ODEFSEY 200mg / 25mg / 25mg film-coated tablets medication leaflet

Odefsey 200 mg/25 mg/25 mg film-coated tablets

Each film-coated tablet contains 200 mg of emtricitabine, rilpivirine hydrochloride equivalent to25 mg of rilpivirine and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide.

Each tablet contains 180.3 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Grey, capsule-shaped, film-coated tablet, of dimensions 15 mm x 7 mm, debossed with “GSI” on oneside of the tablet and “255” on the other side of the tablet.

Odefsey is indicated for the treatment of adults and adolescents (aged 12 years and older with bodyweight at least 35 kg) infected with human immunodeficiency virus-1 (HIV-1) without knownmutations associated with resistance to the non-nucleoside reverse transcriptase inhibitor (NNRTI)class, tenofovir or emtricitabine and with a viral load ≤ 100,000 HIV-1 RNA copies/mL (seesections 4.2, pct. 4.4 and 5.1).

Therapy should be initiated by a physician experienced in the management of HIV infection.

One tablet to be taken once daily with food (see section 5.2).

If the patient misses a dose of Odefsey within 12 hours of the time it is usually taken, the patientshould take Odefsey with food as soon as possible and resume the normal dosing schedule. If apatient misses a dose of Odefsey by more than 12 hours, the patient should not take the missed doseand simply resume the usual dosing schedule.

If the patient vomits within 4 hours of taking Odefsey another tablet should be taken with food. If apatient vomits more than 4 hours after taking Odefsey they do not need to take another dose of

Odefsey until the next regularly scheduled dose.

No dose adjustment of Odefsey is required in elderly patients (see section 5.2).

No dose adjustment of Odefsey is required in adults or in adolescents (aged at least 12 years and of atleast 35 kg body weight) with estimated creatinine clearance (CrCl) ≥ 30 mL/min. Odefsey should bediscontinued in patients with estimated CrCl that declines below 30 mL/min during treatment (seesection 5.2).

No dose adjustment of Odefsey is required in adults with end stage renal disease (estimated

CrCl < 15 mL/min) on chronic haemodialysis; however, Odefsey should, generally, be avoided butmay be used with caution in these patients if the potential benefits are considered to outweigh thepotential risks (see sections 4.4 and 5.2). On days of haemodialysis, Odefsey should be administeredafter completion of haemodialysis treatment.

Odefsey 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 Odefsey has not been establishedin these populations.

No data are available to make dose recommendations in children less than 18 years with end stagerenal disease.

No dose adjustment of Odefsey is required in patients with mild (Child Pugh Class A) or moderate(Child Pugh Class B) hepatic impairment. Odefsey should be used with caution in patients withmoderate hepatic impairment. Odefsey has not been studied in patients with severe hepaticimpairment (Child Pugh Class C); therefore, Odefsey is not recommended for use in patients withsevere hepatic impairment (see sections 4.4 and 5.2).

The safety and efficacy of Odefsey in children younger than 12 years of age, or weighing < 35 kg,have not yet been established. No data are available.

Oral use.

Odefsey should be taken orally, once daily with food (see section 5.2). It is recommended that thefilm-coated tablet is not chewed, crushed or split due to the bitter taste.

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

Odefsey should not be co-administered with medicinal products that can result in significant decreasesin rilpivirine plasma concentrations (due to cytochrome P450 [CYP]3A enzyme induction or gastricpH increase), which may result in loss of therapeutic effect of Odefsey (see section 4.5), including:

* carbamazepine, oxcarbazepine, phenobarbital, phenytoin

* rifabutin, rifampicin, rifapentine

* omeprazole, esomeprazole, dexlansoprazole, lansoprazole, pantoprazole, rabeprazole

* dexamethasone (oral and parenteral doses), except as a single dose treatment

* St. John’s wort (Hypericum perforatum)

Virologic failure and development of resistance

There are insufficient data to justify the use in patients with prior NNRTI failure. Resistance testingand/or historical resistance data should guide the use of Odefsey (see section 5.1).

In the pooled efficacy analysis from the two Phase 3 clinical studies in adults (C209 [ECHO] and

C215 [THRIVE]) through 96 weeks, patients treated with emtricitabine/tenofovir disoproxilfumarate + rilpivirine with a baseline viral load > 100,000 HIV-1 RNA copies/mL had a greater risk ofvirologic failure (17.6% with rilpivirine versus 7.6% with efavirenz) compared to patients with abaseline viral load ≤ 100,000 HIV-1 RNA copies/mL (5.9% with rilpivirine versus 2.4% withefavirenz). The virologic failure rate in patients treated with emtricitabine/tenofovir disoproxilfumarate + rilpivirine at Week 48 and Week 96 was 9.5% and 11.5% respectively, and 4.2% and 5.1%in the emtricitabine/tenofovir disoproxil fumarate + efavirenz arm. The difference in the rate of newvirologic failures from the Week 48 to Week 96 analysis between rilpivirine and efavirenz arms wasnot statistically significant. Patients with a baseline viral load > 100,000 HIV-1 RNA copies/mL whoexperienced virologic failure exhibited a higher rate of treatment-emergent resistance to the NNRTIclass. More patients who failed virologically on rilpivirine than who failed virologically on efavirenzdeveloped lamivudine/emtricitabine associated resistance (see section 5.1).

Findings in adolescents (12 to less than 18 years of age) in Study C213 were generally in line withthese data (for details see section 5.1).

Only adolescents deemed likely to have good adherence to antiretroviral therapy should be treatedwith rilpivirine, as suboptimal adherence can lead to development of resistance and the loss of futuretreatment options.

At supratherapeutic doses (75 mg once daily and 300 mg once daily), rilpivirine has been associatedwith prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5 and 4.9).

Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevanteffect on QTc. Odefsey should be used with caution when co-administered with medicinal productswith a known risk of Torsade de Pointes.

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk forsevere and potentially fatal hepatic adverse reactions.

The safety and efficacy of Odefsey 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 Odefsey therapyin patients co-infected with HIV and HBV may be associated with severe acute exacerbations ofhepatitis. Patients co-infected with HIV and HBV who discontinue Odefsey should be closelymonitored with both clinical and laboratory follow-up for at least several months after stoppingtreatment.

The safety and efficacy of Odefsey in patients with significant underlying liver disorders have notbeen established.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy (CART) andshould be monitored according to standard practice. If there is evidence of worsening liver disease insuch patients, interruption or discontinuation of treatment must be considered.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and lifestyle. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is mostpronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; thesehave predominantly concerned treatment with regimens containing zidovudine. The main adversereactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurologicaldisorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether suchneurological disorders are transient or permanent is currently unknown. These findings should beconsidered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinicalfindings of unknown aetiology, particularly neurologic findings. These findings do not affect currentnational recommendations to use antiretroviral therapy in pregnant women to prevent verticaltransmission of HIV.

In HIV infected patients with severe immune deficiency at the time of institution of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and causeserious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observedwithin the first few weeks or months of initiation of CART. Relevant examples includecytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystisjirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted whennecessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment.

Patients receiving Odefsey may continue to develop opportunistic infections and other complicationsof HIV infection, and therefore should remain under close clinical observation by physiciansexperienced in the treatment of patients with HIV associated diseases.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported 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, jointstiffness or difficulty in movement.

Post-marketing cases of renal impairment, including acute renal failure and proximal renaltubulopathy have been reported with tenofovir alafenamide-containing products. A potential risk ofnephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofoviralafenamide cannot be excluded (see section 5.3).

It is recommended that renal function is assessed in all patients prior to, or when initiating, therapywith Odefsey and that it is also monitored during therapy in all patients as clinically appropriate. Inpatients who develop clinically significant decreases in renal function, or evidence of proximal renaltubulopathy, discontinuation of Odefsey should be considered.

Odefsey should generally be avoided but may be used with caution in adults with end stage renaldisease (estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits outweigh thepotential risks (see section 4.2). In a study of emtricitabine + tenofovir alafenamide in combinationwith elvitegravir + cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in HIV-1 infected adultswith end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy wasmaintained through 48 weeks but emtricitabine exposure was significantly higher than in patients withnormal renal function. Although there were no new safety issues identified, the implications ofincreased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Lower exposures of rilpivirine were observed when rilpivirine 25 mg once daily was taken duringpregnancy. In the Phase 3 studies (C209 and C215), lower rilpivirine exposure, similar to that seenduring pregnancy, has been associated with an increased risk of virological failure, therefore viral loadshould be monitored closely (see sections 4.6, 5.1 and 5.2). Alternatively, switching to anotherantiretroviral regimen could be considered.

Some medicinal products should not be co-administered with Odefsey (see sections 4.3 and 4.5).

Odefsey should not be co-administered with other antiretroviral medicinal products (see section 4.5).

Odefsey should not be co-administered with other medicinal products containing tenofoviralafenamide, lamivudine, tenofovir disoproxil or adefovir dipivoxil (see section 4.5).

Odefsey contains lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

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

Odefsey is indicated for use as a complete regimen for the treatment of HIV-1 infection and should notbe co-administered with other antiretroviral medicinal products. Therefore, information regardingdrug-drug interactions with other antiretroviral medicinal products is not provided. Interaction studieshave only been performed in adults.

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 tubularsecretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product.

Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Rilpivirine

Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3Amay thus affect the clearance of rilpivirine (see section 5.2). Rilpivirine inhibits P-glycoprotein (P-gp)in vitro (50% inhibitory concentration [IC50] is 9.2 µM). In a clinical study, rilpivirine did notsignificantly affect the pharmacokinetics of digoxin. Additionally, in a clinical drug-drug interactionstudy with tenofovir alafenamide, which is more sensitive to intestinal P-gp inhibition, rilpivirine didnot affect tenofovir alafenamide exposures when administered concurrently, indicating that rilpivirineis not a P-gp inhibitor in vivo.

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

Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). Medicinalproducts that affect P-gp and BCRP activity may lead to changes in tenofovir alafenamide absorption(see Table 1). Medicinal products that induce P-gp activity (e.g., rifampicin, rifabutin, carbamazepine,phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreasedplasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of

Odefsey and development of resistance. Co-administration of Odefsey with other medicinal productsthat inhibit P-gp and BCRP activity (e.g., ketoconazole, fluconazole, itraconazole, posaconazole,voriconazole, ciclosporin) is expected to increase the absorption and plasma concentration of tenofoviralafenamide. Based on data from an in vitro study, co-administration of tenofovir alafenamide andxanthine oxidase inhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovirin vivo.

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or

CYP2D6 in vitro. Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo. Tenofoviralafenamide is a substrate of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of

OATP1B1 and OATP1B3.

Co-administration of Odefsey and medicinal products that induce CYP3A has been observed todecrease the plasma concentrations of rilpivirine which could potentially lead to loss of virologicresponse to Odefsey (see section 4.3) and possible resistance to rilpivirine and to the NNRTI class.

Co-administration of Odefsey with proton pump inhibitors has been observed to decrease the plasmaconcentrations of rilpivirine (due to an increase in gastric pH) which could potentially lead to loss ofvirologic response to Odefsey (see section 4.3) and possible resistance to rilpivirine and to the

NNRTI class.

Concomitant use where caution is recommended

CYP enzyme inhibitors

Co-administration of Odefsey with medicinal products that inhibit CYP3A enzyme activity has beenobserved to increase rilpivirine plasma concentrations.

QT prolonging medicinal products

Odefsey should be used with caution when co-administered with a medicinal product with a knownrisk of Torsade de Pointes (see section 4.4).

Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase(UGT) 1A1 in vitro. It is not known whether emtricitabine, or tenofovir alafenamide are inhibitors ofother UGT enzymes. Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGTsubstrate in vitro.

Interactions between Odefsey or its individual component(s) and co-administered medicinal productsare listed in Table 1 below (increase is indicated as “↑”, decrease as “↓” and no change as “↔”).

Table 1: Interactions between Odefsey or its individual component(s) and other medicinalproducts

Medicinal product by therapeutic Effects on medicinal product Recommendation concerningareas levels. co-administration with Odefsey

Mean percent change in AUC,

Cmax, Cmin

ANTI-INFECTIVES

Antifungals

Ketoconazole (400 mg once daily)/ Ketoconazole: Co-administration is not

Rilpivirine1 AUC: ↓ 24% recommended.

Cmin: ↓ 66%

Cmax: ↔

Rilpivirine:

AUC: ↑ 49%

Cmin: ↑ 76%

Cmax: ↑ 30%

Inhibition of CYP3A

Expected:

AUC: ↑

Cmax: ↑

Inhibition of P-gp

Interaction not studied withtenofovir alafenamide.

Co-administration of ketoconazoleis expected to increase plasmaconcentrations of tenofoviralafenamide (inhibition of P-gp).

Fluconazole Interaction not studied with any of Co-administration is not

Itraconazole the components of Odefsey. recommended.

Posaconazole Co-administration of these

Voriconazole antifungal agents is expected toincrease plasma concentrations ofrilpivirine (inhibition of CYP3A)and tenofovir alafenamide(inhibition of P-gp).

Medicinal product by therapeutic Effects on medicinal product Recommendation concerningareas levels. co-administration with Odefsey

Mean percent change in AUC,

Cmax, Cmin

Antimycobacterials

Rifampicin/ Rilpivirine Rifampicin: Co-administration is

AUC: ↔ contraindicated.

Cmin: N/A

Cmax: ↔25-desacetyl-rifampicin:

AUC: ↓ 9%

Cmin: N/A

Cmax: ↔

Rilpivirine:

AUC: ↓ 80%

Cmin: ↓ 89%

Cmax: ↓ 69%

Induction of CYP3A

Expected:

AUC: ↓

Cmax: ↓

Induction of P-gp

Interaction not studied withtenofovir alafenamide.

Co-administration is likely to causesignificant decreases in the plasmaconcentrations of tenofoviralafenamide (induction of P-gp).

Rifapentine Interaction not studied with any of Co-administration isthe components of Odefsey. contraindicated.

Co-administration is likely to causesignificant decreases in the plasmaconcentrations of rilpivirine(induction of CYP3A) and tenofoviralafenamide (induction of P-gp).

Medicinal product by therapeutic Effects on medicinal product Recommendation concerningareas levels. co-administration with Odefsey

Mean percent change in AUC,

Cmax, Cmin

Rifabutin (300 mg once daily)/ Rifabutin: Co-administration is

Rilpivirine1 AUC: ↔ contraindicated.

Cmin: ↔

Cmax: ↔25-O-desacetyl-rifabutin:

AUC: ↔

Cmin: ↔

Cmax: ↔

Rifabutin (300 mg once daily)/ Rilpivirine:

Rilpivirine AUC: ↓ 42%

Cmin: ↓ 48%

Cmax: ↓ 31%

Induction of CYP3A

Expected:

AUC: ↓

Cmax: ↓

Induction of P-gp

Interaction not studied withtenofovir alafenamide.

Co-administration is likely to causesignificant decreases in the plasmaconcentrations of tenofoviralafenamide (induction of P-gp).

Clarithromycin Interaction not studied with any of Co-administration is not

Erythromycin the components of Odefsey. The recommended.

combination of Odefsey with thesemacrolide antibiotics may cause anincrease in the plasmaconcentrations of rilpivirine(inhibition of CYP3A) andtenofovir alafenamide (inhibition of

P-gp).

Antiviral agents

Ledipasvir/Sofosbuvir Ledipasvir: No dose adjustment is required.

(90 mg/400 mg once daily)/ AUC: ↑ 2%

Rilpivirine Cmin: ↑ 2%

Cmax: ↑ 1%

AUC: ↑ 5%

Cmax: ↓ 4%

Sofosbuvir metabolite GS-331007:

AUC: ↑ 8%

Cmin: ↑ 10%

Cmax: ↑ 8%

Rilpivirine:

AUC: ↓ 5%

Cmin: ↓ 7%

Cmax: ↓ 3%

Medicinal product by therapeutic Effects on medicinal product Recommendation concerningareas levels. co-administration with Odefsey

Mean percent change in AUC,

Cmax, Cmin

Ledipasvir/Sofosbuvir Tenofovir alafenamide:

(90 mg/400 mg once daily)/ AUC: ↑ 32%

Tenofovir alafenamide Cmax: ↑ 3%

Sofosbuvir/Velpatasvir Sofosbuvir: No dose adjustment is required.

(400 mg/100 mg once daily)/ AUC: ↔

Rilpivirine2 Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

Rilpivirine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Sofosbuvir/Velpatasvir/Voxilaprevir Sofosbuvir: No dose adjustment is required.

(400 mg/100 mg/100 mg + 100 mg AUC: ↔once daily)3/ Cmin: N/A

Emtricitabine/Rilpivirine/Tenofovir Cmax: ↔alafenamide (200 mg/25 mg/25 mgonce daily) Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmin: N/A

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

Rilpivirine:

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↑ 52%

Cmin: N/A

Cmax: ↑ 32%

Medicinal product by therapeutic Effects on medicinal product Recommendation concerningareas levels. co-administration with Odefsey

Mean percent change in AUC,

Cmax, Cmin

Sofosbuvir (400 mg once daily)/ Sofosbuvir: No dose adjustment is required.

Rilpivirine (25 mg once daily) AUC: ↔

Cmax: ↑ 21%

Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmax: ↔

Rilpivirine:

AUC: ↔

Cmin: ↔

Cmax: ↔

ANTICONVULSANTS

Carbamazepine Interaction not studied with any of Co-administration is

Oxcarbazepine the components of Odefsey. contraindicated.

Phenobarbital Co-administration may cause

Phenytoin significant decreases in the plasmaconcentrations of rilpivirine(induction of CYP3A) and tenofoviralafenamide (induction of P-gp).

GLUCOCORTICOIDS

Dexamethasone (systemic, except for Interaction not studied with any of Co-administration issingle dose use) the components of Odefsey. contraindicated.

Significant dose dependentdecreases in rilpivirine plasmaconcentrations are expected(induction of CYP3A).

PROTON PUMP INHIBITORS

Omeprazole (20 mg once daily)/ Omeprazole: Co-administration is

Rilpivirine1 AUC: ↓ 14% contraindicated.

Cmin: N/A

Cmax: ↓ 14%

Rilpivirine:

AUC: ↓ 40%

Cmin: ↓ 33%

Cmax: ↓ 40%

Reduced absorption, increase ingastric pH

Lansoprazole Interaction not studied with any of Co-administration is

Rabeprazole the components of Odefsey. contraindicated.

Pantoprazole Significant decreases in rilpivirine

Esomeprazole plasma concentrations are expected

Dexlansoprazole (reduced absorption, increase ingastric pH).

HERBAL PRODUCTS

St. John’s wort (Hypericum Interaction not studied with any of Co-administration isperforatum) the components of Odefsey. contraindicated.

Co-administration may causesignificant decreases in the plasmaconcentrations of rilpivirine(induction of CYP3A) and tenofoviralafenamide (induction of P-gp).

Medicinal product by therapeutic Effects on medicinal product Recommendation concerningareas levels. co-administration with Odefsey

Mean percent change in AUC,

Cmax, Cmin

H2-RECEPTOR ANTAGONISTS

Famotidine (40 mg single dose taken Rilpivirine: Only H2-receptor antagonists that12 hours before rilpivirine)/ AUC: ↓ 9% can be dosed once daily should be

Rilpivirine1 Cmin: N/A used. A strict dosing schedule

Cmax: ↔ with intake of the H2-receptorantagonists at least 12 hours

Famotidine (40 mg single dose taken Rilpivirine: before or at least 4 hours after2 hours before rilpivirine)/ AUC: ↓ 76% Odefsey should be used.

Rilpivirine1 Cmin: N/A

Cmax: ↓ 85%

Reduced absorption, increase ingastric pH

Famotidine (40 mg single dose taken Rilpivirine:

4 hours after rilpivirine)/ Rilpivirine1 AUC: ↑ 13%

Cmin: N/A

Cmax: ↑ 21%

Cimetidine Interaction not studied with any of

Nizatidine the components of Odefsey.

Ranitidine Co-administration may causesignificant decreases in rilpivirineplasma concentrations (reducedabsorption, increase in gastric pH).

ANTACIDS

Antacids (e.g., aluminium or Interaction not studied with any of Antacids should only bemagnesium hydroxide, calcium the components of Odefsey. administered either at leastcarbonate) Co-administration may cause 2 hours before or at least 4 hourssignificant decreases in rilpivirine after Odefsey.

plasma concentrations (reducedabsorption, increase in gastric pH).

ORAL CONTRACEPTIVES

Ethinylestradiol (0.035 mg once Ethinylestradiol: No dose adjustment is required.

daily)/ Rilpivirine AUC: ↔

Cmin: ↔

Cmax: ↑ 17%

Norethindrone (1 mg once daily)/ Norethindrone:

Rilpivirine AUC: ↔

Cmin: ↔

Cmax: ↔

Rilpivirine:

AUC: ↔*

Cmin: ↔*

Cmax: ↔*

*based on historic controls

Medicinal product by therapeutic Effects on medicinal product Recommendation concerningareas levels. co-administration with Odefsey

Mean percent change in AUC,

Cmax, Cmin

Norgestimate (0.180/0.215/0.250 mg Norelgestromin: No dose adjustment is required.

once daily)/ Ethinylestradiol AUC: ↔(0.025 mg once daily)/ Cmin: ↔

Emtricitabine/Tenofovir alafenamide Cmax: ↔(200/25 mg once daily)

Norgestrel:

AUC: ↔

Cmin: ↔

Cmax: ↔

Ethinylestradiol:

AUC: ↔

Cmin: ↔

Cmax: ↔

NARCOTIC ANALGESICS

Methadone (60-100 mg once daily, R(-) methadone: No dose adjustments are required.

individualised dose)/ Rilpivirine AUC: ↓ 16%

Cmin: ↓ 22% Clinical monitoring is

Cmax: ↓ 14% recommended as methadonemaintenance therapy may need to

S(+) methadone: be adjusted in some patients.

AUC: ↓ 16%

Cmin: ↓ 21%

Cmax: ↓ 13%

Rilpivirine:

AUC: ↔*

Cmin: ↔*

Cmax: ↔*

*based on historic controls

ANALGESICS

Paracetamol (500 mg single dose)/ Paracetamol: No dose adjustment is required.

Rilpivirine1 AUC: ↔

Cmin: N/A

Cmax: ↔

Rilpivirine:

AUC: ↔

Cmin: ↑ 26%

Cmax: ↔

ANTIARRHYTHMICS

Digoxin/ Rilpivirine Digoxin: No dose adjustment is required.

AUC: ↔

Cmin: N/A

Cmax: ↔

ANTICOAGULANTS

Dabigatran etexilate Interaction not studied with any of Co-administration should be usedthe components of Odefsey. with caution.

A risk for increases in dabigatranplasma concentrations cannot beexcluded (inhibition of intestinal

P-gp).

Medicinal product by therapeutic Effects on medicinal product Recommendation concerningareas levels. co-administration with Odefsey

Mean percent change in AUC,

Cmax, Cmin

IMMUNOSUPPRESSANTS

Ciclosporin Interaction not studied with any of Co-administration is notthe components of Odefsey. recommended.

Co-administration of ciclosporin isexpected to increase plasmaconcentrations of rilpivirine(inhibition of CYP3A) andtenofovir alafenamide (inhibition of

P-gp).

ANTIDIABETICS

Metformin (850 mg single dose)/ Metformin: No dose adjustment is required.

Rilpivirine AUC: ↔

Cmin: N/A

Cmax: ↔

HMG CO-A REDUCTASE INHIBITORS

Atorvastatin (40 mg once daily)/ Atorvastatin: No dose adjustment is required.

Rilpivirine1 AUC: ↔

Cmin: ↓ 15%

Cmax: ↑ 35%

Rilpivirine:

AUC: ↔

Cmin: ↔

Cmax: ↓ 9%

PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS

Sildenafil (50 mg single dose)/ Sildenafil: No dose adjustment is required.

Rilpivirine1 AUC: ↔

Cmin: N/A

Cmax: ↔

Rilpivirine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Vardenafil Interaction not studied with any of No dose adjustment is required.

Tadalafil the components of Odefsey. Theseare medicinal products within classwhere similar interactions could bepredicted.

HYPNOTICS/SEDATIVES

Midazolam (2.5 mg, orally, single Midazolam: No dose adjustment is required.

dose)/ Tenofovir alafenamide AUC: ↑ 12%

Cmin: N/A

Cmax: ↑ 2%

Midazolam (1 mg, intravenously, Midazolam:

single dose)/ Tenofovir alafenamide AUC: ↑ 8%

Cmin: N/A

Cmax: ↓ 1%

N/A = not applicable1 This interaction study has been performed with a dose higher than the recommended dose for rilpivirine hydrochlorideassessing the maximal effect on the co-administered medicinal product. The dosing recommendation is applicable to therecommended dose of rilpivirine of 25 mg once daily.

2 Study conducted with emtricitabine/rilpivirine/tenofovir disoproxil fumarate fixed-dose combination tablet.

3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV infectedpatients.

Based on drug-drug interaction studies conducted with the components of Odefsey, no clinicallysignificant interactions are expected when Odefsey is combined with the following medicinalproducts: buprenorphine, naloxone and norbuprenorphine.

Women of childbearing potential/contraception in males and females

The use of Odefsey should be accompanied by the use of effective contraception.

There are no adequate and well-controlled studies of Odefsey or its components in pregnant women.

There is a limited amount of data (less than 300 pregnancy outcomes) from the use of tenofoviralafenamide in pregnant women. A moderate amount of data on pregnant women (between 300-1,000pregnancy outcomes) indicate no malformative or foetal/neonatal toxicity of rilpivirine (seesections 4.4, 5.1 and 5.2). Lower exposures of rilpivirine were observed during pregnancy; thereforeviral load should be monitored closely. A large amount of data on pregnant women (more than1,000 exposed outcomes) indicate no malformative nor foetal/neonatal toxicity associated withemtricitabine.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3) with the components of Odefsey.

Odefsey should be used during pregnancy only if the potential benefit justifies the potential risk to thefoetus.

Emtricitabine is excreted in human milk. It is not known whether rilpivirine or tenofovir alafenamideare excreted in human milk. In animal studies it has been shown that tenofovir is excreted in milk.

Rilpivirine is excreted in the milk of rats.

There is insufficient information on the effects of all the components of Odefsey in newborns/infants.

Because of the potential for adverse reactions in breastfed infants, women should be instructed not tobreast-feed if they are receiving Odefsey.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed their infants.

No human data on the effect of Odefsey on fertility are available. Animal studies do not indicateharmful effects of emtricitabine, rilpivirine hydrochloride or tenofovir alafenamide on fertility (seesection 5.3).

Odefsey may have minor influence on the ability to drive and use machines. Patients should beinformed that fatigue, dizziness and somnolence have been reported during treatment with thecomponents of Odefsey (see section 4.8). This should be considered when assessing a patient’s abilityto drive or operate machinery.

The most frequently reported adverse reactions in clinical studies of treatment-naïve patients takingemtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat were nausea(11%), diarrhoea (7%), and headache (6%). The most frequently reported adverse reactions in clinicalstudies of treatment-naïve patients taking rilpivirine hydrochloride in combination withemtricitabine + tenofovir disoproxil fumarate were nausea (9%), dizziness (8%), abnormal dreams(8%), headache (6%), diarrhoea (5%) and insomnia (5%).

Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies in whichpatients received emtricitabine + tenofovir alafenamide given with elvitegravir + cobicistat as afixed-dose combination tablet, pooled data from patients who received rilpivirine 25 mg once daily incombination with other antiretroviral medicinal products in the controlled studies TMC278-C209 and

TMC278-C215, patients who received Odefsey in Studies GS-US-366-1216 and GS-US-366-1160,and post-marketing experience.

The adverse reactions in Table 2 are listed by system organ class and highest frequency observed.

Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) or uncommon(≥ 1/1,000 to < 1/100).

Table 2: Tabulated list of adverse reactions

Frequency Adverse reaction

Common: decreased white blood cell count1, decreased haemoglobin1, decreased platelet count1

Uncommon: anaemia2

Uncommon: immune reactivation syndrome1

Very common: increased total cholesterol (fasted)1, increased LDL-cholesterol (fasted)1

Common: decreased appetite1, increased triglycerides (fasted)1

Very common: insomnia1

Common: depression1, abnormal dreams1, 3, sleep disorders1, depressed mood1

Very common: headache1, 3, dizziness1, 3

Common: somnolence1

Very common: nausea1, 3, increased pancreatic amylase1abdominal pain1, 3, vomiting1, 3, increased lipase1, abdominal discomfort1, dry

Common:

mouth1, flatulence3, diarrhoea3

Uncommon: dyspepsia3

Very common: increased transaminases (AST and/or ALT)1

Common: increased bilirubin1

Common: rash1, 3

Uncommon: severe skin reactions with systemic symptoms4, angioedema5, 6, pruritus3, urticaria6

Uncommon: arthralgia3

Common: fatigue1, 31 Adverse reactions identified from rilpivirine clinical studies.

2 This adverse reaction was not observed in the Phase 3 studies of emtricitabine + tenofovir alafenamide in combinationwith elvitegravir + cobicistat or in the Phase 3 studies with Odefsey but identified from clinical studies or post-marketingexperience of emtricitabine when used with other antiretrovirals.

3 Adverse reactions identified from clinical studies of emtricitabine + tenofovir alafenamide-containing products.

4 Adverse reaction identified through post-marketing surveillance of emtricitabine/rilpivirine/tenofovir disoproxilfumarate.

5 Adverse reaction identified through post-marketing surveillance for emtricitabine-containing products.

6 Adverse reaction identified through post-marketing surveillance for tenofovir alafenamide-containing products.

Changes in serum creatinine for rilpivirine-containing regimens

The pooled data from the Phase 3 TMC278-C209 and TMC278-C215 studies of treatment-naïvepatients also demonstrate that serum creatinine increased and estimated glomerular filtration rate(eGFR) decreased over 96 weeks of treatment with rilpivirine. Most of this increase in creatinine anddecrease in eGFR occurred within the first four weeks of treatment. Over 96 weeks of treatment withrilpivirine mean changes of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) for creatinine and

- 13.3 mL/min/1.73 m2 (range: -63.7 mL/min/1.73 m2 to 40.1 mL/min/1.73 m2) for eGFR wereobserved. In patients who entered the studies with mild or moderate renal impairment, the serumcreatinine increase observed was similar to that seen in patients with normal renal function. Theseincreases do not reflect a change in actual glomerular filtration rate (GFR).

In studies in treatment-naïve patients receiving emtricitabine + tenofovir alafenamide (FTC + TAF) oremtricitabine + tenofovir disoproxil fumarate (FTC + TDF), both given with elvitegravir + cobicistatas a fixed-dose combination tablet, increases from baseline were observed in both treatment groups forthe fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)- and high-densitylipoprotein (HDL)-cholesterol, and triglycerides at Week 144. The median increase from baseline forthese parameters was greater in patients receiving FTC + TAF compared with patients receiving

FTC + TDF (p < 0.001 for the difference between treatment groups for fasting total cholesterol, direct

LDL- and HDL-cholesterol, and triglycerides). Median (Q1, Q3) change from baseline at Week 144in total cholesterol to HDL-cholesterol ratio was 0.2 (-0.3, 0.7) in patients receiving FTC + TAF and0.1 (-0.4, 0.6) in patients receiving FTC + TDF (p = 0.006 for the difference between treatmentgroups).

Switching from a TDF-based regimen to Odefsey may lead to slight increases in lipid parameters. In astudy of virologically suppressed patients switching from FTC/RPV/TDF to Odefsey (Study

GS-US-366-1216), increases from baseline were observed in fasting values of total cholesterol, direct

LDL-cholesterol, HDL-cholesterol, and triglycerides in the Odefsey arm; and no clinically relevantchanges from baseline in median fasting values for total cholesterol to HDL-cholesterol ratio wereobserved in either treatment arm at Week 96. In a study of virologically suppressed patients switchingfrom EFV/FTC/TDF to Odefsey (Study GS-US-366-1160), decreases from baseline were observed inthe fasting values of total cholesterol and HDL-cholesterol in the Odefsey arm; no clinically relevantchanges from baseline in median fasting values for total cholesterol to HDL-cholesterol ratio, direct

LDL-cholesterol or triglycerides were observed in either treatment arm at Week 96.

Cortisol

In the pooled Phase 3 TMC278-C209 and TMC278-C215 studies of treatment-naïve patients, at

Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (-30.85;

- 7.37) nmol/L in the rilpivirine arm and of -0.6 (-13.29; 12.17) nmol/L in the efavirenz arm. At

Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in therilpivirine arm (+18.4 ± 8.36 nmol/L) than in the efavirenz arm (+54.1 ± 7.24 nmol/L). Mean valuesfor the rilpivirine arm for both basal and ACTH-stimulated cortisol at Week 96 were within the normalrange. These changes in adrenal safety parameters were not clinically relevant. There were no clinicalsigns or symptoms suggestive of adrenal or gonadal dysfunction in adults.

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

In HIV infected patients with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment (see section 4.4).

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

Severe skin reactions

Severe skin reactions with systemic symptoms have been reported during post-marketing experienceof emtricitabine/rilpivirine/tenofovir disoproxil fumarate including rashes accompanied by fever,blisters, conjunctivitis, angioedema, elevated liver function tests, and/or eosinophilia.

The safety of emtricitabine + tenofovir alafenamide was evaluated through 48 weeks in an open-labelclinical study (GS-US-292-0106) in which 50 HIV-1 infected, treatment-naïve paediatric patients aged12 to < 18 years received emtricitabine + tenofovir alafenamide in combination withelvitegravir + cobicistat as a fixed-dose combination tablet. In this study, the safety profile inadolescent patients was similar to that in adults (see section 5.1).

The safety assessment of rilpivirine is based on Week 48 data from one single-arm open-label study(TMC278-C213) in 36 paediatric patients 12 to < 18 years and weighing at least 32 kg. No patientsdiscontinued rilpivirine due to adverse reactions. No new adverse reactions were identified comparedto those seen in adults. Most adverse reactions were Grade 1 or 2. Adverse reactions (all grades) ofvery common frequency were headache, depression, somnolence and nausea. No Grade 3-4laboratory abnormalities for AST/ALT or Grade 3-4 adverse reactions of transaminase increased werereported (see section 5.1).

The safety of emtricitabine + tenofovir alafenamide was evaluated through 144 weeks in an open-labelclinical study (GS-US-292-0112), in which 248 HIV-1 infected patients who were eithertreatment-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) receivedemtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dosecombination tablet. The safety profile in patients with mild to moderate renal impairment was similarto that in patients with normal renal function (see section 5.1).

The safety of emtricitabine + tenofovir alafenamide was evaluated through 48 weeks in a single arm,open-label clinical study (GS-US-292-1825) in which 55 virologically suppressed HIV-1 infectedpatients with end stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis receivedemtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dosecombination tablet. There were no new safety issues identified in patients with end stage renal diseaseon chronic haemodialysis receiving emtricitabine + tenofovir alafenamide, given with elvitegravir +cobicistat as a fixed-dose combination tablet (see section 5.2).

The safety of emtricitabine + tenofovir alafenamide in combination with elvitegravir and cobicistat asa fixed-dose combination tablet (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide[E/C/F/TAF]) was evaluated in 72 HIV/HBV co-infected patients receiving treatment for HIV in anopen-label clinical study (GS-US-292-1249), through Week 48, in which patients were switched fromanother antiretroviral regimen (which included TDF in 69 of 72 patients) to E/C/F/TAF. Based onthese limited data, the safety profile of emtricitabine + tenofovir alafenamide in combination withelvitegravir and cobicistat as a fixed-dose combination tablet, in patients with HIV/HBV co-infection,was similar to that in patients with HIV-1 monoinfection.

In patients co-infected with hepatitis B or C virus receiving rilpivirine, the incidence of hepaticenzyme elevation was higher than in patients receiving rilpivirine who were not co-infected. Thepharmacokinetic exposure of rilpivirine in co-infected patients was comparable to that in patientswithout co-infection.

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. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), andstandard supportive treatment applied as necessary including observation of the clinical status of thepatient and monitoring of vital signs and ECG (QT interval).

There is no specific antidote for overdose with Odefsey. Up to 30% of the emtricitabine dose can beremoved by haemodialysis. Tenofovir is efficiently removed by haemodialysis with an extractioncoefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removedby peritoneal dialysis. Since rilpivirine is highly protein bound, dialysis is unlikely to result insignificant removal of the active substance. Further management should be as clinically indicated oras recommended by the national poisons centre, where available.

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections,combinations, ATC code: J05AR19

Mechanism of action and pharmacodynamic effects

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and analogue of 2’-deoxycytidine.

Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabinetriphosphate competitively inhibits HIV-1 reverse transcriptase (RT), resulting in deoxyribonucleicacid (DNA) chain termination. Emtricitabine has activity against HIV-1, HIV-2, and HBV.

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1. Rilpivirine activity is mediated bynon-competitive inhibition of HIV-1 RT. Rilpivirine does not inhibit the human cellular DNApolymerases α, β and mitochondrial DNA polymerase γ.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and prodrug of tenofovir(2’-deoxyadenosine monophosphate analogue). Due to increased plasma stability and intracellularactivation through hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovirdisoproxil fumarate in loading tenofovir into peripheral blood mononuclear cells (PBMCs) (includinglymphocytes and other HIV target cells) and macrophages. Intracellular tenofovir is subsequentlyphosphorylated to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits

HIV RT, resulting in DNA chain termination. Tenofovir has activity against HIV-1, HIV-2 and HBV.

The combinations of emtricitabine, rilpivirine, and tenofovir alafenamide were not antagonistic andshowed synergistic effects with each other in cell culture combination antiviral activity assays.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed inlymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The 50% effective concentration(EC50) values for emtricitabine were in the range of 0.0013 to 0.64 µM. Emtricitabine displayedantiviral activity in cell culture against HIV-1 subtype A, B, C, D, E, F, and G (EC50 values rangedfrom 0.007 to 0.075 µM) and showed activity against HIV-2 (EC50 values ranged from 0.007 to1.5 µM).

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected

T-cell line with a median EC50 value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine alsodemonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H)primary isolates with EC50 values ranging from 0.07 to 1.01 nM (0.03 to 0.37 ng/mL), group Oprimary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL), and showedlimited in vitro activity against HIV-2 with EC50 values ranging from 2,510 to 10,830 nM (920 to3,970 ng/mL).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1subtype 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 to14.7 nM. Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV-1 groups(M, N, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) andshowed activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).

Considering all of the available in vitro data and data generated in treatment-naïve patients, thefollowing resistance-associated mutations in HIV-1 RT, when present at baseline, may affect theactivity of Odefsey: K65R, K70E, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L,

Y181C, Y181I, Y181V, M184I, M184V, Y188L, H221Y, F227C, M230I, M230L and thecombination of L100I and K103N.

A negative impact by NNRTI mutations other than those listed above (e.g., mutations K103N or L100Ias single mutations) cannot be excluded, since this was not studied in vivo in a sufficient number ofpatients.

As with other antiretroviral medicinal products, resistance testing and/or historical resistance datashould guide the use of Odefsey (see section 4.4).

In vitro

Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 RT.

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of differentorigins and subtypes as well as NNRTI-resistant HIV-1. The most commonly observed amino acidsubstitutions that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C,and M230I.

HIV-1 isolates with reduced susceptibility to tenofovir alafenamide expressed a K65R mutation in

HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed.

In treatment-naïve adult patients

In the Week 144 pooled analysis of antiretroviral-naïve patients receivingelvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in the Phase 3 studies

GS-US-292-0104 and GS-US-292-0111, the development of one or more primaryresistance-associated mutations was observed in HIV-1 isolates from 12 of 866 (1.4%) patients treatedwith E/C/F/TAF. Among these 12 HIV-1 isolates, 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.

In the Week 96 pooled analysis for patients receiving emtricitabine/tenofovir disoproxil fumarate(FTC/TDF) + rilpivirine hydrochloride in the Phase 3 clinical studies TMC278-C209 and

TMC278-C215, HIV-1 isolates from 43 patients had an amino acid substitution associated with

NNRTI (n = 39) or NRTI (n = 41) resistance. The NNRTI resistance-associated mutations thatdeveloped most commonly were: V90I, K101E, E138K/Q, V179I, Y181C, V189I, H221Y and F227C.

The presence of V90I and V189I at baseline did not affect the response. Fifty-two percent of HIV-1isolates with emergent resistance in the rilpivirine arm developed concomitant NNRTI and NRTImutations, most frequently E138K and M184V. The mutations associated with NRTI resistance thatdeveloped in 3 or more patient isolates were: K65R, K70E, M184V/I and K219E.

Through Week 96, fewer patients in the rilpivirine arm with baseline viral load ≤ 100,000 copies/mLhad emerging resistance-associated substitutions and/or phenotypic resistance to rilpivirine (7/288)than patients with baseline viral load > 100,000 copies/mL (30/262).

One patient with emergent resistance (M184M/I) was identified in a clinical study of virologicallysuppressed patients who switched from a regimen containing emtricitabine + tenofovir disoproxilfumarate to E/C/F/TAF in a fixed-dose combination (FDC) tablet (GS-US-292-0109, n = 959).

Through Week 96, in patients who switched to Odefsey from emtricitabine/rilpivirine/tenofovirdisoproxil fumarate (FTC/RPV/TDF) or efavirenz/emtricitabine/tenofovir disoproxil fumarate(EFV/FTC/TDF) (Studies GS-US-366-1216 and GS-US-366-1160; n = 754), no treatment-emergentresistance-associated mutations were detected.

In a clinical study of HIV virologically suppressed patients co-infected with chronic hepatitis B, whoreceived E/C/F/TAF for 48 weeks (GS-US-292-1249, n = 72), 2 patients qualified for resistanceanalysis. In these 2 patients, no amino acid substitutions associated with resistance to any of thecomponents of E/C/F/TAF were identified in HIV-1 or HBV.

Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, butretained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

In a panel of 67 HIV-1 recombinant laboratory strains with one resistance-associated mutation at RTpositions associated with NNRTI resistance, the only single resistance-associated mutations associatedwith a loss of susceptibility to rilpivirine were K101P and Y181V/I. The K103N substitution alonedid not result in reduced susceptibility to rilpivirine, but the combination of K103N and L100I resultedin a 7-fold reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in areduced susceptibility to rilpivirine of 9-fold for clinical isolates and 6-fold for site-directed mutants.

In patients receiving rilpivirine hydrochloride in combination with FTC/TDF in Phase 3 studies(TMC278-C209 and TMC278-C215 pooled data), most HIV-1 isolates with emergent phenotypicresistance to rilpivirine had cross-resistance to at least one other NNRTI (28/31).

The K65R and also the K70E substitution result in reduced susceptibility to abacavir, didanosine,lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine.

Clinical efficacy of Odefsey was established from studies conducted with emtricitabine + tenofoviralafenamide when given with elvitegravir + cobicistat as an E/C/F/TAF FDC tablet, from studiesconducted with rilpivirine when given with FTC/TDF as individual components or as a

FTC/RPV/TDF FDC tablet, and from studies conducted with Odefsey.

Emtricitabine + tenofovir alafenamide containing regimens

Treatment-naïve and virologically suppressed HIV-1 infected adult patients

In Study GS-US-292-0104 and Study GS-US-292-0111, patients received either E/C/F/TAF (n = 866)or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) (n = 867) oncedaily, both given as FDC tablets.

The mean age was 36 years (range 18-76), 85% were male, 57% were White, 25% were Black, and10% were Asian. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies/mL (range 1.3-7.0) and23% of patients had baseline viral loads > 100,000 copies/mL. The mean baseline CD4+ cell countwas 427 cells/mm3 (range 0-1,360) and 13% had CD4+ cell counts < 200 cells/mm3.

In Studies GS-US-292-0104 and GS-US-292-0111, E/C/F/TAF demonstrated statistical superiority inachieving HIV-1 RNA < 50 copies/mL when compared to E/C/F/TDF at Week 144. The difference inpercentage was 4.2% (95% CI: 0.6% to 7.8%). Pooled treatment outcomes at 48 and 144 weeks areshown in Table 3.

In Study GS-US-292-0109, the efficacy and safety of switching from either EFV/FTC/TDF, FTC/TDFplus atazanavir (boosted by either cobicistat or ritonavir), or E/C/F/TDF to E/C/F/TAF FDC tabletwere evaluated in a randomised, open-label study of virologically suppressed (HIV-1 RNA< 50 copies/mL) HIV-1 infected adults (n = 959 switching to E/C/F/TAF, n = 477 Stayed on Baseline

Regimen [SBR]). 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 (range79-1,951).

In Study GS-US-292-0109, switching from a tenofovir disoproxil fumarate-based regimen to

E/C/F/TAF was superior in maintaining HIV-1 RNA < 50 copies/mL compared to staying on thebaseline regimen. Pooled treatment outcomes at 48 weeks are shown in Table 3.

Table 3: Virologic outcomes of Studies GS-US-292-0104, GS-US-292-0111 at Week 48 and

Week 144a, and GS-US-292-0109 at Week 48a

Treatment-naïve adults in Studies GS-US-292-0104 and Virologically suppressed

GS-US-292-0111b adults in Study

GS-US-292-0109

Week 48 Week 144 Week 48

E/C/F/TAF E/C/F/TDF E/C/F/TAF E/C/F/TDF E/C/F/TAF Baseline(n = 866) (n = 867) (n = 866) (n = 867) (n = 959) regimen(n = 477)

HIV-1 RNA 92% 90% 84% 80% 97% 93%< 50 copies/mL

Treatment 2.0% (95% CI: -0.7% to 4.7%) 4.2% (95% CI: 0.6% to 7.8%) 4.1% (95% CI: 1.6% todifference 6.7%, p < 0.001c)

HIV-1 RNA 4% 4% 5% 4% 1% 1%≥ 50 copies/mLd

No virologic data in 4% 6% 11% 16% 2% 6%

Week 48 or144 window

Discontinued 1% 2% 1% 3% 1% 1%study drug dueto AE or deathe

Discontinued 2% 4% 9% 11% 1% 4%study drug dueto other reasonsand lastavailable

HIV-1 RNA< 50 copies/mLf

Missing data 1% < 1% 1% 1% 0% < 1%during windowbut on studydrug

HIV-1 RNA 84% 84% 81% 76%< 20 copies/mL

Treatment 0.4% (95% CI: -3.0% to 3.8%) 5.4% (95% CI: 1.5% to 9.2%)difference

Proportion (%) ofpatients with

HIV-1 RNA< 50 copies/mL byprior treatmentregimend

EFV/FTC/TDF 96% 90%

FTC/TDF plus 97% 92%boostedatazanavir

E/C/F/TDF 98% 97%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 P-value for the superiority test comparing the percentages of virologic success was from the CMH(Cochran-Mantel-Haenszel) test stratified by the prior treatment regimen (EFV/FTC/TDF, FTC/TDF plus boostedatazanavir, or E/C/F/TDF).

d Includes patients who had ≥ 50 copies/mL in the Week 48 or Week 144 window; patients who discontinued early due tolack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss ofefficacy 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 thisresulted 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., withdrewconsent, loss to follow-up, etc.

In Studies GS-US-292-0104 and GS-US-292-0111, the rate of virologic success was similar acrosspatient subgroups (age, gender, race, baseline HIV-1 RNA, or baseline CD4+ cell count).

The mean increase from baseline in CD4+ cell count was 230 cells/mm3 in E/C/F/TAF-treated patientsand 211 cells/mm3 in E/C/F/TDF-treated patients (p = 0.024) at Week 48 and 326 cells/mm3 in

E/C/F/TAF-treated patients and 305 cells/mm3 in E/C/F/TDF-treated patients (p = 0.06) at Week 144.

Rilpivirine-containing regimens

Treatment-naïve HIV-1 infected adult patients

The efficacy of rilpivirine is based on the analyses of 96 weeks data from two randomised,double-blind, controlled studies in treatment-naïve patients (TMC278-C209 andemtricitabine + tenofovir disoproxil fumarate subset of TMC278-C215).

In the pooled analysis for TMC278-C209 and TMC278-C215 of 1,096 patients who received abackground regimen (BR) of FTC/TDF, demographic and baseline characteristics were balancedbetween the rilpivirine and efavirenz (EFV) arms. The median age was 36 years, 78% were male and62% White and 24% Black/African American. Median plasma HIV-1 RNA was 5.0 log10 copies/mLand median CD4+ cell count was 255 cells/mm3.

Overall response and a subgroup analysis of the virologic response (< 50 HIV-1 RNA copies/mL) atboth 48 weeks and 96 weeks, and virologic failure by baseline viral load (pooled data from the two

Phase 3 clinical studies, TMC278-C209 and TMC278-C215, for patients receiving the FTC/TDF BR)are presented in Table 4.

Table 4: Virologic outcomes of randomised treatment of Studies TMC278-C209 and

TMC278-C215 (pooled data for patients receiving rilpivirine hydrochloride or efavirenz incombination with FTC/TDF) at Week 48 (primary) and Week 96

RPV + FTC/TDF EFV + FTC/TDF RPV + FTC/TDF EFV + FTC/TDF(n = 550) (n = 546) (n = 550) (n = 546)

Week 48 Week 96

Overall response 83.5% (459/550) 82.4% (450/546) 76.9% (423/550) 77.3% (422/546)(HIV-1 RNA< 50 copies/mL(TLOVRa))b

By baseline viral load (copies/mL)≤ 100,000 89.6% (258/288) 84.8% (217/256) 83.7% (241/288) 80.8% (206/255)> 100,000 76.7% (201/262) 80.3% (233/290) 69.5% (182/262) 74.2% (216/291)

Non-response

Virologic failure 9.5% (52/550) 4.2% (23/546) 11.5% (63/550)c 5.1% (28/546)d(all patients)

RPV + FTC/TDF EFV + FTC/TDF RPV + FTC/TDF EFV + FTC/TDF(n = 550) (n = 546) (n = 550) (n = 546)

Week 48 Week 96

By baseline viral load (copies/mL)≤ 100,000 4.2% (12/288) 2.3% (6/256) 5.9% (17/288) 2.4% (6/255)> 100,000 15.3% (40/262) 5.9% (17/290) 17.6% (46/262) 7.6% (22/291)

Death 0 0.2% (1/546) 0 0.7% (4/546)

Discontinued due 2.2% (12/550) 7.1% (39/546) 3.6% (20/550) 8.1% (44/546)to adverse event(AE)

Discontinued for 4.9% (27/550) 6.0% (33/546) 8% (44/550) 8.8% (48/546)non-AE reasone

EFV = efavirenz; RPV = rilpivirinea ITT TLOVR = Intention to treat time to loss of virologic response.

b The difference of response rate at Week 48 is 1% (95% confidence interval -3% to 6%) using normal approximation.

c There were 17 new virologic failures between the Week 48 primary analysis and Week 96 (6 patients with baseline viralload ≤ 100,000 copies/mL and 11 patients with baseline viral load > 100,000 copies/mL). There were alsoreclassifications in the Week 48 primary analysis with the most common being reclassification from virologic failure todiscontinued for non-AE reasons.

d There were 10 new virologic failures between the Week 48 primary analysis and Week 96 (3 patients with baseline viralload ≤ 100,000 copies/mL and 7 patients with baseline viral load > 100,000 copies/mL). There were alsoreclassifications in the Week 48 primary analysis with the most common being reclassification from virologic failure todiscontinued for non-AE reasons.

e e.g., lost to follow up, non-compliance, withdrew consent.

FTC/TDF + rilpivirine hydrochloride was non-inferior in achieving HIV-1 RNA < 50 copies/mLcompared to FTC/TDF + efavirenz.

Odefsey regimen

Virologically suppressed HIV-1 infected adult patients

In Study GS-US-366-1216, the efficacy and safety of switching from FTC/RPV/TDF to Odefsey wereevaluated in a randomised, double-blind study of virologically suppressed HIV-1 infected adults.

Patients had a mean age of 45 years (range 23-72), 90% were male, 75% were White, and 19% were

Black. The mean baseline CD4+ cell count was 709 cells/mm3 (range 104-2,527).

In Study GS-US-366-1160, the efficacy and safety of switching from EFV/FTC/TDF to Odefsey wereevaluated in a randomised, double-blind study of virologically suppressed HIV-1 infected adults.

Patients had a mean age of 48 years (range 19-76), 87% were male, 67% were White, and 27% were

Black. The mean baseline CD4+ cell count was 700 cells/mm3 (range 140-1,862).

Treatment outcomes of Studies GS-US-366-1216 and GS-US-366-1160 are presented in Table 5.

Table 5: Virologic outcomes of Studies GS-US-366-1216 and GS-US-366-1160 at Weeks 48a and96b

GS-US-366-1216 GS-US-366-1160

Week 48 Week 96 Week 48 Week 96

ODE FTC/RPV ODE FTC/RPV ODE EFV/FTC ODE EFV/FTC(n = 316) /TDF (n = 316) /TDF (n = 438) /TDF (n = 438) /TDF(n = 313)c (n = 313)c (n = 437) (n = 437)

HIV-1 RNA 94% 94% 89% 88% 90% 92% 85% 85%< 50 copies/mL

Treatment -0.3% (95% CI: 0.7% (95% CI: -2.0% (95% CI: 0% (95% CI:

difference -4.2% to 3.7%) -4.3% to 5.8%) -5.9% to 1.8%) -4.8% to 4.8%)

HIV-1 RNA 1% 0% 1% 1% 1% 1% 1% 1%≥ 50 copies/mLd

No virologic data 6% 6% 10% 11% 9% 7% 14% 14%in Week 48 or 96window

Discontinued 2% 1% 2% 3% 3% 1% 4% 3%study drug due to

AE or death andlast available

HIV-1 RNA< 50 copies/mL

Discontinued 4% 4% 8% 8% 5% 5% 10% 11%study drug due toother reasons andlast available

HIV-1 RNA< 50 copies/mLe

Missing data < 1% 1% 1% 0 1% 1% < 1% 0during windowbut on study drug

ODE = Odefseya Week 48 window was between Day 295 and 378 (inclusive).

b Week 96 window was between Day 631 and 714 (inclusive).

c One patient who was not on FTC/RPV/TDF prior to screening was excluded from the analysis.

d Includes patients who had ≥ 50 copies/mL in the Week 48 or Week 96 window; patients who discontinued early due tolack or loss of efficacy; patients who discontinued for reasons other than lack or loss of efficacy and at the time ofdiscontinuation had a viral value of ≥ 50 copies/mL.

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

At Week 96, switching to Odefsey was non-inferior in maintaining HIV-1 RNA < 50 copies/mL whencompared to patients who stayed on FTC/RPV/TDF or on EFV/FTC/TDF in respective studies.

In Study GS-US-366-1216, the mean change from baseline in CD4+ cell count at Week 96 was12 cells/mm3 in patients who switched to Odefsey and 16 cells/mm3 in those who remained on

FTC/RPV/TDF. In Study GS-US-366-1160, the mean change from baseline in CD4+ cell count at

Week 96 was 12 cells/mm3 in patients who switched to Odefsey and 6 cells/mm3 in those who stayedon EFV/FTC/TDF.

HIV-1 infected adult patients with mild to moderate renal impairment

In Study GS-US-292-0112, the efficacy and safety of E/C/F/TAF FDC tablet were evaluated in anopen-label clinical study of 242 HIV-1 infected, virologically suppressed patients with mild tomoderate renal impairment (eGFRCG: 30-69 mL/min).

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 Black, and 14% were Asian. Thirty-fivepercent of patients were on a treatment regimen that did not contain tenofovir disoproxil fumarate. Atbaseline, median eGFRCG was 56 mL/min, and 33% of patients had an eGFRCG from 30 to 49 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

E/C/F/TAF FDC tablet.

In Study GS-US-292-1825, the efficacy and safety of E/C/F/TAF 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 E/C/F/TAF

FDC tablet. Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least6 months before switching.

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+ cellcount 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 E/C/F/TAF. There were no clinically significant changes infasting lipid laboratory tests in patients who switched.

In open-label Study GS-US-292-1249, the efficacy and safety of E/C/F/TAF were evaluated in adultpatients co-infected with HIV-1 and chronic hepatitis B. Sixty-nine of the 72 patients were on prior

TDF-containing antiretroviral therapy. At the start of treatment with E/C/F/TAF, the 72 patients hadbeen HIV suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months with or without suppressionof HBV DNA and had compensated liver function. The mean age was 50 years (range 28-67), 92% ofpatients 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 toanti-HBe at Week 48. Of the patients who were HBsAg positive at baseline, 3/70 (4.3%) achievedseroconversion to anti-HBs at Week 48.

At Week 48, 92% of patients (66/72) maintained HIV-1 RNA < 50 copies/mL after switching to

E/C/F/TAF. 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 and3 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.

Alanine aminotransferase (ALT) normalisation was achieved in 40% (4/10) of subjects with ALTgreater than upper limit of normal (ULN) at baseline.

There are limited clinical data on the use of E/C/F/TAF in HIV/HBV co-infected patients who aretreatment-naïve.

In studies in treatment-naïve adult patients, E/C/F/TAF was associated with smaller reductions in bonemineral density (BMD) compared to E/C/F/TDF through 144 weeks of treatment as measured by dualenergy X ray absorptiometry (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).

Small improvements in BMD were noted at 48 weeks after switching to E/C/F/TAF compared tomaintaining the tenofovir disoproxil fumarate-containing regimen.

In Odefsey studies in virologically suppressed adult patients, increases in BMD were noted at96 weeks after switching to Odefsey compared to minimal changes with maintaining FTC/RPV/TDFor EFV/FTC/TDF at the hip (mean change 1.6% for Odefsey versus -0.6% for FTC/RPV/TDF,p < 0.001; 1.8% for Odefsey versus -0.6% for EFV/FTC/TDF, p < 0.001) and the spine (mean change2.0% for Odefsey versus -0.3% for FTC/RPV/TDF, p < 0.001; 1.7% for Odefsey versus 0.1% for

EFV/FTC/TDF, p < 0.001).

In studies in treatment-naïve adult patients, E/C/F/TAF was associated with lower impact on renalsafety parameters (as measured after 144 weeks treatment by eGFRCG and urine protein to creatinineratio [UPCR] and after 96 weeks treatment by urine albumin to creatinine ratio [UACR]) compared to

E/C/F/TDF. Through 144 weeks of treatment, no subject discontinued E/C/F/TAF due to atreatment-emergent renal adverse event compared with 12 subjects who discontinued E/C/F/TDF(p < 0.001). In studies in virologically suppressed adult patients, through 96 weeks of treatment therewere minimal changes or decreases in albuminuria (UACR) in patients receiving Odefsey comparedwith increases from baseline in patients who stayed on FTC/RPV/TDF or EFV/FTC/TDF. See alsosection 4.4.

Emtricitabine + tenofovir alafenamide regimen

In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of E/C/F/TAF FDC tablet wereevaluated in an open-label study of 50 HIV-1 infected, treatment-naïve adolescents. Patients had amean age of 15 years (range 12-17), were 56% female, 12% Asian, and 88% Black. At baseline,median plasma HIV-1 RNA was 4.7 log10 copies/mL, median CD4+ cell count was 456 cells/mm3(range 95 to 1,110), and median CD4+% was 23% (range 7-45). Overall, 22% had baseline plasma

HIV-1 RNA > 100,000 copies/mL.

At 48 weeks, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL, similar to response rates in studiesof treatment-naïve HIV-1 infected adults. No emergent resistance to E/C/F/TAF was detected through

Week 48.

Rilpivirine-containing regimen

The pharmacokinetics, safety, tolerability, and efficacy of rilpivirine 25 mg once daily, in combinationwith an investigator-selected BR containing two NRTIs, were evaluated in Study TMC278-C213, asingle-arm, open-label Phase 2 study in antiretroviral-naïve HIV-1 infected paediatric patients 12 to< 18 years of age and weighing at least 32 kg. The median duration of exposure for patients was63.5 weeks.

Thirty-six patients had a median age of 14.5 years and were 55.6% female, 88.9% Black, and 11.1%

Asian. The median baseline plasma HIV-1 RNA was 4.8 log10 copies/mL, and the median baseline

CD4+ cell count was 414 cells/mm3. The proportion of patients with HIV-1 RNA < 50 copies/mL at

Week 48 (TLOVR) was 72.2% (26/36). The combination of NRTIs most frequently used togetherwith rilpivirine was FTC/TDF (24 subjects [66.7%]).

The proportion of responders was higher in subjects with a baseline viral load ≤ 100,000 copies/mL(78.6%, 22/28) as compared to those with a baseline viral load > 100,000 copies/mL (50.0%, 4/8).

The proportion of virologic failures was 22.2% (8/36).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Odefsey 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).

Rilpivirine (one of the components of Odefsey) in combination with a background regimen wasevaluated in Study TMC114HIV3015 in 19 pregnant women during the 2nd and 3rd trimesters, andpostpartum. The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a partof an antiretroviral regimen was approximately 30% lower during pregnancy compared withpostpartum (6-12 weeks). The virologic response was generally preserved throughout the study: of the12 patients that completed the study, 10 patients were suppressed at the end of the study; in the other2 patients an increase in viral load was observed only postpartum, for at least 1 patient due tosuspected suboptimal adherence. No mother to child transmission occurred in all 10 infants born tothe mothers who completed the study and for whom the HIV status was available. Rilpivirine waswell tolerated during pregnancy and postpartum. There were no new safety findings compared withthe known safety profile of rilpivirine in HIV-1 infected adults (see sections 4.4 and 5.2).

Odefsey: Emtricitabine and tenofovir alafenamide exposures were bioequivalent when comparing one

Odefsey 200/25/25 mg film-coated tablet to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide(150/150/200/10 mg) fixed-dose combination tablet following single dose administration to healthysubjects (n = 82) under fed conditions. Rilpivirine exposures were bioequivalent when comparing

Odefsey 200/25/25 mg to one rilpivirine (as hydrochloride) 25 mg film-coated tablet following singledose administration to healthy subjects (n = 95) under fed conditions.

Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasmaconcentrations occurring at 1 to 2 hours post-dose. Following multiple dose oral administration ofemtricitabine to 20 HIV-1 infected subjects, the (mean ± SD) area-under the plasmaconcentration-time curve over a 24-hour dosing interval (AUC) was 10.0 ± 3.1 h*µg/mL. The meansteady-state plasma trough concentration at 24 hours post-dose was equal to or greater than the meanin vitro IC90 value for anti-HIV-1 activity. The absolute bioavailability of emtricitabine from 200 mghard capsules was estimated to be 93%. Emtricitabine systemic exposure was unaffected whenemtricitabine was administered with food.

After oral administration, the maximum plasma concentration of rilpivirine is generally achievedwithin 4 to 5 hours. The absolute bioavailability of rilpivirine is unknown. Relative to fastingconditions, the administration of Odefsey to healthy adult subjects with food resulted in increasedrilpivirine exposure (AUC) by 13-72%.

Tenofovir alafenamide is rapidly absorbed following oral administration, with peak plasmaconcentrations occurring at 15-45 minutes post-dose. Relative to fasting conditions, the administrationof Odefsey to healthy adult subjects with food resulted in increased tenofovir alafenamide exposure(AUC) by 45-53%.

It is recommended that Odefsey be taken with food.

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent ofconcentration over the range of 0.02-200 µg/mL.

In vitro binding of rilpivirine to human plasma proteins is approximately 99.7%, primarily to albumin.

In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentrationover the range of 0.01-25 µg/mL. Ex vivo binding of tenofovir alafenamide to human plasma proteinsin samples collected during clinical studies was approximately 80%.

The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3’-sulfoxidediastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form2’-O-glucuronide (approximately 4% of dose). Emtricitabine did not inhibit in vitro drug metabolismmediated by any of the major human CYP isoforms involved in drug biotransformation. Also,emtricitabine did not inhibit uridine-5’-diphosphoglucuronyl transferase (UGT), the enzymeresponsible for glucuronidation.

In vitro experiments indicate that rilpivirine hydrochloride primarily undergoes oxidative metabolismmediated by the CYP3A system.

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 totenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV targetcells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide ishydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the activemetabolite tenofovir diphosphate. In human clinical studies, a 10 mg oral dose of tenofoviralafenamide given with emtricitabine, cobicistat and elvitegravir resulted in tenofovir diphosphateconcentrations > 4-fold higher in PBMCs and > 90% lower concentrations of tenofovir in plasma ascompared to a 245 mg oral dose of tenofovir disoproxil (as fumarate) given with emtricitabine,cobicistat and elvitegravir.

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or

CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4. Upon co-administrationwith the moderate CYP3A inducer probe efavirenz, tenofovir alafenamide exposure was notsignificantly affected. Following administration of tenofovir alafenamide, plasma [14C] -radioactivityshowed a time-dependent profile, with tenofovir alafenamide as the most abundant species in theinitial few hours and uric acid in the remaining period.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved inurine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabinedose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately10 hours.

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

Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminatedin urine. Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. Tenofovir isrenally eliminated by both glomerular filtration and active tubular secretion.

Age, gender and ethnicity

No clinically relevant pharmacokinetic differences due to age, gender or ethnicity have been identifiedfor emtricitabine, rilpivirine or tenofovir alafenamide.

The pharmacokinetics of rilpivirine in antiretroviral-naïve HIV-1 infected paediatric patients 12 to< 18 years of age receiving rilpivirine 25 mg once daily was comparable to that in treatment-naïve

HIV-1 infected adults receiving rilpivirine 25 mg once daily. There was no impact of body weight onrilpivirine pharmacokinetics in paediatric patients in Study C213 (33 to 93 kg), similar to what wasobserved in adults. The pharmacokinetics of rilpivirine in paediatric patients < 12 years of age isunder investigation.

Exposures of emtricitabine and tenofovir alafenamide given with elvitegravir + cobicistat achieved in24 paediatric patients aged 12 to < 18 years were similar to exposures achieved in treatment-naïveadults (Table 6).

Table 6: Pharmacokinetics of emtricitabine and tenofovir alafenamide in antiretroviral-naïveadolescents and adults

Adolescents Adults

Emtricitabine + tenofovir alafenamide Emtricitabine + tenofovir alafenamide

FTCa TAFb TFVb FTCa TAFc TFVc

AUCtau (ng*h/mL) 14,424.4 (23.9) 242.8 (57.8) 275.8 (18.4) 11,714.1 (16.6) 206.4 (71.8) 292.6 (27.4)

Cmax (ng/mL) 2,265.0 (22.5) 121.7 (46.2) 14.6 (20.0) 2,056.3 (20.2) 162.2 (51.1) 15.2 (26.1)

Ctau (ng/mL) 102.4 (38.9)b N/A 10.0 (19.6) 95.2 (46.7) N/A 10.6 (28.5)

FTC = emtricitabine; TAF = tenofovir alafenamide; TFV = tenofovir, N/A = not applicable

Data are presented as mean (%CV).

a n = 24 adolescents (GS-US-292-0106); n = 19 adults (GS-US-292-0102).

b n = 23 adolescents (GS-US-292-0106, population PK analysis).

c n = 539 (TAF) or 841 (TFV) adults (GS-US-292-0111 and GS-US-292-0104, population PK analysis).

No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics wereobserved between healthy subjects and patients with severe renal impairment (estimated

CrCl ≥ 15 mL/min and < 30 mL/min) in a Phase 1 study of tenofovir alafenamide. In a separate

Phase 1 study of emtricitabine alone, mean systemic emtricitabine exposure was higher in patientswith severe renal impairment (estimated CrCl < 30 mL/min) (33.7 µg*h/mL) than in subjects withnormal renal function (11.8 µg*h/mL). The safety of emtricitabine + tenofovir alafenamide has notbeen 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 emtricitabine + tenofovir alafenamide incombination with elvitegravir + cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in Study

GS-US-292-1825 were significantly higher than in patients with normal renal function. No clinicallyrelevant differences in tenofovir alafenamide pharmacokinetics were observed in patients withend 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 chronichaemodialysis receiving emtricitabine + tenofovir alafenamide, given with elvitegravir + cobicistat asa fixed-dose combination tablet (see section 4.8).

There are no pharmacokinetic data on emtricitabine or tenofovir alafenamide in patients with end stagerenal disease (estimated CrCl < 15 mL/min) not on chronic haemodialysis. The safety of emtricitabineand tenofovir alafenamide has not been established in these patients.

The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renalelimination of rilpivirine is negligible. In patients with severe renal impairment or end-stage renaldisease, plasma concentrations may be increased due to alteration of drug absorption, distributionand/or metabolism secondary to renal dysfunction. As rilpivirine is highly bound to plasma proteins,it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis (seesection 4.9).

The pharmacokinetics of emtricitabine have not been studied in patients with varying degrees ofhepatic insufficiency; however, emtricitabine is not significantly metabolised by liver enzymes, so theimpact of liver impairment should be limited.

Rilpivirine hydrochloride is primarily metabolised and eliminated by the liver. In a study comparing8 patients with mild hepatic impairment (Child-Pugh Class A) to 8 matched controls and 8 patientswith moderate hepatic impairment (Child-Pugh Class B) to 8 matched controls, the multiple doseexposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher inpatients with moderate hepatic impairment. However, it may not be excluded that thepharmacologically active, unbound, rilpivirine exposure is significantly increased in moderateimpairment. Rilpivirine has not been studied in patients with severe hepatic impairment (Child Pugh

Class C) (see section 4.2).

Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolitetenofovir were not observed in patients with mild or moderate hepatic impairment. In patients withsevere hepatic impairment, total plasma concentrations of tenofovir alafenamide and tenofovir arelower 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 andnormal hepatic function are similar.

The pharmacokinetics of emtricitabine, rilpivirine and tenofovir alafenamide have not been fullyevaluated in patients co-infected with hepatitis B and/or C virus.

After taking rilpivirine 25 mg once daily as part of an antiretroviral regimen, the total exposure ofrilpivirine was lower during pregnancy (similar for the 2nd and 3rd trimester) compared withpostpartum. The decrease in the unbound free fraction of rilpivirine exposure (i.e., active) duringpregnancy compared to postpartum was less pronounced than for total exposure of rilpivirine.

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

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studiesof safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity toreproduction and development.

Non-clinical data on rilpivirine hydrochloride reveal no special hazard for humans based on studies ofsafety pharmacology, drug disposition, genotoxicity, carcinogenic potential, toxicity to reproductionand development. Liver toxicity associated with liver enzyme induction was observed in rodents. Indogs cholestasis-like effects were noted.

Carcinogenicity studies with rilpivirine in mice and rats revealed tumorigenic potential specific forthese species, but are regarded as of no relevance for humans.

Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primarytarget organs of toxicity. Bone toxicity was observed as reduced bone mineral density in rats and dogsat tenofovir exposures at least four times greater than those expected after administration of Odefsey.

A minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide andtenofovir exposures of approximately 4 and 17 times greater, respectively, than those expected afteradministration of Odefsey.

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 tenofoviralafenamide compared to tenofovir disoproxil fumarate, carcinogenicity studies and a ratperi-postnatal study were conducted only with tenofovir disoproxil fumarate. No special hazard forhumans was revealed in conventional studies of carcinogenic potential and toxicity to reproductionand development. Reproductive toxicity studies in rats and rabbits showed no effects on mating,fertility, pregnancy or foetal parameters. However, tenofovir disoproxil fumarate reduced the viabilityindex and weight of pups in a peri-postnatal toxicity study at maternally toxic doses.

Croscarmellose sodium

Lactose (as monohydrate)

Magnesium stearate

Microcrystalline cellulose

Polysorbate 20

Povidone

Macrogol

Polyvinyl alcohol

Talc

Titanium dioxide (E171)

Iron oxide black (E172)

Not applicable.

3 years.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

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 bottlecontains silica gel desiccant and polyester coil.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets andouter cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/16/1112/001

EU/1/16/1112/002

Date of first authorisation: 21 June 2016

Date of latest renewal: 14 January 2021

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

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