performed in non-HIV-1 infected patients 
with moderate hepatic impairment (Child-Pugh Class B).  No clinically relevant differences in 
elvitegravir or cobicistat pharmacokinetics were observed between patients with moderate hepatic 
impairment and subjects with normal hepatic function.  The effect of severe hepatic impairment 
(Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied. 
 
The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment; 
however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver 
impairment should be limited. 
 
Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite 
tenofovir were not observed in patients with mild or moderate hepatic impairment.  In patients with 
severe hepatic impairment, total plasma concentrations of tenofovir alafenamide and tenofovir are 
lower than those seen in subjects with normal hepatic function.  When corrected for protein binding, 
unbound (free) plasma concentrations of tenofovir alafenamide in severe hepatic impairment and 
normal hepatic function are similar. 
 
Hepatitis B and/or hepatitis C virus co-infection 
The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in 
patients co-infected with hepatitis B and/or C virus.  Limited data from population pharmacokinetic 
analysis (n = 24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on 
the exposure of boosted elvitegravir. 
 
Pregnancy and postpartum 
The results reported from a prospective study (IMPAACT P1026s) showed that treatment with 
cobicistat and elvitegravir-containing regimens during pregnancy results in lower elvitegravir and 
cobicistat exposures (Table 7).  
 
Table 7: Changes in pharmacokinetic parameters from the IMPAACT P1026s study for 
elvitegravir and cobicistat in women receiving cobicistat and elvitegravir-containing regimens 
during the second and third trimesters of pregnancy compared to paired postpartum data 
 

Comparison to paired 
postpartum data, n 

Mean % change of elvitegravir 
pharmacokinetic parametersa 

Mean % change of cobicistat 
pharmacokinetic parametersa 

AUC24 Cmax C24 AUC24 Cmax C24 
2T/PP, n = 14 ↓ 24%b ↓ 8% ↓ 81%b ↓ 44%b ↓ 28%b ↓ 60%b 
3T/PP, n = 24 ↓ 44%b ↓ 28%b ↓ 89%b ↓ 59%b ↓ 38%b ↓ 76%b 



 

34 

2T = second trimester; 3T = third trimester; PP =postpartum 
a paired comparisons 
b P<0.10 compared with postpartum 
 
5.3 Preclinical safety data 
 
Elvitegravir was negative in an in vitro bacterial mutagenicity test (Ames test) and negative in an 
in vivo rat micronucleus assay at doses up to 2,000 mg/kg.  In an in vitro chromosomal aberration test, 
elvitegravir was negative with metabolic activation; however, an equivocal response was observed 
without activation. 
 
Cobicistat was not mutagenic or clastogenic in conventional genotoxicity assays.  Ex vivo rabbit 
studies and in vivo dog studies suggest that cobicistat has a low potential for QT prolongation, and 
may slightly prolong the PR interval and decrease left ventricular function at concentrations at least 
11-fold higher than the human exposure at the recommended 150 mg daily dose.  In a human clinical 
study of 35 healthy subjects, echocardiograms performed at baseline and after receiving 150 mg 
cobicistat once daily for at least 15 days indicated no clinically significant change in left ventricular 
function. 
 
Reproductive toxicity studies in rats and rabbits with cobicistat showed no effects on mating, fertility, 
pregnancy or foetal parameters.  However increased post-implantation loss and decreased foetal 
weights were observed in rats associated with significant decreases in maternal body weights at 
125 mg/kg/day. 
 
Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies 
of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to 
reproduction and development. 
 
Elvitegravir, cobicistat, and emtricitabine have all demonstrated low carcinogenic potential in mice 
and rats. 
 
Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primary 
target organs of toxicity.  Bone toxicity was observed as reduced bone mineral density in rats and dogs 
at tenofovir exposures at least 4 times greater than those expected after administration of Genvoya.  A 
minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide and 
tenofovir exposures of approximately 4 and 17 times greater, respectively, than those expected after 
administration of Genvoya. 
 
Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxicity assays. 
 
Because there is a lower tenofovir exposure in rats and mice after the administration of tenofovir 
alafenamide compared to tenofovir disoproxil, carcinogenicity studies and a rat peri-postnatal study 
were conducted only with tenofovir disoproxil.  No special hazard for humans was revealed in 
conventional studies of carcinogenic potential and toxicity to reproduction and development.  
Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or 
foetal parameters.  However, tenofovir disoproxil reduced the viability index and weight of pups in a 
peri-postnatal toxicity study at maternally toxic doses. 
 
 



 

35 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Lactose (as monohydrate) 
Microcrystalline cellulose 
Croscarmellose sodium 
Hydroxypropyl cellulose 
Silicon dioxide 
Sodium lauryl sulfate 
Magnesium stearate 
 
Film-coating 
 
Polyvinyl alcohol (E1203) 
Titanium dioxide (E171) 
Polyethylene glycol (E1521) 
Talc (E553b) 
Indigo carmine aluminium lake (E132) 
Iron oxide yellow (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottle with a polypropylene continuous-thread, child-resistant cap, 
lined with an induction activated aluminium foil liner containing 30 film-coated tablets.  Each bottle 
contains silica gel desiccant and polyester coil. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
outer cartons containing 90 (3 bottles of 30) film-coated tablets. 
 
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. 
 
 



 

36 

7. MARKETING AUTHORISATION HOLDER 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1061/001 
EU/1/15/1061/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 November 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  



 

37 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



 

38 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

  



 

39 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



 

40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

41 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE AND CARTON LABELLING 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Genvoya 150 mg/150 mg/200 mg/10 mg film-coated tablets 
Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine 
and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose, see leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
30 tablets 
 
90 (3 bottles of 30) film-coated tablets 
90 (3 bottles of 30) tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 

42 

9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
 
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 
 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/15/1061/001 30 film-coated tablets 
EU/1/15/1061/002 90 (3 bottles of 30) film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Genvoya [Outer packaging only] 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. [Outer packaging only] 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
[Outer packaging only] 
  



 

43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

44 

Package leaflet: Information for the user 
 

Genvoya 150 mg/150 mg/200 mg/10 mg film-coated tablets 
Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 

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

safety information.  You can help by reporting any side effects you may get.  See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet.  You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only.  Do not pass it on to others.  It may harm them, 

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

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet 
 
1. What Genvoya is and what it is used for 
2. What you need to know before you take Genvoya 
3. How to take Genvoya 
4. Possible side effects 
5. How to store Genvoya 
6. Contents of the pack and other information 
 
If Genvoya has been prescribed for your child, please note that all the information in this leaflet 
is addressed to your child (in this case please read “your child” instead of “you”). 
 
 
1. What Genvoya is and what it is used for 
 
Genvoya contains four active substances: 
 
• elvitegravir, an antiretroviral medicine known as an integrase inhibitor 
• cobicistat, a booster (pharmacokinetic enhancer) of the effects of elvitegravir 
• emtricitabine, an antiretroviral medicine known as a nucleoside reverse transcriptase inhibitor 

(NRTI) 
• tenofovir alafenamide, an antiretroviral medicine known as a nucleotide reverse transcriptase 

inhibitor (NtRTI) 
 
Genvoya is a single tablet for the treatment of human immunodeficiency virus 1 (HIV-1) infection 
in adults, adolescents and children 6 years of age and older, who weigh at least 25 kg. 
 
Genvoya reduces the amount of HIV in your body.  This will improve your immune system and 
reduce the risk of developing illnesses linked to HIV infection. 
 
 
2. What you need to know before you take Genvoya 
 
Do not take Genvoya: 
• If you are allergic to elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide or any of 

the other ingredients of this medicine (listed in section 6 of this leaflet). 
 



 

45 

• If you are taking one of these medicines: 
- alfuzosin (used to treat an enlarged prostate gland) 
- dabigatran (used to prevent and treat blood clots) 
- amiodarone, quinidine (used to correct irregular heartbeats) 
- carbamazepine, phenobarbital, phenytoin (used to prevent seizures) 
- rifampicin (used to prevent and treat tuberculosis and other infections) 
- dihydroergotamine, ergometrine, ergotamine (used to treat migraine headache) 
- cisapride (used to relieve certain stomach problems) 
- St. John’s wort (Hypericum perforatum, a herbal remedy used for depression and 

anxiety) or products that contain it 
- lovastatin, simvastatin (used to lower blood cholesterol) 
- pimozide, lurasidone (used to treat abnormal thoughts or feelings) 
- sildenafil (when used to treat pulmonary arterial hypertension – a lung disease that makes 

breathing difficult) 
- orally administered midazolam, triazolam (used to help you sleep and/or relieve 

anxiety) 
 
 If any of these applies to you, do not take Genvoya and tell your doctor immediately. 
 
Warnings and precautions 
 
You must remain under the care of your doctor while taking Genvoya. 
 
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.  This medicine is not a cure for HIV infection.  While taking Genvoya you may still develop 
infections or other illnesses associated with HIV infection. 
 
Talk to your doctor before taking Genvoya: 
 
• If you have liver problems or a history of liver disease, including hepatitis.  Patients with 

liver disease including chronic hepatitis B or C, who are treated with antiretrovirals, have a 
higher risk of severe and potentially fatal liver complications.  If you have hepatitis B infection, 
your doctor will carefully consider the best treatment regimen for you. 

 
If you have hepatitis B infection, liver problems may become worse after you stop taking 
Genvoya.  It is important not to stop taking Genvoya without talking to your doctor: see 
section 3, Do not stop taking Genvoya. 

 
• If you are intolerant to lactose (see Genvoya contains lactose later in this section). 
 
While you are taking Genvoya 
 
Once you start taking Genvoya, look out for: 
 
• Signs of inflammation or infection 
• Joint pain, stiffness or bone problems 
 
 If you notice any of these symptoms, tell your doctor immediately.  For more information see 

section 4, Possible side effects. 
 
Children and adolescents 
 
Do not give this medicine to children aged 5 years or under, or weighing less than 25 kg regardless 
of age.  The use of Genvoya in children aged 5 years or under has not yet been studied. 
 



 

46 

Other medicines and Genvoya 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  Genvoya may interact with other medicines.  As a result, the amounts of Genvoya or other 
medicines in your blood may be affected.  This may stop your medicines from working properly, or 
may make any side effects worse.  In some cases, your doctor may need to adjust your dose or check 
your blood levels. 
 
Medicines that must never be taken with Genvoya: 

- alfuzosin (used to treat an enlarged prostate gland) 
- amiodarone, quinidine (used to correct irregular heartbeats) 
- carbamazepine, phenobarbital, phenytoin (used to prevent seizures) 
- dabigatran (used to prevent and treat blood clots) 
- rifampicin (used to prevent and treat tuberculosis and other infections) 
- dihydroergotamine, ergometrine, ergotamine (used to treat migraine headache) 
- cisapride (used to relieve certain stomach problems) 
- St. John’s wort (Hypericum perforatum, a herbal remedy used for depression and 

anxiety) or products that contain it 
- lovastatin, simvastatin (used to lower blood cholesterol) 
- pimozide, lurasidone (used to treat abnormal thoughts or feelings) 
- sildenafil (when used to treat pulmonary arterial hypertension – a lung disease that makes 

breathing difficult) 
- orally administered midazolam, triazolam (used to help you sleep and/or relieve 

anxiety) 
 If you are taking any of these medicines, do not take Genvoya and tell your doctor immediately. 
 
Medicines used in treating hepatitis B infection: 
 
You should not take Genvoya with medicines containing: 
• tenofovir alafenamide 
• tenofovir disoproxil 
• lamivudine 
• adefovir dipivoxil 
 
 Tell your doctor if you are taking any of these medicines. 
 
Other types of medicine: 
Talk to your doctor if you are taking: 
• antifungals, used to treat fungal infections, such as: 

- ketoconazole, itraconazole, voriconazole, posaconazole and fluconazole 
• antibiotics, used to treat bacterial infections including tuberculosis, containing: 

- rifabutin, clarithromycin and telithromycin 
• antidepressants, used to treat depression: 

- medicines containing trazodone or escitalopram 
• sedatives and hypnotics, used to treat anxiety: 

- buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem and lorazepam 
• immunosuppressants, used to control your body’s immune response after a transplant, such as: 

- ciclosporin, sirolimus and tacrolimus 
• corticosteroids including: 

- betamethasone, budesonide, fluticasone, mometasone, prednisone, triamcinolone. 
These medicines are used to treat allergies, asthma, inflammatory bowel diseases, inflammatory 
conditions of the eyes, joints and muscles and other inflammatory conditions.  If alternatives 
cannot be used, its use should only take place after medical evaluation and under close 
monitoring by your doctor for corticosteroid side effects. 

• medicines used to treat diabetes: 
- metformin 



 

47 

• contraceptive pill, used to prevent pregnancy 
• erectile dysfunction medicines, used to treat impotence, such as: 

- sildenafil, tadalafil and vardenafil 
• heart medicines, such as: 

- digoxin, disopyramide, flecainide, lidocaine, mexiletine, propafenone, metoprolol, 
timolol, amlodipine, diltiazem, felodipine, nicardipine, nifedipine and verapamil 

• medicines used to treat pulmonary arterial hypertension: 
- bosentan and tadalafil 

• anticoagulants, used to prevent and treat blood clots, such as: 
- apixaban, edoxaban, rivaroxaban and warfarin 

• bronchodilators, used to treat asthma and other lung-related problems: 
- salmeterol 

• cholesterol lowering medicines, such as: 
- atorvastatin and pitavastatin 

• medicines used to treat gout: 
- colchicine 

 
 Tell your doctor if you are taking these or any other medicines.  Do not stop your treatment 

without contacting your doctor. 
 
• antacids, used to treat heartburn or acid reflux (see also section 3, How to take Genvoya). 
 
 If you are taking an antacid or a multivitamin supplement, take it at least 4 hours before or at 

least 4 hours after Genvoya. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
• Tell your doctor immediately if you are pregnant, think you may be pregnant or are 

planning to have a baby.  Pregnant women should not take Genvoya.  The amount of this 
medicine in your blood may decrease during pregnancy which may stop it from working 
properly. 

• Use effective contraception while taking Genvoya. 
• Do not breast-feed during treatment with Genvoya.  This is because some of the active 

substances in this medicine pass into human breast milk.  It is recommended that you do not 
breast-feed to avoid passing the virus to the baby in breast milk. 

 
Driving and using machines 
 
Genvoya can cause dizziness.  If you feel dizzy when taking Genvoya, do not drive or ride a bicycle 
and do not use any tools or machines. 
 
Genvoya contains lactose 
 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
 If any of these applies to you, talk to your doctor before taking Genvoya. 
 
 
3. How to take Genvoya 
 
Always take this medicine exactly as your doctor has told you.  Check with your doctor or pharmacist 
if you are not sure. 



 

48 

 
The recommended dose is: 
 
Adults: one tablet each day with food 
Adolescents and children 6 years of age and older, who weigh at least 25 kg: one tablet each day 
with food 
 
Do not chew or crush the tablet. 
 
If you have difficulty swallowing the tablet whole, you can split it in half.  Take both halves of the 
tablet one after the other to get the full dose.  Do not store the split tablet. 
 
Always take the dose recommended by your doctor.  This is to make sure that your medicine is 
fully effective, and to reduce the risk of developing resistance to the treatment.  Do not change the 
dose unless your doctor tells you to. 
 
Do not take antacids or multivitamins at the same time as Genvoya.  If you are taking an antacid 
such as aluminium/magnesium hydroxide or a multivitamin supplement, take it at least 4 hours 
before or at least 4 hours after Genvoya. 
 
If you are on dialysis, take your daily dose of Genvoya following completion of dialysis. 
 
If you take more Genvoya than you should 
 
If you accidentally take more than the recommended dose of Genvoya you may be at increased risk of 
experiencing possible side effects with this medicine (see section 4, Possible side effects). 
 
Contact your doctor or nearest emergency department immediately for advice.  Keep the tablet bottle 
with you so that you can easily describe what you have taken. 
 
If you forget to take Genvoya 
 
It is important not to miss a dose of Genvoya. 
 
If you do miss a dose: 
• If you notice within 18 hours of the time you usually take Genvoya, you must take the tablet as 

soon as possible.  Always take the tablet with food.  Then take the next dose as usual. 
• If you notice 18 hours or more after the time you usually take Genvoya, then do not take the 

missed dose.  Wait and take the next dose, with food, at your usual time. 
 
If you vomit less than 1 hour after taking Genvoya, take another tablet with food. 
 
Do not stop taking Genvoya 
 
Do not stop taking Genvoya without talking to your doctor.  Stopping Genvoya can seriously 
affect your response to future treatment.  If Genvoya is stopped for any reason, speak to your doctor 
before you restart taking Genvoya tablets. 
 
When your supply of Genvoya starts to run low, get more from your doctor or pharmacist.  This is 
very important because the amount of virus may start to increase if the medicine is stopped for even a 
short time.  The disease may then become harder to treat. 
 



 

49 

If you have both HIV infection and hepatitis B, it is especially important not to stop your Genvoya 
treatment without talking to your doctor first.  You may require blood tests for several months after 
stopping treatment.  In some patients with advanced liver disease or cirrhosis, stopping treatment is not 
recommended as this may lead to worsening of your hepatitis, which may be life-threatening. 
 
 Tell your doctor immediately about new or unusual symptoms after you stop treatment, 

particularly symptoms you associate with hepatitis B infection. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side 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 life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  When 
treating HIV infection, it is not always possible to tell whether some of the unwanted effects are 
caused by Genvoya or by other medicines that you are taking at the same time, or by the HIV disease 
itself. 
 
Possible serious side effects: tell a doctor immediately 
 
• Any signs of inflammation or infection.  In some patients with advanced HIV infection 

(AIDS) and a history of opportunistic infections (infections that occur in people with a weak 
immune system), signs and symptoms of inflammation from previous infections may occur soon 
after anti-HIV treatment is started.  It is thought that these symptoms are due to an improvement 
in the body’s immune response, enabling the body to fight infections that may have been 
present with no obvious symptoms. 

 
• Autoimmune disorders, when the immune system attacks healthy body tissue, may also occur 

after you start taking medicines for HIV infection.  Autoimmune disorders may occur many 
months after the start of treatment.  Look out for any symptoms of infection or other symptoms 
such as: 
- muscle weakness 
- weakness beginning in the hands and feet and moving up towards the trunk of the body 
- palpitations, tremor or hyperactivity. 

 
 If you notice the side effects described above, tell your doctor immediately. 
 
Very common side effects 
(may affect more than 1 in 10 people) 
• feeling sick (nausea) 
 
Common side effects 
(may affect up to 1 in 10 people) 
• abnormal dreams 
• headache 
• dizziness 
• diarrhoea 
• vomiting 
• stomach pain 
• wind (flatulence) 
• rash 
• tiredness (fatigue) 



 

50 

 
Uncommon side effects 
(may affect up to 1 in 100 people) 
• low red blood cell count (anaemia) 
• suicidal thoughts and suicide attempt (in patients who have had depression or mental health 

problems before), depression 
• problems with digestion resulting in discomfort after meals (dyspepsia) 
• swelling of the face, lips, tongue or throat (angioedema) 
• itching (pruritus) 
• hives (urticaria) 
 
 If any of the side effects get serious tell your doctor. 
 
Other effects that may be seen during HIV treatment 
 
The frequency of the following side effects is not known (frequency cannot be estimated from the 
available data). 
 
• Bone problems.  Some patients taking combination antiretroviral medicines such as Genvoya 

may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood 
supply to the bone).  Taking this type of medicine for a long time, taking corticosteroids, 
drinking alcohol, having a very weak immune system, and being overweight, may be some of 
the many risk factors for developing this disease.  Signs of osteonecrosis are: 
- joint stiffness 
- joint aches and pains (especially of the hip, knee and shoulder) 
- difficulty with movement 

 If you notice any of these symptoms tell your doctor. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side effects 
not listed in this leaflet.  You can also report side effects directly via the national reporting system 
listed in Appendix V.  By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Genvoya 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and bottle after {EXP}.  
The expiry date refers to the last day of that month. 
 
Store in the original package in order to protect from moisture.  Keep the bottle tightly closed. 
 
Do not 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 Genvoya contains 
 
The active substances are elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide.  Each 
Genvoya film-coated tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of 
emtricitabine and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. 
 

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


 

51 

The other ingredients are 
 
Tablet core: 
Lactose (as monohydrate), microcrystalline cellulose, croscarmellose sodium, hydroxypropyl 
cellulose, silicon dioxide, sodium lauryl sulfate, magnesium stearate. 
 
Film-coating: 
Polyvinyl alcohol (E1203), titanium dioxide (E171), polyethylene glycol (E1521), talc (E553b), indigo 
carmine aluminium lake (E132), iron oxide yellow (E172). 
 
What Genvoya looks like and contents of the pack 
 
Genvoya film-coated tablets are green, capsule-shaped tablets, debossed on one side with “GSI” and 
the number “510” on the other side of the tablet.  Genvoya comes in bottles of 30 tablets (with a silica 
gel desiccant that must be kept in the bottle to help protect your tablets).  The silica gel desiccant is 
contained in a separate sachet or canister and should not be swallowed. 
 
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and 
outer cartons containing 90 (3 bottles of 30) film-coated tablets.  Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Gilead Sciences Ireland UC 
Carrigtohill 
County Cork, T45 DP77 
Ireland 
 
Manufacturer 
Gilead Sciences Ireland UC 
IDA Business & Technology Park 
Carrigtohill 
County Cork 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Lietuva 
Gilead Sciences Poland Sp. z o.o. 
Tel.: +48 22 262 8702 
 

България 
Gilead Sciences Ireland UC 
Тел.: + 353 (0) 1 686 1888 
 

Luxembourg/Luxemburg 
Gilead Sciences Belgium SPRL-BVBA 
Tél/Tel: + 32 (0) 24 01 35 50 
 

Česká republika 
Gilead Sciences s.r.o. 
Tel: + 420 910 871 986 
 

Magyarország 
Gilead Sciences Ireland UC 
Tel.: + 353 (0) 1 686 1888 
 

Danmark 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Malta 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Deutschland 
Gilead Sciences GmbH 
Tel: + 49 (0) 89 899890-0 
 

Nederland 
Gilead Sciences Netherlands B.V. 
Tel: + 31 (0) 20 718 36 98 
 



 

52 

Eesti 
Gilead Sciences Poland Sp. z o.o. 
Tel.: +48 22 262 8702 
 

Norge 
Gilead Sciences Sweden AB 
Tlf: + 46 (0) 8 5057 1849 
 

Ελλάδα 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Österreich 
Gilead Sciences GesmbH 
Tel: + 43 1 260 830 
 

España 
Gilead Sciences, S.L. 
Tel: + 34 91 378 98 30 
 

Polska 
Gilead Sciences Poland Sp. z o.o. 
Tel.: +48 22 262 8702 
 

France 
Gilead Sciences 
Tél: + 33 (0) 1 46 09 41 00 
 

Portugal 
Gilead Sciences, Lda. 
Tel: + 351 21 7928790 
 

Hrvatska 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

România 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 
 

Ireland 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 214 825 999 
 

Slovenija 
Gilead Sciences Ireland UC 
Tel: + 353 (0) 1 686 1888 

Ísland 
Gilead Sciences Sweden AB 
Sími: + 46 (0) 8 5057 1849 
 

Slovenská republika 
Gilead Sciences Slovakia s.r.o. 
Tel: + 421 232 121 210 
 

Italia 
Gilead Sciences S.r.l. 
Tel: + 39 02 439201 
 

Suomi/Finland 
Gilead Sciences Sweden AB 
Puh/Tel: + 46 (0) 8 5057 1849 
 

Κύπρος 
Gilead Sciences Ελλάς Μ.ΕΠΕ. 
Τηλ: + 30 210 8930 100 
 

Sverige 
Gilead Sciences Sweden AB 
Tel: + 46 (0) 8 5057 1849 
 

Latvija 
Gilead Sciences Poland Sp. z o.o. 
Tel.: +48 22 262 8702 
 

United Kingdom 
Gilead Sciences Ltd. 
Tel: + 44 (0) 8000 113 700 
 

 
This leaflet was last revised in <{MM/YYYY}> <{month YYYY}> 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

  



 

53 

 
 
 
 
 
 
 
 
 
 
 
 
 

Annex IV 

Scientific conclusions and grounds for the variation to the terms of the marketing 
authorisation(s) 

 
 
 
 
 

 



 

54 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for cobicistat / elvitegravir / 
emtricitabine / tenofovir alafenamide, the scientific conclusions of CHMP are as follows:  

A cumulative review of all cases related to suicide-related events showed a total of 42 valid cases 
reporting 48 suicide-related events for Genvoya (13 from spontaneous, 29 from clinical trials). Since 
the previous review, 6 new cases were identified (5 valid and 1 invalid). The cases evaluated in this 
review mostly occurred in patients with history of psychiatric events or other external factors reported 
that may have contributed to the event. Disproportionality analysis did not highlight events that met 
the criteria for signal of disproportionate reporting. However, based on the information retrieved in 
literature and in the product information of integrase inhibitors containing medicinal products, it could 
be concluded that the following psychiatric disorders: depression, suicidal ideation and suicidal 
behaviour (particularly in patients with pre-existing history of psychiatric illness) are class-effect of 
integrase inhibitors and these are listed in the SmPC of other medicinal products containing integrase 
inhibitors in monotherapy and in fixed-dose combination (FDC). 

Similar patterns of psychiatric disorders were observed in comparative studies of 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) versus 
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), which lists these 
events in its product information (studies GS-US-292-0104 or GS-US-292-0111). Based on this, 
section 4.8 of the SmPC of medicinal products containing 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide FDC has been updated to add suicidal 
ideation and suicide attempt (in patients with a pre-existing history of depression or psychiatric illness) 
as new adverse drug reactions. In clinical trials, the incidence of SAEs related to suicide for Genvoya 
was 0.6% (26/4137 subjects), therefore, the frequency proposed is “uncommon”. 

 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for cobicistat / elvitegravir / emtricitabine / tenofovir 
alafenamide the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) 
containing cobicistat / elvitegravir / emtricitabine / tenofovir alafenamide is unchanged subject to the 
proposed changes to the product information 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)