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Odefsey (emtricitabine / rilpivirine hydrochloride...) – Summary of product characteristics - J05AR19

Updated on site: 08-Oct-2017

Medication nameOdefsey
ATC CodeJ05AR19
Substanceemtricitabine / rilpivirine hydrochloride / tenofovir alafenamide
ManufacturerGilead Sciences International Ltd 

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

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

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 200 mg of emtricitabine, rilpivirine hydrochloride equivalent to

25 mg of rilpivirine and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide.

Excipients with known effect

Each tablet contains 189.8 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Film-coated tablet.

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

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Odefsey is indicated for the treatment of adults and adolescents (aged 12 years and older with body weight at least 35 kg) infected with human immunodeficiency virus-1 (HIV-1) without known mutations 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 (see sections 4.2, 4.4 and 5.1).

4.2Posology and method of administration

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

Posology

Adults and adolescents aged 12 years and older, weighing at least 35 kg

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 patient should take Odefsey with food as soon as possible and resume the normal dosing schedule. If a patient misses a dose of Odefsey by more than 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

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

Elderly

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

Renal impairment

No dose adjustment of Odefsey is required in adults or in adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) ≥ 30 mL/min.

Odefsey should not be initiated in patients with estimated CrCl < 30 mL/min, as there are no data available regarding the use of Odefsey in this population (see sections 5.1 and 5.2).

Odefsey should be discontinued in patients with estimated creatinine clearance that declines below 30 mL/min during treatment (see sections 5.1 and 5.2).

Hepatic impairment

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 with moderate hepatic impairment. Odefsey has not been studied in patients with severe hepatic impairment (Child Pugh Class C); therefore, Odefsey 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 Odefsey in children younger than 12 years of age, or weighing < 35 kg, have not yet been established. No data are available.

Method of administration

Odefsey should be taken orally, once daily with food (see section 5.2). The film-coated tablet should not be chewed, crushed or split.

4.3Contraindications

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 decreases in rilpivirine plasma concentrations (due to cytochrome P450 [CYP]3A enzyme induction or gastric pH 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).

4.4Special 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.

Virologic failure and development of resistance

There are insufficient data to justify the use in patients with prior NNRTI failure. Resistance testing and/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 disoproxil fumarate+rilpivirine with a baseline viral load > 100,000 HIV-1 RNA copies/mL had a greater risk of

virologic failure (17.6% with rilpivirine versus 7.6% with efavirenz) compared to patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies/mL (5.9% with rilpivirine versus 2.4% with efavirenz). The virologic failure rate in patients treated with emtricitabine/tenofovir disoproxil fumarate+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 new virologic failures from the Week 48 to Week 96 analysis between rilpivirine and efavirenz arms was not statistically significant. Patients with a baseline viral load > 100,000 HIV-1 RNA copies/mL who experienced virologic failure exhibited a higher rate of treatment emergent resistance to the NNRTI class. More patients who failed virologically on rilpivirine than who failed virologically on efavirenz developed 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 with these data (for details see section 5.1).

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

Cardiovascular

At supratherapeutic doses (75 mg once daily and 300 mg once daily), rilpivirine has been associated with 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 relevant effect on QTc. Odefsey should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.

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 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 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 Odefsey 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 Odefsey 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.

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 (hyperlactatemia, hyperlipasemia). 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 etiology, 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) 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 Odefsey 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).

Co-administration of other medicinal products

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 tenofovir alafenamide, lamivudine, tenofovir disoproxil or adefovir dipivoxil (see section 4.5).

Excipients

Odefsey contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

4.5Interaction with other medicinal products and other forms of interaction

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

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.

Rilpivirine

Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may 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 not significantly affect the pharmacokinetics of digoxin. Additionally, in a clinical drug-drug interaction study with tenofovir alafenamide, which is more sensitive to intestinal P-gp inhibition, rilpivirine did not affect tenofovir alafenamide exposures when administered concurrently, indicating that rilpivirine is 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 clinical implications of this finding are currently unknown.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). Medicinal products 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 decreased plasma 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 products that inhibit P-gp and BCRP activity (e.g., ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, ciclosporin) is expected to increase the absorption and plasma concentration of tenofovir alafenamide. It is not known whether the co-administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., febuxostat) would increase systemic exposure to tenofovir.

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 CYP3A4 in vivo. Tenofovir alafenamide is a substrate of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3

in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP1B1 and OATP1B3.

Concomitant use contraindicated

Co-administration of Odefsey and medicinal products that induce CYP3A has been observed to decrease the plasma concentrations of rilpivirine which could potentially lead to loss of virologic response 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 plasma concentrations of rilpivirine (due to an increase in gastric pH) which could potentially lead to loss of virologic 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 been observed to increase rilpivirine plasma concentrations.

QT prolonging medicinal products

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

Other interactions

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 of other UGT enzymes. Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGT substrate in vitro.

Interactions between Odefsey or its individual component(s) and co-administered medicinal products are 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 medicinal products

Medicinal product by

Effects on medicinal product levels.

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with Odefsey

 

Cmax, Cmin

 

ANTI-INFECTIVES

 

 

Antifungals

 

 

Ketoconazole (400 mg once

Ketoconazole:

Co-administration is not

daily)/ Rilpivirine1

AUC: ↓ 24%

recommended.

 

Cmin: ↓ 66%

 

 

Cmax: ↔

 

 

Rilpivirine:

 

 

AUC: ↑ 49%

 

 

Cmin: ↑ 76%

 

 

Cmax: ↑ 30%

 

 

Inhibition of CYP3A

 

 

Tenofovir Alafenamide:

 

 

AUC: ↑

 

 

Cmax: ↑

 

 

Inhibition of P-gp

 

 

Interaction not studied with tenofovir

 

 

alafenamide. Co-administration of

 

 

ketoconazole is expected to increase

 

 

plasma concentrations of tenofovir

 

Medicinal product by

Effects on medicinal product levels.

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with Odefsey

 

Cmax, Cmin

 

 

alafenamide (inhibition of P-gp).

 

Fluconazole

Interaction not studied with any of the

Co-administration is not

Itraconazole

components of Odefsey.

recommended.

Posaconazole

Co-administration of these antifungal

 

Voriconazole

agents is expected to increase plasma

 

 

concentrations of rilpivirine

 

 

(inhibition of CYP3A) and tenofovir

 

 

alafenamide (inhibition of P-gp).

 

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

 

 

Tenofovir Alafenamide:

 

 

AUC: ↓

 

 

Cmax: ↓

 

 

Induction of P-gp

 

 

Interaction not studied with tenofovir

 

 

alafenamide. Co-administration is

 

 

likely to cause significant decreases

 

 

in the plasma concentrations of

 

 

tenofovir alafenamide (induction of

 

 

P-gp).

 

Rifapentine

Interaction not studied with any of the

Co-administration is

 

components of Odefsey.

contraindicated.

 

Co-administration is likely to cause

 

 

significant decreases in the plasma

 

 

concentrations of rilpivirine

 

 

(induction of CYP3A) and tenofovir

 

 

alafenamide (induction of P-gp).

 

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

 

Medicinal product by

Effects on medicinal product levels.

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with Odefsey

 

Cmax, Cmin

 

 

Tenofovir Alafenamide:

 

 

AUC: ↓

 

 

Cmax: ↓

 

 

Induction of P-gp

 

 

Interaction not studied with tenofovir

 

 

alafenamide. Co-administration is

 

 

likely to cause significant decreases

 

 

in the plasma concentrations of

 

 

tenofovir alafenamide (induction of

 

 

P-gp).

 

Macrolide antibiotics

 

 

Clarithromycin

Interaction not studied with any of the

Co-administration is not

Erythromycin

components of Odefsey. The

recommended.

 

combination of Odefsey with these

 

 

macrolide antibiotics may cause an

 

 

increase in the plasma concentrations

 

 

of rilpivirine (inhibition of CYP3A)

 

 

and tenofovir alafenamide (inhibition

 

 

of P-gp).

 

Antiviral agents

 

 

Boceprevir

Interaction not studied with any of the

Co-administration is not

 

components of Odefsey.

recommended.

 

 

Boceprevir has the potential to

 

 

adversely affect the intracellular

 

 

activation and clinical antiviral

 

 

efficacy of tenofovir alafenamide

 

 

based on in vitro data.

Ledipasvir/Sofosbuvir

Ledipasvir:

No dose adjustment is required.

(90 mg/400 mg once daily)/

AUC: ↑ 2%

 

Rilpivirine

Cmin: ↑ 2%

 

 

Cmax: ↑ 1%

 

 

Sofosbuvir:

 

 

AUC: ↑ 5%

 

 

Cmax: ↓ 4%

 

 

Sofosbuvir metabolite GS-331007:

 

 

AUC: ↑ 8%

 

 

Cmin: ↑ 10%

 

 

Cmax: ↑ 8%

 

 

Rilpivirine:

 

 

AUC: ↓ 5%

 

 

Cmin: ↓ 7%

 

 

Cmax: ↓ 3%

 

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: ↔

 

 

 

 

Medicinal product by

Effects on medicinal product levels.

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with Odefsey

 

Cmax, Cmin

 

 

Velpatasvir:

 

 

AUC: ↔

 

 

Cmin: ↔

 

 

Cmax: ↔

 

 

Rilpivirine:

 

 

AUC: ↔

 

 

Cmin: ↔

 

 

Cmax: ↔

 

Sofosbuvir/Velpatasvir

Interaction not studied.

 

(400 mg/100 mg once daily)/

Expected:

 

Tenofovir alafenamide

Tenofovir alafenamide:

 

 

AUC: ↑

 

 

Cmax: ↑

 

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: ↔

 

Simeprevir (150 mg once daily)/

Simeprevir:

No dose adjustment is required.

Rilpivirine

AUC: ↑ 6%

 

 

Cmin: ↓ 4%

 

 

Cmax: ↑ 10%

 

 

Rilpivirine:

 

 

AUC: ↑ 12%

 

 

Cmin: ↑ 25%

 

 

Cmax: ↑ 4%

 

ANTICONVULSANTS

 

 

Carbamazepine

Interaction not studied with any of the

Co-administration is

Oxcarbazepine

components of Odefsey.

contraindicated.

Phenobarbital

Co-administration may cause

 

Phenytoin

significant decreases in the plasma

 

 

concentrations of rilpivirine

 

 

(induction of CYP3A) and tenofovir

 

 

alafenamide (induction of P-gp).

 

GLUCOCORTICOIDS

 

 

Dexamethasone (systemic, except

Interaction not studied with any of the

Co-administration is

for single dose use)

components of Odefsey. Significant

contraindicated.

 

dose dependent decreases in

 

 

rilpivirine plasma concentrations 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%

 

Medicinal product by

Effects on medicinal product levels.

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with Odefsey

 

Cmax, Cmin

 

 

Reduced absorption, increase in

 

 

gastric pH

 

Lansoprazole

Interaction not studied with any of the

Co-administration is

Rabeprazole

components of Odefsey. Significant

contraindicated.

Pantoprazole

decreases in rilpivirine plasma

 

Esomeprazole

concentrations are expected (reduced

 

Dexlansoprazole

absorption, increase in gastric pH).

 

HERBAL PRODUCTS

 

 

St. John’s wort (Hypericum

Interaction not studied with any of the

Co-administration is

perforatum)

components of Odefsey.

contraindicated.

 

Co-administration may cause

 

 

significant decreases in the plasma

 

 

concentrations of rilpivirine

 

 

(induction of CYP3A) and tenofovir

 

 

alafenamide (induction of P-gp).

 

H2-RECEPTOR ANTAGONISTS

 

 

Famotidine (40 mg single dose

Rilpivirine:

Only H2-receptor antagonists that

taken 12 hours before rilpivirine)/

AUC: ↓ 9%

can be dosed once daily should be

Rilpivirine1

Cmin: N/A

used. A strict dosing schedule with

 

Cmax: ↔

intake of the H2-receptor

 

 

antagonists at least 12 hours before

Famotidine (40 mg single dose

Rilpivirine:

or at least 4 hours after Odefsey

taken 2 hours before rilpivirine)/

AUC: ↓ 76%

should be used.

Rilpivirine1

Cmin: N/A

 

 

Cmax: ↓ 85%

 

 

Reduced absorption, increase in

 

 

gastric pH

 

Famotidine (40 mg single dose

Rilpivirine:

 

taken 4 hours after rilpivirine)/

AUC: ↑ 13%

 

Rilpivirine1

Cmin: N/A

 

 

Cmax: ↑ 21%

 

Cimetidine

Interaction not studied with any of the

 

Nizatidine

components of Odefsey.

 

Ranitidine

Co-administration may cause

 

 

significant decreases in rilpivirine

 

 

plasma concentrations (reduced

 

 

absorption, increase in gastric pH).

 

ANTACIDS

 

 

Antacids (e.g., aluminium or

Interaction not studied with any of the

Antacids should only be

magnesium hydroxide, calcium

components of Odefsey.

administered either at least 2 hours

carbonate)

Co-administration may cause

before or at least 4 hours after

 

significant decreases in rilpivirine

Odefsey.

 

plasma concentrations (reduced

 

 

absorption, 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: ↔*

 

Medicinal product by

Effects on medicinal product levels.

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with Odefsey

 

Cmax, Cmin

 

 

Cmax: ↔*

 

 

*based on historic controls

 

Norgestimate

Norelgestromin:

No dose adjustment is required.

(0.180/0.215/0.250 mg once

AUC: ↔

 

daily)/ Ethinylestradiol (0.025 mg

Cmin: ↔

 

once daily)/

Cmax: ↔

 

Emtricitabine/Tenofovir

Norgestrel:

 

alafenamide (200/25 mg once

 

daily)

AUC: ↔

 

 

Cmin: ↔

 

 

Cmax: ↔

 

 

Ethinylestradiol:

 

 

AUC: ↔

 

 

Cmin: ↔

 

 

Cmax: ↔

 

NARCOTIC ANALGESICS

 

 

Methadone (60-100 mg once

R(-) methadone:

No dose adjustments are required.

daily, individualised dose)/

AUC: ↓ 16%

 

Rilpivirine

Cmin: ↓ 22%

Clinical monitoring is

 

Cmax: ↓ 14%

recommended as methadone

 

S(+) methadone:

maintenance therapy may need to

 

be adjusted in some patients.

 

AUC: ↓ 16%

 

 

Cmin: ↓ 21%

 

 

Cmax: ↓ 13%

 

 

Rilpivirine:

 

 

AUC: ↔*

 

 

Cmin: ↔*

 

 

Cmax: ↔*

 

 

*based on historic controls

 

ANALGESICS

 

 

Paracetamol (500 mg single

Paracetamol:

No dose adjustment is required.

dose)/ 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 the

Co-administration should be used

 

components of Odefsey.

with caution.

 

A risk for increases in dabigatran

 

 

plasma concentrations cannot be

 

 

excluded (inhibition of intestinal

 

 

P-gp).

 

IMMUNOSUPPRESSANTS

 

 

Ciclosporin

Interaction not studied with any of the

Co-administration is not

 

components of Odefsey.

recommended.

 

Co-administration of ciclosporin is

 

Medicinal product by

Effects on medicinal product levels.

Recommendation concerning

therapeutic areas

Mean percent change in AUC,

co-administration with Odefsey

 

Cmax, Cmin

 

 

expected to increase plasma

 

 

concentrations of rilpivirine

 

 

(inhibition of CYP3A) and tenofovir

 

 

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 the

No dose adjustment is required.

Tadalafil

components of Odefsey. These are

 

 

medicinal products within class where

 

 

similar interactions could be

 

 

predicted.

 

HYPNOTICS/SEDATIVES

 

 

Midazolam (2.5 mg, orally, once

Midazolam:

No dose adjustment is required.

daily)/ Tenofovir alafenamide

AUC: ↑ 12%

 

 

Cmin: N/A

 

 

Cmax: ↑ 2%

 

Midazolam (1 mg, intravenously,

Midazolam:

 

once daily)/ Tenofovir

AUC: ↑ 8%

 

alafenamide

Cmin: N/A

 

 

Cmax: ↓ 1%

 

N/A = not applicable

 

 

1This interaction study has been performed with a dose higher than the recommended dose for rilpivirine hydrochloride assessing the maximal effect on the co-administered medicinal product. The dosing recommendation is applicable to the recommended dose of rilpivirine of 25 mg once daily.

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

Studies conducted with other medicinal products

Based on drug-drug interaction studies conducted with the components of Odefsey, no clinically significant interactions are expected when Odefsey is combined with the following medicinal products: buprenorphine, naloxone, norbuprenorphine and norgestimate/ethinylestradiol.

4.6Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

The use of Odefsey should be accompanied by the use of effective contraception (see section 4.5).

Pregnancy

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

Studies in animals have shown no reproductive toxicity with emtricitabine or tenofovir alafenamide (see section 5.3). Studies in animals have shown limited placenta passage of rilpivirine. It is not known whether placental transfer of rilpivirine occurs in pregnant women. There was no teratogenicity with rilpivirine in rats and rabbits.

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

Breast-feeding

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

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

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

4.7Effects on ability to drive and use machines

Patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with the components of Odefsey (see section 4.8). This should be considered when assessing a patient's ability to drive or operate machinery.

4.8Undesirable effects

Summary of the safety profile

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

No new adverse reactions were identified through Week 48 in 2 clinical studies of virologically suppressed patients who switched from emtricitabine/rilpivirine/tenofovir disoproxil fumarate

(FTC/RPV/TDF) to Odefsey (Study GS-US-366-1216) or from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) to Odefsey (Study GS-US-366-1160).

Tabulated summary of adverse reactions

Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies in which 2,396 patients received emtricitabine+tenofovir alafenamide given with elvitegravir+cobicistat as a fixed-dose combination tablet, pooled data from 686 patients who received rilpivirine 25 mg once daily in combination with other antiretroviral medicinal products in the controlled studies TMC278-C209 and TMC278-C215, 754 patients who received Odefsey in Studies GS-US-366-1216 and GS-US-366-1160, and on post-marketing experience with FTC/RPV/TDF.

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), uncommon (≥ 1/1,000 to < 1/100) or rare (≥ 1/10,000 to < 1/1,000).

Table 2: Tabulated list of adverse reactions

Frequency

Adverse reaction

Blood and lymphatic system disorders

Common:

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

Uncommon:

anaemia2

Immune system disorders

 

Uncommon:

immune reactivation syndrome1

Metabolism and nutrition disorders

Very common:

increased total cholesterol (fasted)1, increased LDL-cholesterol (fasted)1

Common:

decreased appetite1, increased triglycerides (fasted)1

Psychiatric disorders

 

Very common:

insomnia1

Common:

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

Nervous system disorders

 

Very common:

headache1, 3, dizziness1, 3

Common:

somnolence1

Gastrointestinal disorders

 

Very common:

nausea1, 3, increased pancreatic amylase1

Common:

abdominal pain1, 3, vomiting1, 3, increased lipase1, abdominal discomfort1, dry

mouth1, flatulence3, diarrhoea3

 

Uncommon:

dyspepsia3

Hepatobiliary disorders

 

Very common:

increased transaminases (AST and/or ALT)1

Common:

increased bilirubin1

Skin and subcutaneous tissue disorders

Common:

rash1, 3

Uncommon:

severe skin reactions with systemic symptoms4, 5, angioedema2, 6, pruritus3

Musculoskeletal and connective tissue disorders

Uncommon:

arthralgia3

General disorders and administration site conditions

Common:

fatigue1, 3

1Adverse reactions identified from rilpivirine clinical studies.

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

3Adverse reactions identified from emtricitabine+tenofovir alafenamide clinical studies.

4Adverse reaction identified through post-marketing surveillance of emtricitabine/rilpivirine/tenofovir disoproxil fumarate

5This adverse reaction was not observed in randomised controlled clinical studies for emtricitabine/rilpivirine/tenofovir disoproxil fumarate, so the frequency category was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine/rilpivirine/tenofovir disoproxil fumarate or all of its components in randomised controlled clinical studies (n = 1261). See description of selected adverse reactions.

6This adverse reaction was identified through post-marketing surveillance for emtricitabine but was not observed in randomised controlled clinical studies in adults or paediatric HIV clinical studies of emtricitabine. The frequency

category of uncommon was estimated from a statistical calculation based on the total number of patients exposed to emtricitabine in these clinical studies (n = 1,563).

Laboratory abnormalities

Changes in serum creatinine for rilpivirine-containing regimens

The pooled data from the Phase 3 TMC278-C209 and TMC278-C215 studies of treatment-naïve patients 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 and decrease in eGFR occurred within the first four weeks of treatment. Over 96 weeks of treatment with rilpivirine 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 were observed. In patients who entered the studies with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in patients with normal renal function. These increases do not reflect a change in actual glomerular filtration rate (GFR).

Changes in lipid laboratory tests

In studies in treatment-naïve patients receiving emtricitabine+tenofovir alafenamide (FTC+TAF) or emtricitabine+tenofovir disoproxil fumarate (FTC+TDF), both given with elvitegravir+cobicistat as a fixed-dose combination tablet, 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 these 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 144 in total cholesterol to HDL-cholesterol ratio was 0.2 (-0.3, 0.7) in patients receiving FTC+TAF and 0.1 (-0.4, 0.6) in patients receiving FTC+TDF (p = 0.006 for the difference between treatment groups).

Switching from a TDF-based regimen to Odefsey may lead to slight increases in lipid parameters. In a study 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 relevant changes from baseline in median fasting values for total cholesterol to HDL ratio were observed in either treatment arm at Week 48. In a study of virologically suppressed patients switching from EFV/FTC/TDF to Odefsey (Study GS-US-366-1160), decreases from baseline were observed in the fasting values of total cholesterol, HDL cholesterol, and triglycerides in the Odefsey arm; no clinically relevant changes from baseline in median fasting values for total cholesterol to HDL ratio or direct LDL cholesterol were observed in either treatment arm at Week 48.

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 the

rilpivirine arm (+18.4 ± 8.36 nmol/L) than in the efavirenz arm (+54.1 ± 7.24 nmol/L). Mean values for the rilpivirine arm for both basal and ACTH-stimulated cortisol at Week 96 were within the normal range. These changes in adrenal safety parameters were not clinically relevant. There were no clinical signs or symptoms suggestive of adrenal or gonadal dysfunction in adults.

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) 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).

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).

Severe skin reactions

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

Paediatric population

The safety of emtricitabine+tenofovir alafenamide was evaluated through 48 weeks in an open-label clinical study (GS-US-292-0106) in which 50 HIV-1 infected, treatment-naïve paediatric patients aged 12 to < 18 years received emtricitabine+tenofovir alafenamide in combination with elvitegravir+cobicistat as a fixed-dose combination tablet. In this study, the safety profile in adolescent 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 patients discontinued rilpivirine due to adverse reactions. No new adverse reactions were identified compared to those seen in adults. Most adverse reactions were Grade 1 or 2. Adverse reactions (all grades) of very common frequency were headache, depression, somnolence and nausea. No Grade 3-4 laboratory abnormalities for AST/ALT or Grade 3-4 adverse reactions of transaminase increased were reported (see section 5.1).

Other special populations

Patients with renal impairment

The safety of emtricitabine+tenofovir alafenamide was evaluated through 144 weeks in an open-label clinical study (GS-US-292-0112), in which 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) received emtricitabine+tenofovir alafenamide in combination with elvitegravir+cobicistat as a fixed-dose combination tablet. The safety profile in patients with mild to moderate renal impairment was similar to that in patients with normal renal function (see section 5.1).

Patients co-infected with HIV and HBV

The safety of emtricitabine+tenofovir alafenamide in combination with elvitegravir and cobicistat as a 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 an open-label clinical study (GS-US-292-1249), through Week 48, in which patients were switched from another antiretroviral regimen (which included TDF in 69 of 72 patients) to E/C/F/TAF. Based on these limited data, the safety profile of emtricitabine+tenofovir alafenamide in combination with elvitegravir 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 hepatic enzyme elevation was higher than in patients receiving rilpivirine who were not co-infected. The pharmacokinetic exposure of rilpivirine in co-infected patients was comparable to that in patients without co-infection.

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.

4.9Overdose

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary including observation of the clinical status of the patient 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 be removed by haemodialysis. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis. Since rilpivirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

Administration of activated charcoal may also be used to aid in removal of unabsorbed rilpivirine hydrochloride.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

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. Emtricitabine triphosphate competitively inhibits HIV-1 reverse transcriptase (RT), resulting in deoxyribonucleic acid (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 by non-competitive inhibition of HIV-1 RT. Rilpivirine does not inhibit the human cellular DNA polymerases 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 intracellular activation through hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil fumarate in loading tenofovir into peripheral blood mononuclear cells (PBMCs) (including lymphocytes and other HIV target cells) and macrophages. Intracellular tenofovir is subsequently phosphorylated 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.

Antiviral activity in vitro

The combinations of emtricitabine, rilpivirine, and tenofovir alafenamide were not antagonistic and showed 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 in lymphoblastoid 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 displayed

antiviral activity in cell culture against HIV-1 subtype A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 µM) and showed activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 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 also demonstrated 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 O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL), and showed limited in vitro activity against HIV-2 with EC50 values ranging from 2,510 to 10,830 nM (920 to 3,970 ng/mL.

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, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) and showed activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).

Resistance

Considering all of the available in vitro data and data generated in treatment-naïve patients, the following resistance-associated mutations in HIV-1 RT, when present at baseline, may affect the activity of Odefsey: K65R, K70E, K101E, K101P, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, Y188L, H221Y, F227C, M230I, M230L and the combination of L100I and K103N.

A negative impact by NNRTI mutations other than those listed above (e.g., mutations K103N or L100I as single mutations) cannot be excluded, since this was not studied in vivo in a sufficient number of patients.

As with other antiretroviral medicinal products, resistance testing and/or historical resistance data should 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 different origins and subtypes as well as NNRTI-resistant HIV-1. The most commonly observed amino acid substitutions that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C, and M230I.

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 receiving elvitegravir/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 primary resistance-associated mutations was observed in HIV-1 isolates from 12 of 866 (1.4%) patients treated with 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 that developed 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-1 isolates with emergent resistance in the rilpivirine arm developed concomitant NNRTI and NRTI mutations, most frequently E138K and M184V. The mutations associated with NRTI resistance that developed 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/mL had emerging resistance-associated substitutions and/or phenotypic resistance to rilpivirine (7/288) than patients with baseline viral load > 100,000 copies/mL (30/262).

In virologically suppressed patients

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

Through Week 48, in patients who switched to Odefsey from emtricitabine/rilpivirine/tenofovir disoproxil 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 resistance-associated mutations were detected. Of the patients treated with Odefsey in Study GS-US-366-1216 who had historical evidence of the NNRTI-associated K103N substitution, 9 of 10 patients maintained virologic suppression through 48 weeks and one discontinued prior to Week 48 with HIV-1 RNA

< 50 copies/mL.

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 E/C/F/TAF 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 E/C/F/TAF were identified in HIV-1 or HBV.

Cross-resistance

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

In a panel of 67 HIV-1 recombinant laboratory strains with one resistance-associated mutation at RT positions associated with NNRTI resistance, the only single resistance-associated mutations associated with a loss of susceptibility to rilpivirine were K101P and Y181V/I. The K103N substitution alone did not result in reduced susceptibility to rilpivirine, but the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a reduced 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 phenotypic resistance 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 data

Clinical efficacy of Odefsey was established from studies conducted with emtricitabine+tenofovir alafenamide when given with elvitegravir+cobicistat as an E/C/F/TAF FDC tablet, from studies conducted 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) once daily, both given as FDC tablets.

The mean age was 36 years (range 18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies/mL (range 1.3-7.0) and 23% of patients 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 CD4+ cell counts < 200 cells/mm3.

In Studies GS-US-292-0104 and GS-US-292-0111, E/C/F/TAF 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.

In Study GS-US-292-0109, the efficacy and safety of switching from either EFV/FTC/TDF, FTC/TDF plus atazanavir (boosted by either cobicistat or ritonavir), or E/C/F/TDF to E/C/F/TAF FDC tablet were 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 (range 79-1,951).

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 the baseline 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(n

E/C/F/TAF

E/C/F/TDF

E/C/F/TAF

Baseline

 

(n = 866)

= 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% to

difference

 

 

 

 

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 or

 

 

 

 

 

 

144 window

 

 

 

 

 

 

Discontinued

1%

2%

1%

3%

1%

1%

study drug due

 

 

 

 

 

 

to AE ore

 

 

 

 

 

 

Discontinued

2%

4%

9%

11%

1%

4%

study drug due

 

 

 

 

 

 

to other reasons

 

 

 

 

 

 

and last

 

 

 

 

 

 

available

 

 

 

 

 

 

HIV-1 RNA

 

 

 

 

 

 

< 50 copies/mLf

 

 

 

 

 

 

 

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(n

E/C/F/TAF

 

E/C/F/TDF

E/C/F/TAF

Baseline

 

(n = 866)

= 867)

(n = 866)

 

(n = 867)

(n = 959)

regimen

 

 

 

 

 

 

 

(n = 477)

Missing data

1%

< 1%

1%

 

1%

0%

<1%

during window

 

 

 

 

 

 

 

but on study

 

 

 

 

 

 

 

drug

 

 

 

 

 

 

 

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 (%) of

 

 

 

 

 

 

 

patients with

 

 

 

 

 

 

 

HIV-1 RNA

 

 

 

 

 

 

 

< 50 copies/mL by

 

 

 

 

 

 

 

prior treatment

 

 

 

 

 

 

 

regimend

 

 

 

 

 

 

 

EFV/FTC/TDF

 

 

 

 

 

96%

90%

FTC/TDF plus

 

 

 

 

 

97%

92%

boosted

 

 

 

 

 

 

 

atazanavir

 

 

 

 

 

 

 

E/C/F/TDF

 

 

 

 

 

98%

97%

aWeek 48 window was between Day 294 and 377 (inclusive); Week 144 window was between Day 966 and 1049 (inclusive).

bIn 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).

cP-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 boosted atazanavir, or E/C/F/TDF).

dIncluded 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.

eIncludes 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.

fIncludes 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.

In Studies GS-US-292-0104 and GS-US-292-0111, the rate of virologic success was similar across patient 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 patients and 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 and emtricitabine+tenofovir disoproxil fumarate subset of TMC278-C215).

In the pooled analysis for TMC278-C209 and TMC278-C215 of 1096 patients who received a background regimen (BR) of FTC/TDF, demographic and baseline characteristics were balanced between the rilpivirine and efavirenz (EFV) arms. The median age was 36 years, 78% were male and 62% White and 24% Black/African American. Median plasma HIV-1 RNA was 5.0 log10 copies/mL and median CD4+ cell count was 255 cells/mm3.

Overall response and a subgroup analysis of the virologic response (< 50 HIV-1 RNA copies/mL) at both 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) is 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 in combination 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)

 

 

 

 

 

 

 

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

 

0.2% (1/546)

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 = rilpivirine

aITT TLOVR = Intention to treat time to loss of virologic response.

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

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

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

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

FTC/TDF + rilpivirine hydrochloride was non-inferior in achieving HIV-1 RNA < 50 copies/mL compared 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 were evaluated 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 were evaluated 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 Table 5.

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

 

GS-US-366-1216

GS-US-366-1160

 

Odefsey

FTC/RPV/TDF

Odefsey

EFV/FTC/TDF

 

(n = 316)

(n = 313)b

(n = 438)

(n = 437)

HIV-1 RNA

94%

94%

90%

92%

< 50 copies/mLc

 

 

 

 

Treatment

-0.3% (95% CI: -4.2% to 3.7%)

-2.0% (95% CI: -5.9% to 1.8%)

difference

 

 

 

 

HIV-1 RNA

1%

0%

1%

1%

≥ 50 copies/mLc

 

 

 

 

No virologic data in

6%

6%

9%

7%

Week 48 window

 

 

 

 

Discontinued

2%

1%

3%

1%

study drug due to

 

 

 

 

AE or death and

 

 

 

 

last available

 

 

 

 

HIV-1 RNA

 

 

 

 

< 50 copies/mL

 

 

 

 

Discontinued

4%

4%

5%

5%

study drug due to

 

 

 

 

other reasons and

 

 

 

 

last available

 

 

 

 

HIV-1 RNA

 

 

 

 

< 50 copies/mLd

 

 

 

 

Missing data

< 1%

1%

1%

1%

during window

 

 

 

 

but on study drug

 

 

 

 

aWeek 48 window was between Day 295 and 378 (inclusive).

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

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

dIncludes 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.

At Week 48, switching to Odefsey was noninferior in maintaining HIV-1 RNA < 50 copies/mL when compared 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 48 was 9 cells/mm3 in patients who switched to Odefsey and -1 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 48 was 23 cells/mm3 in patients who switched to Odefsey and 12 cells/mm3 in those who stayed on 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 an open-label clinical study of 242 HIV-1 infected, virologically suppressed patients with mild to moderate 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-five percent of patients were on a treatment regimen that did not contain tenofovir disoproxil fumarate. At baseline, 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.

Patients co-infected with HIV and HBV

In open-label Study GS-US-292-1249, the efficacy and safety of E/C/F/TAF were evaluated in adult patients 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 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 263-1498). 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 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 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. Alanine aminotransferase (ALT) normalisation was achieved in 40% (4/10) of subjects with ALT greater 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 are treatment-naïve.

Changes in measures of bone mineral density

In studies in treatment-naïve adult patients, E/C/F/TAF was associated with smaller reductions in bone mineral density (BMD) compared to E/C/F/TDF through 144 weeks of treatment as measured by dual energy X ray absorptiometry (DXA) analysis of hip (mean change: −0.8% vs −3.4%, p < 0.001) and lumbar spine (mean change: −0.9% vs −3.0%, p < 0.001).

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

In Odefsey studies in virologically suppressed adult patients, increases in BMD were noted at

48 weeks after switching to Odefsey compared to minimal changes with maintaining FTC/RPV/TDF or EFV/FTC/TDF at the hip (mean change 1.0% for Odefsey vs -0.2% for FTC/RPV/TDF, p<0.001; 1.3% for Odefsey vs -0.1% for EFV/FTC/TDF, p<0.001) and the spine (mean change 1.6% for Odefsey vs 0.1% for FTC/RPV/TDF, p<0.001; 1.6% for Odefsey vs -0.1 for EFV/FTC/TDF; p<0.001).

Changes in measures of renal function

In studies in treatment-naïve adult patients, E/C/F/TAF was associated with lower impact on renal safety parameters (as measured after 144 weeks treatment by eGFRCG and urine protein to creatinine ratio [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 a treatment-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 48 weeks of treatment there were decreases in proteinuria (UPCR and UACR) in patients receiving Odefsey compared with minimal changes or increases from baseline in patients who stayed on FTC/RPV/TDF or EFV/FTC/TDF. See also section 4.4.

Paediatric population

Emtricitabine+tenofovir alafenamide regimen

In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of E/C/F/TAF FDC tablet were evaluated in an open-label study of 50 HIV-1 infected, treatment-naïve adolescents. Patients had a mean 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 studies of 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 combination with an investigator-selected BR containing two NRTIs, were evaluated in Study TMC278-C213, a single-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 was 63.5 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 together with 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).

5.2Pharmacokinetic properties

Absorption

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 healthy subjects (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 single dose administration to healthy subjects (n = 95) under fed conditions.

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

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

Tenofovir alafenamide is rapidly absorbed following oral administration, with peak plasma concentrations occurring at 15-45 minutes post-dose. Relative to fasting conditions, the administration of 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.

Distribution

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration 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 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

The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2’-O-glucuronide (approximately 4% of dose). Emtricitabine did not inhibit in vitro drug metabolism mediated by any of the major human CYP isoforms involved in drug biotransformation. Also, emtricitabine did not inhibit uridine-5’-diphosphoglucuronyl transferase (UGT), the enzyme responsible for glucuronidation.

In vitro experiments indicate that rilpivirine hydrochloride primarily undergoes oxidative metabolism mediated 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 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 given with emtricitabine, cobicistat and elvitegravir 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) 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-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

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.

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

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

Pharmacokinetics in special populations

Age, gender and ethnicity

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

Paediatric population

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 on rilpivirine pharmacokinetics in paediatric patients in Study C213 (33 to 93 kg), similar to what was observed in adults. The pharmacokinetics of rilpivirine in paediatric patients < 12 years of age is under investigation.

Exposures of emtricitabine and tenofovir alafenamide given with elvitegravir+cobicistat achieved in 24 paediatric patients aged 12 to < 18 years were similar to exposures achieved in treatment-naïve adults (Table 6).

Table 6: Pharmacokinetics of emtricitabine, and tenofovir alafenamide in antiretroviral-naïve adolescents 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).

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

bn = 23 adolescents (GS-US-292-0106, population PK analysis)

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

Renal impairment

Emtricitabine is principally eliminated by renal excretion and the exposure to emtricitabine increases in patients with renal impairment. Mean systemic emtricitabine exposure was higher in patients with severe renal impairment (CrCl < 30 mL/min) (33.7 µgh/mL) than in subjects with normal renal function (11.8 µgh/mL).

The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renal elimination of rilpivirine is negligible. In patients with severe renal impairment or end-stage renal disease, plasma concentrations may be increased due to alteration of drug absorption, distribution and/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 (see section 4.9).

No clinically relevant differences in tenofovir alafenamide, or tenofovir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment (estimated CrCl from 15 to < 30 mL/min) in studies of cobicistat-boosted elvitegravir or of tenofovir alafenamide, respectively.

Hepatic impairment

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

Rilpivirine hydrochloride is primarily metabolised and eliminated by the liver. In a study comparing 8 patients with mild hepatic impairment (Child-Pugh Class A) to 8 matched controls and 8 patients with moderate hepatic impairment (Child-Pugh Class B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. However, it may not be excluded that the pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate impairment. 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 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, rilpivirine and tenofovir alafenamide have not been fully evaluated in patients co-infected with hepatitis B and/or C virus.

5.3Preclinical safety data

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.

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

Carcinogenicity studies with rilpivirine in mice and rats revealed tumorigenic potential specific for these 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 primary target organs of toxicity. Bone toxicity was observed as reduced bone mineral density in rats and dogs at 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 and tenofovir exposures of approximately 4- and 17-times greater, respectively, than those expected after administration 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 tenofovir alafenamide compared to tenofovir disoproxil fumarate, carcinogenicity studies and a rat

peri-postnatal study were conducted only with tenofovir disoproxil fumarate. 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 fumarate reduced the viability index and weight of pups in a peri-postnatal toxicity study at maternally toxic doses.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Tablet core

Croscarmellose sodium

Lactose (as monohydrate)

Magnesium stearate

Microcrystalline cellulose

Polysorbate 20

Povidone

Film-coating

Macrogol

Polyvinyl alcohol

Talc

Titanium dioxide (E171)

Iron oxide black (E172)

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

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

6.5Nature 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.

6.6Special precautions for disposal

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

7.MARKETING AUTHORISATION HOLDER

Gilead Sciences International Ltd.

Cambridge

CB21 6GT

United Kingdom

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/16/1112/001

EU/1/16/1112/002

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 June 2016

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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