英文药名：ODEFSEY(rilpivirine/emtricitabine/tenofovir alafenamide filmcoated tablets)

中文药名：恩曲他滨/利匹韦林/替诺福韦艾拉酚胺富马酸三合一复合剂

生产厂家：吉利德科学公司
药品介绍
艾滋病三合一新药Odefsey获欧盟批准
2016年6月23日，欧盟委员会（EC）已批准该公司三合一HIV复方片Odefsey（R/F/TAF，25mg/200mg/25mg），用于无已知非核苷类逆转录酶抑制剂（NNRTI）相关耐药突变且病毒载量低于100000拷贝/毫升的HIV-1成人感染者以及12岁及以上体重至少35千克的青少年感染者。Odefsey也由此成为吉利德在欧洲市场成功获批的第3款以替诺福韦艾拉酚胺（TAF）为基础的HIV药物。
在美国，Odefsey已于今年3月初获FDA批准。Odefsey（R/F/TAF，25mg/200mg/25mg）由强生的利匹韦林（rilpivirine，R，25mg）及吉利德自身的2款药物恩曲他滨(emtricitabine，F，200mg)和替诺福韦艾拉酚胺富马酸（tenofovir alafenamide fumarate，TAF，25mg）组成。
Odefsey 200 mg/25 mg/25 mg film-coated tablets
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
4.1 Therapeutic 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).
4.2 Posology 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.
4.3 Contraindications
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).
4.4 Special warnings and precautions for use
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
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 HBV or HCV has not been established. Tenofovir alafenamide is active against HBV but its clinical efficacy against this virus is not yet fully established.
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 (as fumarate) 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.
4.5 Interaction 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 (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 therapeutic areas	Effects on medicinal product levels. Mean percent change in AUC, Cmax, Cmin	Recommendation concerning co-administration with Odefsey
ANTI-INFECTIVES
Antifungals
Ketoconazole (400 mg once daily)/ Rilpivirine1	Ketoconazole: AUC: ↓ 24% 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 alafenamide (inhibition of P-gp).	Co-administration is not recommended.
Fluconazole Itraconazole Posaconazole Voriconazole	Interaction not studied with any of the components of Odefsey. Co-administration of these antifungal agents is expected to increase plasma concentrations of rilpivirine (inhibition of CYP3A) and tenofovir alafenamide (inhibition of P-gp).	Co-administration is not recommended.
Antimycobacterials
Rifampicin/ Rilpivirine	Rifampicin: AUC: ↔ 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).	Co-administration is contraindicated.
Rifapentine	Interaction not studied with any of the components of Odefsey. Co-administration is likely to cause significant decreases in the plasma concentrations of rilpivirine (induction of CYP3A) and tenofovir alafenamide (induction of P-gp).	Co-administration is contraindicated.
Rifabutin (300 mg once daily)/ Rilpivirine1     Rifabutin (300 mg once daily)/ Rilpivirine	Rifabutin: AUC: ↔ Cmin: ↔ Cmax: ↔ 25-O-desacetyl-rifabutin: AUC: ↔ Cmin: ↔ Cmax: ↔ Rilpivirine: AUC: ↓ 42% Cmin: ↓ 48% Cmax: ↓ 31% 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).	Co-administration is contraindicated.
Macrolide antibiotics
Clarithromycin Erythromycin	Interaction not studied with any of the components of Odefsey. The 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).	Co-administration is not recommended.
Antiviral agents
Boceprevir	Interaction not studied with any of the components of Odefsey.	Co-administration is not recommended. Boceprevir or telaprevir have the potential to adversely affect the intracellular activation and clinical antiviral efficacy of tenofovir alafenamide based on in vitro data.
Telaprevir (750 mg every 8 hours)/ Rilpivirine	Telaprevir: AUC: ↓ 5% Cmin: ↓ 11% Cmax: ↓ 3% Rilpivirine: AUC: ↑ 78% Cmin: ↑ 93% Cmax: ↑ 49%
Ledipasvir/Sofosbuvir (90 mg/400 mg once daily)/ Rilpivirine	Ledipasvir: AUC: ↑ 2% 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%	No dose adjustment is required.
Ledipasvir/Sofosbuvir (90 mg/400 mg once daily)/ Tenofovir alafenamide	Tenofovir alafenamide: AUC: ↑ 32% Cmax: ↑ 3%
Sofosbuvir (400 mg once daily)/ Rilpivirine (25 mg once daily)	Sofosbuvir: AUC: ↔ Cmax: ↑ 21% Sofosbuvir metabolite GS-331007: AUC: ↔ Cmax: ↔ Rilpivirine: AUC: ↔ Cmin: ↔ Cmax: ↔	No dose adjustment is required.
Simeprevir (150 mg once daily)/ Rilpivirine	Simeprevir: AUC: ↑ 6% Cmin: ↓ 4% Cmax: ↑ 10% Rilpivirine: AUC: ↑ 12% Cmin: ↑ 25% Cmax: ↑ 4%	No dose adjustment is required,
ANTICONVULSANTS
Carbamazepine Oxcarbazepine Phenobarbital Phenytoin	Interaction not studied with any of the components of Odefsey. Co-administration may cause significant decreases in the plasma concentrations of rilpivirine (induction of CYP3A) and tenofovir alafenamide (induction of P-gp).	Co-administration is contraindicated.
GLUCOCORTICOIDS
Dexamethasone (systemic, except for single dose use)	Interaction not studied with any of the components of Odefsey. Significant dose dependent decreases in rilpivirine plasma concentrations are expected (induction of CYP3A).	Co-administration is contraindicated.
PROTON PUMP INHIBITORS
Omeprazole (20 mg once daily)/ Rilpivirine1	Omeprazole: AUC: ↓ 14% Cmin: N/A Cmax: ↓ 14% Rilpivirine: AUC: ↓ 40% Cmin: ↓ 33% Cmax: ↓ 40% Reduced absorption, increase in gastric pH	Co-administration is contraindicated.
Lansoprazole Rabeprazole Pantoprazole Esomeprazole Dexlansoprazole	Interaction not studied with any of the components of Odefsey. Significant decreases in rilpivirine plasma concentrations are expected (reduced absorption, increase in gastric pH).	Co-administration is contraindicated.
HERBAL PRODUCTS
St. John's wort (Hypericum perforatum)	Interaction not studied with any of the components of Odefsey. Co-administration may cause significant decreases in the plasma concentrations of rilpivirine (induction of CYP3A) and tenofovir alafenamide (induction of P-gp).	Co-administration is contraindicated.
H2-RECEPTOR ANTAGONISTS
Famotidine (40 mg single dose taken 12 hours before rilpivirine)/ Rilpivirine1   Famotidine (40 mg single dose taken 2 hours before rilpivirine)/ Rilpivirine1       Famotidine (40 mg single dose taken 4 hours after rilpivirine)/ Rilpivirine1	Rilpivirine: AUC: ↓ 9% Cmin: N/A Cmax: ↔ Rilpivirine: AUC: ↓ 76% Cmin: N/A Cmax: ↓ 85% Reduced absorption, increase in gastric pH Rilpivirine: AUC: ↑ 13% Cmin: N/A Cmax: ↑ 21%	Only H2-receptor antagonists that can be dosed once daily should be used. A strict dosing schedule with intake of the H2-receptor antagonists at least 12 hours before or at least 4 hours after Odefsey should be used.
Cimetidine Nizatidine Ranitidine	Interaction not studied with any of the components of Odefsey. Co-administration may cause significant decreases in rilpivirine plasma concentrations (reduced absorption, increase in gastric pH).
ANTACIDS
Antacids (e.g. aluminium or magnesium hydroxide, calcium carbonate)	Interaction not studied with any of the components of Odefsey. Co-administration may cause significant decreases in rilpivirine plasma concentrations (reduced absorption, increase in gastric pH).	Antacids should only be administered either at least 2 hours before or at least 4 hours after Odefsey.
ORAL CONTRACEPTIVES
Ethinylestradiol (0.035 mg once daily)/ Rilpivirine     Norethindrone (1 mg once daily)/ Rilpivirine	Ethinylestradiol: AUC: ↔ Cmin: ↔ Cmax: ↑ 17% Norethindrone: AUC: ↔ Cmin: ↔ Cmax: ↔ Rilpivirine: AUC: ↔* Cmin: ↔* Cmax: ↔* *based on historic controls	No dose adjustment is required.
NARCOTIC ANALGESICS
Methadone (60-100 mg once daily, individualised dose)/ Rilpivirine	R(-) methadone: AUC: ↓ 16% Cmin: ↓ 22% Cmax: ↓ 14% S(+) methadone: AUC: ↓ 16% Cmin: ↓ 21% Cmax: ↓ 13% Rilpivirine: AUC: ↔* Cmin: ↔* Cmax: ↔* *based on historic controls	No dose adjustments are required. Clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
ANALGESICS
Paracetamol (500 mg single dose)/ Rilpivirine1	Paracetamol: AUC: ↔ Cmin: N/A Cmax: ↔ Rilpivirine: AUC: ↔ Cmin: ↑ 26% Cmax: ↔	No dose adjustment is required.
ANTIARRHYTHMICS
Digoxin/ Rilpivirine	Digoxin: AUC: ↔ Cmin: N/A Cmax: ↔	No dose adjustment is required.
ANTICOAGULANTS
Dabigatran etexilate	Interaction not studied with any of the components of Odefsey. A risk for increases in dabigatran plasma concentrations cannot be excluded (inhibition of intestinal P-gp).	Co-administration should be used with caution.
IMMUNOSUPPRESSANTS
Ciclosporin	Interaction not studied with any of the components of Odefsey. Co-administration of ciclosporin is expected to increase plasma concentrations of rilpivirine (inhibition of CYP3A) and tenofovir alafenamide (inhibition of P-gp).	Co-administration is not recommended.
ANTIDIABETICS
Metformin (850 mg single dose)/ Rilpivirine	Metformin: AUC: ↔ Cmin: N/A Cmax: ↔	No dose adjustment is required.
HMG CO-A REDUCTASE INHIBITORS
Atorvastatin (40 mg once daily)/ Rilpivirine1	Atorvastatin: AUC: ↔ Cmin: ↓ 15% Cmax: ↑ 35% Rilpivirine: AUC: ↔ Cmin: ↔ Cmax: ↓ 9%	No dose adjustment is required.
PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS
Sildenafil (50 mg single dose)/ Rilpivirine1	Sildenafil: AUC: ↔ Cmin: N/A Cmax: ↔ Rilpivirine: AUC: ↔ Cmin: ↔ Cmax: ↔	No dose adjustment is required.
Vardenafil Tadalafil	Interaction not studied with any of the components of Odefsey. These are medicinal products within class where similar interactions could be predicted.	No dose adjustment is required.
HYPNOTICS/SEDATIVES
Midazolam (2.5 mg, orally, once daily)/ Tenofovir alafenamide     Midazolam (1 mg, intravenously, once daily)/ Tenofovir alafenamide	Midazolam: AUC: ↑ 12% Cmin: N/A Cmax: ↑ 2% Midazolam: AUC: ↑ 8% Cmin: N/A Cmax: ↓ 1%	No dose adjustment is required.

N/A = not applicable
1 This 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.
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/ethinyl estradiol.
4.6 Fertility, 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 fetal/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 fetus.
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).
4.7 Effects on ability to drive and use machines
Patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with the components of Odefsey (see section 4.8). This should be considered when assessing a patient's ability to drive or operate machinery.
4.8 Undesirable effects
Summary of the safety profile
No data are available from clinical studies of Odefsey in HIV-1 infected patients. The most frequently reported adverse reactions in clinical studies of treatment-naïve patients taking emtricitabine+tenofovir alafenamide in combination with elvitegravir+cobicistat were nausea (10%), 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%).
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 in the controlled studies TMC278-C209 and TMC278-C215 in antiretroviral treatment-naïve HIV-1 infected adults, who received rilpivirine 25 mg once daily in combination with other antiretroviral medicinal products, and on post-marketing experience with emtricitabine/rilpivirine/tenofovir disoproxil fumarate.
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 amalyse1
Common:	abdominal pain1, 3, vomiting1, 3, increased lipase1, abdominal discomfort1, dry mouth1, flatulence3, diarrhea3
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, 2

1 Adverse reactions identified from rilpivirine clinical studies.
2 This adverse reaction was not observed in the Phase 3 studies of emtricitabine+tenofovir alafenamide in combination with elvitegravir+cobicistat but identified from clinical studies or post-marketing experience of emtricitabine when used with other antiretrovirals.
3 Adverse reactions identified from emtricitabine+tenofovir alafenamide clinical studies.
4 Adverse reaction identified through post-marketing surveillance of emtricitabine/rilpivirine/tenofovir disoproxil fumarate
5 This 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.
6 This 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 for emtricitabine+tenofovir alafenamide-containing regimens
In studies in treatment-naïve patients, increases from baseline were observed in both treatment groups for the fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, and triglycerides at Week 96. The median increase from baseline for these parameters was greater in patients receiving emtricitabine+tenofovir alafenamide compared with patients receiving emtricitabine+tenofovir disoproxil fumarate, both given with elvitegravir+cobicistat as a fixed-dose combination tablet (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 96 in total cholesterol to HDL-cholesterol ratio was 0.1 (-0.3, 0.7) in patients receiving emtricitabine+tenofovir alafenamide and 0.0 (-0.4, 0.5) in patients receiving emtricitabine+tenofovir disoproxil fumarate (p < 0.001 for the difference between treatment groups).
Changes in lipid laboratory tests for rilpivirine-containing regimens
At 96 weeks in the pooled Phase 3 C209 and C215 studies of treatment-naïve patients, in the rilpivirine+emtricitabine/tenofovir disoproxil fumarate arm the mean change from baseline in total cholesterol (fasted) was 2 mg/dL, in HDL-cholesterol (fasted) 4 mg/dL, in LDL-cholesterol (fasted) -1 mg/dL, and in triglycerides (fasted) -14 mg/dL. In the efavirenz+emtricitabine/tenofovir disoproxil fumarate arm the mean change from baseline in total cholesterol (fasted) was 26 mg/dL, in HDL-cholesterol (fasted) 11 mg/dL, in LDL-cholesterol (fasted) 14 mg/dL, and in triglycerides (fasted) 6 mg/dL. The clinical implication of these findings has not been demonstrated.
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 48 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 hepatitis B and/or hepatitis C virus
The safety of emtricitabine+tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet was evaluated in approximately 70 HIV/HBV co-infected patients currently receiving treatment for HIV in an open-label clinical study (GS-US-292-1249). Based on this limited experience the safety profile of Odefsey in patients with HIV/HBV co-infection appears to be 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:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
4.9 Overdose
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
5.1 Pharmacodynamic 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 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 96 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 10 of 866 (1.2%) patients treated with E/C/F/TAF. Among these 10 HIV-1 isolates, the mutations that emerged were M184V/I (n = 9) 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).
Study GS-US-264-0106: Of the 469 emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) -treated patients (317 patients who switched at baseline and 152 patients who switched at Week 24). HIV-1 isolates from 4 of these patients had developed resistance by Week 48 (total of 4 of 469 patients, 0.9%). Of the 24 patients treated that had the NNRTI-associated K103N substitution pre-existing at baseline in their HIV-1, 22 maintained virologic suppression after switching to FTC/RPV/TDF. One patient with pre-existing K103N at baseline had virologic failure with additional emergent resistance by Week 48.
Study GS-US-264-0111: Through Week 48, no emergent resistance developed among patients that switched to FTC/RPV/TDF from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) (0 of 49 patients).
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
No data are available from clinical studies of Odefsey in HIV-1 infected patients. 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; and from studies with rilpivirine when given with FTC/TDF as individual components or as a FTC/RPV/TDF FDC tablet.
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 met the non-inferiority criteria in achieving HIV-1 RNA < 50 copies/mL when compared to E/C/F/TDF. Pooled treatment outcomes at 48 and 96 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 96 a, and GS-US-292-0109 at Week 48a

Treatment-naïve adults in studies GS-US-292-0104 and GS-US-292-0111b				Virologically suppressed adults in study GS-US-292-0109
	Week 48		Week 96		Week 48
	E/C/F/TAF (n = 866)	E/C/F/TDF(n = 867)	E/C/F/TAF (n = 866)	E/C/F/TDF (n = 867)	E/C/F/TAF (n = 959)	Baseline regimen (n = 477)
HIV-1 RNA < 50 copies/mL	92%	90%	87%	85%	97%	93%
Treatment difference	2.0% (95% CI: -0.7% to 4.7%)		1.5% (95% CI: -1.8% to 4.8%)		4.1% (95% CI: 1.6% to 6.7%, p < 0.001c)
HIV-1 RNA ≥ 50 copies/mLd	4%	4%	5%	4%	1%	1%
No virologic data in Week 48 or 96 window	4%	6%	9%	11%	2%	6%
Discontinued study drug due to AE ore	1%	2%	1%	2%	1%	1%
Discontinued study drug due to other reasons and last available HIV-1 RNA < 50 copies/mLf	2%	4%	6%	7%	1%	4%
Missing data during window but on study drug	1%	< 1%	2%	1%	0%	<1%
HIV-1 RNA < 20 copies/mL	84%	84%	82%	80%
Treatment difference	0.4% (95% CI: -3.0% to 3.8%)		1.5% (95% CI: -2.2% to 5.2%)
Proportion (%) of patients with HIV-1 RNA < 50 copies/mL by prior treatment regimend
EFV/FTC/TDF					96%	90%
FTC/TDF plus boosted atazanavir					97%	92%
E/C/F/TDF					98%	97%

a Week 48 window was between Day 294 and 377 (inclusive); Week 96 window was between Day 630 and 713 (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 boosted atazanavir, or E/C/F/TDF).
d Included patients who had ≥ 50 copies/mL in the Week 48 or 96 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.
e Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
f Includes patients who discontinued for reasons other than an AE, death, or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.
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.
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 (n = 550)	EFV + FTC/TDF (n = 546)	RPV + FTC/TDF (n = 550)	EFV + FTC/TDF (n = 546)
	Week 48		Week 96
Overall response (HIV-1 RNA < 50 copies/mL (TLOVRa))b	83.5% (459/550)	82.4% (450/546)	76.9% (423/550)	77.3% (422/546)
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 (all patients)	9.5% (52/550)	4.2% (23/546)	11.5% (63/550)c	5.1% (28/546)d
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 to adverse event (AE)	2.2% (12/550)	7.1% (39/546)	3.6% (20/550)	8.1% (44/546)
Discontinued for non-AE reasone	4.9% (27/550)	6.0% (33/546)	8% (44/550)	8.8% (48/546)

EFV = efavirenz; RPV = rilpivirine
a 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 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.
d There 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.
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/mL compared to FTC/TDF+efavirenz.
Rilpivirine-containing regimens
Virologically suppressed HIV-1 infected patients
Study GS-US-264-0106: The efficacy and safety of switching from a ritonavir-boosted PI in combination with two NRTIs to FTC/RPV/TDF was evaluated in a randomised, open-label study in virologically suppressed HIV-1 infected adults. Patients had to have been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening. Patients were randomised in a 2:1 ratio to either switch to FTC/RPV/TDF at baseline (n = 317), or SBR for 24 weeks (n = 159) before switching to FTC/RPV/TDF for an additional 24 weeks (Delayed Switch arm, n = 152). Patients had a mean age of 42 years (range 19-73), 88% were male, 77% were White, and 17% were Black. The mean baseline CD4+ cell count was 584 cells/mm3 (range 42-1,484).
At Week 24, switching to FTC/RPV/TDF was non-inferior in maintaining HIV-1 RNA < 50 copies/mL when compared to patients who stayed on a ritonavir-PI in combination with two NRTIs (94% (297/317) vs 90% 143/159), treatment difference [95% CI]: +3.8% [-1.6% to 9.1%]).
Among patients in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to FTC/RPV/TDF, 92% (140/152) of patients had HIV-1 RNA < 50 copies/mL after 24 weeks of FTC/RPV/TDF, consistent with the Week 24 results for patients who switched to FTC/RPV/TDF at baseline.
At Week 48, 89% (283/317) of patients randomised to switch to FTC/RPV/TDF had HIV-1 RNA < 50 copies/mL, 3% (8/317) were considered virologic failures (HIV RNA ≥ 50 copies/mL), and 8% (26/317) did not have data available in the Week 48 window.
There were 7/317 patients (2%) in the emtricitabine/rilpivirine/tenofovir disoproxil fumarate arm and 6/152 patients (4%) in the Delayed Switch arm who permanently discontinued study drug due to a treatment-emergent adverse event (TEAE). No patients discontinued from the study due to a TEAE in the SBR arm.
Study GS-US-264-0111: The efficacy, safety, and pharmacokinetics of switching from EFV/FTC/TDF FDC to FTC/RPV/TDF FDC were evaluated in an open-label study in virologically suppressed HIV-1 infected adults. Patients were switched without a washout period. Among 49 patients who received at least one dose of FTC/RPV/TDF, 100% of patients remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 12 and Week 24. At Week 48, 94% (46/49) of patients remained suppressed, and 4% (2/49) were considered virologic failures (HIV-1 RNA ≥ 50 copies/mL), and 1 patient (2%) had no data in the Week 48 window due to protocol violation with the last available HIV-1 RNA < 50 copies/mL.
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 48, 92% (222/242 patients) maintained HIV-1 RNA < 50 copies/mL after switching to E/C/F/TAF FDC tablet. Three patients had virologic failure at Week 48.
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; as measured by hip and lumbar spine DXA analysis) compared to E/C/F/TDF after 96 weeks of treatment. 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.
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 by eGFRCG, urine protein to creatinine ratio and urine albumin to creatinine ratio) compared to E/C/F/TDF after 96 weeks of treatment (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.
The 36 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).
5.2 Pharmacokinetic 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 eliminated from the body by the kidneys 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 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 5).
Table 5: 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).
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)
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 µg•h/ml) than in subjects with normal renal function (11.8 µg•h/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. Rilpivirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). However, it may not be excluded that the pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate impairment.
Clinically relevant changes in tenofovir pharmacokinetics were not observed in patients with mild to moderate hepatic impairment, and no tenofovir alafenamide dose adjustment is required in patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of tenofovir alafenamide has not been studied.
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.
Switching from an efavirenz-based regimen
The efficacy data from study GS-US-264-0111 (see section 5.1) indicates that the brief period of lower rilpivirine exposure does not impact antiviral efficacy of emtricitabine/rilpivirine/tenofovir disoproxil fumarate. Due to the decline in efavirenz plasma levels, the inductive effect decreased and rilpivirine concentrations started to normalise. During the time period of declining efavirenz plasma levels and increasing rilpivirine plasma levels after switching, none of the patients had efavirenz or rilpivirine levels below their respective IC90 levels at the same time. No dose adjustment is required following the switch from an efavirenz-containing regimen.
5.3 Preclinical 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 fetal 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
6.1 List 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)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.
6.5 Nature and contents of container
High density polyethylene (HDPE) bottle with a polypropylene continuous-thread, child-resistant cap, lined with an induction activated aluminium foil liner containing 30 film-coated tablets. Each bottle contains silica gel desiccant and polyester coil.
The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets and outer cartons containing 90 (3 bottles of 30) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
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
06/2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.