EVIPLERA

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רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ

FULL PRESCRIBING INFORMATION

EVIPLERA

Film coated tablets

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS

and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been

reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a

component of EVIPLERA, in combination with other antiretrovirals [See Warnings and

Precautions (5.1)].

EVIPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection

and the safety and efficacy of EVIPLERA have not been established in patients coinfected

with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in

patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or

VIREAD, which are components of EVIPLERA. Hepatic function should be monitored

closely with both clinical and laboratory follow-up for at least several months in patients

who are coinfected with HIV-1 and HBV and discontinue EVIPLERA. If appropriate,

initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions

(5.2)].

1 INDICATIONS AND USAGE

EVIPLERA, a combination of two nucleoside analog HIV 1 reverse transcriptase

inhibitors (emtricitabine and tenofovir disoproxil fumarate) and one non-nucleoside

reverse transcriptase inhibitor (rilpivirine), is indicated for use as a complete regimen for

the treatment of HIV-1 infection in adult patients with no antiretroviral treatment history

and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy, and

in certain virologically-suppressed (HIV-1 RNA <50 copies/mL) adult patients on a

stable antiretroviral regimen at start of therapy in order to replace their current

antiretroviral treatment regimen (see below).

The following points should be considered when initiating therapy with

EVIPLERA

in adult

patients with no antiretroviral treatment history:

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More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at

the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL)

compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to

100,000 copies/mL

[See Clinical Studies (14)]

Regardless of HIV-1 RNA level at the start of therapy, more rilpivirine-treated

subjects with CD4+ cell count less than 200 cells/mm

experienced virologic failure

compared to rilpivirine-treated subjects with CD4+ cell count greater than or equal to

200 cells/mm

[See Clinical Studies (14)]

The observed virologic failure rate in rilpivirine-treated subjects conferred a higher

rate of overall treatment resistance and cross-resistance to the NNRTI class compared

to efavirenz

[See Microbiology (12.4)]

More subjects treated with rilpivirine developed tenofovir and

lamivudine/emtricitabine associated resistance compared to efavirenz

[See

Microbiology (12.4)]

The efficacy of

EVIPLERA

was established in patients who were virologically-suppressed

(HIV-1 RNA <50 copies/mL) on stable ritonavir-boosted protease inhibitor-containing

regimen. The following points should be met when considering replacing the current regimen

with

EVIPLERA

in virologically-suppressed adults

[See Clinical Studies (14)]

Patients should have no history of virologic failure.

Patients should have been stably suppressed (HIV-1 RNA <50 copies/mL) for at least

6 months prior to switching therapy.

Patients should currently be on their first or second antiretroviral regimen prior to

switching therapy.

Patients should have no current or past history of resistance to any of the three

components of

EVIPLERA

Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after

replacing therapy to assess for potential virologic failure or rebound.

EVIPLERA

is not recommended for patients less than 18 years of age

[See Use in Specific

Populations (8.4)].

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2 DOSAGE AND ADMINISTRATION

Adults:

The recommended dose of EVIPLERA is one tablet taken orally once daily with food

[See Clinical Pharmacology (12.3)]

Renal Impairment:

Because EVIPLERA is a fixed-dose combination, it should not be prescribed

for patients requiring dose reduction such as those with moderate or severe renal impairment

(estimated creatinine clearance below 50 mL per minute).

Rifabutin Coadministration: If EVIPLERA is coadministered with rifabutin, an additional 25 mg

tablet of rilpivirine (Edurant

) once per day is recommended to be taken concomitantly with

EVIPLERA and with a meal for the duration of the rifabutin coadministration [See Drug

Interactions (7.5) and Clinical Pharmacology (12.3)].

If a patient misses a dose of Eviplera within 12 hours of the time it is usually taken, the patient

should take Eviplera with food as soon as possible and resume the normal dosing schedule. If a

patient misses a dose of Eviplera by more than 12 hours, the patient should not take the missed

dose and simply resume the usual dosing schedule.

If a patient vomits within 4 hours of taking Eviplera another Eviplera tablet should be taken with

food . If a patient vomits more than 4 hours after taking Eviplera they do not need to take another

dose of Eviplera until the next regularly scheduled dose.

3 DOSAGE FORMS AND STRENGTHS

EVIPLERA is available as film coated tablets. Each tablet contains 200 mg of emtricitabine

(FTC), 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of rilpivirine) and 300 mg of

tenofovir disoproxil fumarate (tenofovir DF or TDF, equivalent to 245 mg of tenofovir

disoproxil).

The tablets are purplish-pink, capsule-shaped, film-coated, debossed with “GSI” on one side and

plain-faced on the other side.

4 CONTRAINDICATIONS

Hypersensitivity to the active substances or to any of the excipients listed in Description, section

EVIPLERA should not be coadministered with the following drugs, as significant decreases in

rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH

increase, which may result in loss of virologic response and possible resistance to EVIPLERA or

to the class of NNRTIs

[See Drug Interactions (7) and Clinical Pharmacology (12.3)]

the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin

the antimycobacterials, rifampin, rifapentine

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proton pump inhibitors, such as dexlansoprazole, esomeprazole, lansoprazole,

omeprazole, pantoprazole, rabeprazole

the glucocorticoid systemic dexamethasone (more than a single dose)

St. John’s wort (

Hypericum perforatum

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported

with the use of nucleoside analogs, including tenofovir DF, a component of EVIPLERA, in

combination with other antiretrovirals. A majority of these cases have been in women. Obesity

and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised

when administering nucleoside analogs to any patient with known risk factors for liver disease;

however, cases have also been reported in patients with no known risk factors. Treatment with

EVIPLERA should be suspended in any patient who develops clinical or laboratory findings

suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and

steatosis even in the absence of marked transaminase elevations).

5.2 Patients Coinfected with HIV-1 and HBV

It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B

virus before initiating antiretroviral therapy. EVIPLERA is not approved for the treatment of

chronic HBV infection and the safety and efficacy of EVIPLERA have not been established in

patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been

reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine

or tenofovir DF, two of the components of EVIPLERA. In some patients infected with HBV and

treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver

decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be

closely monitored with both clinical and laboratory follow-up for at least several months after

stopping treatment with EVIPLERA. If appropriate, initiation of anti-hepatitis B therapy may be

warranted.

5.3 Skin and Hypersensitivity Reactions

Severe skin and hypersensitivity reactions have been reported during the postmarketing

experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms

(DRESS) with rilpivirine-containing regimens. While some skin reactions were accompanied by

constitutional symptoms such as fever, other skin reactions were associated with organ

dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical

trials, treatment-related rashes with at least Grade 2 severity were reported in 1% of subjects

receiving rilpivirine plus emtricitabine/tenofovir DF. Overall, most rashes were Grade 1 or 2 and

occurred in the first four to six weeks of therapy

[see Adverse Reactions (6.1 and 6.2)]

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Discontinue EVIPLERA immediately if signs or symptoms of severe skin or hypersensitivity

reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters,

mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia.

Clinical status including laboratory parameters should be monitored and appropriate therapy

should be initiated.

5.4 New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular

injury with severe hypophosphatemia), has been reported with the use of tenofovir DF

[See

Adverse Reactions (6.2)]

It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating

therapy and as clinically appropriate during therapy with EVIPLERA.

In patients at risk of renal dysfunction, including patients who have previously experienced

renal events while receiving HEPSERA

, it is recommended that estimated creatinine

clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation

of EVIPLERA, and periodically during EVIPLERA therapy.

EVIPLERA should be avoided with concurrent or recent use of a nephrotoxic agent

(e.g., high-

dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [See Drug Interactions

(7.3)]. Cases of acute renal failure after initiation of high dose or multiple NSAIDs have

been reported in HIV-infected patients with risk factors for renal dysfunction who appeared

stable on tenofovir DF. Some patients required hospitalization and renal replacement

therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for

renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or

weakness may be manifestations of proximal renal tubulopathy and should prompt an

evaluation of renal function in at-risk patients.

Emtricitabine and tenofovir are principally eliminated by the kidney; however, rilpivirine is not.

Since EVIPLERA is a combination product and the dose of the individual components cannot be

altered, patients with estimated creatinine clearance below 50 mL per minute should not receive

EVIPLERA.

5.5 Drug Interactions

Caution should be given to prescribing EVIPLERA with drugs that may reduce the exposure of

rilpivirine

[See Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)]

In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once

daily) have been shown to prolong the QTc interval of the electrocardiogram

[See Drug

Interactions (7) and Clinical Pharmacology (12.2)]

. EVIPLERA should be used with caution

when coadministered with a drug with a known risk of Torsade de Pointes.

5.6 Depressive Disorders

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The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major

depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported

with rilpivirine. Patients with severe depressive symptoms should seek immediate medical

evaluation to assess the possibility that the symptoms are related to EVIPLERA, and if so, to

determine whether the risks of continued therapy outweigh the benefits.

During the Phase 3 trials in adults (N=1368), through 96 weeks, the incidence of depressive

disorders (regardless of causality, severity) reported among rilpivirine (N=686) or efavirenz

(N=682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The

incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both

rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among

rilpivirine or efavirenz was 1% in each arm. Suicidal ideation was reported in 4 subjects in each

arm while suicide attempt was reported in 2 subjects in the rilpivirine arm.

5.7 Hepatotoxicity

Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen.

Patients with underlying hepatitis B or C, or marked elevations in liver-associated tests prior to

treatment may be at increased risk for worsening or development of liver-associated test

elevations with use of EVIPLERA. A few cases of hepatic toxicity have been reported in adult

patients receiving a rilpivirine containing regimen who had no pre-existing hepatic disease or

other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and

monitoring for hepatotoxicity during therapy with EVIPLERA is recommended in patients with

underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-

associated tests prior to treatment initiation. Liver-associated test monitoring should also be

considered for patients without pre-existing hepatic dysfunction or other risk factors.

5.8 Bone Effects of Tenofovir DF

Bone Mineral Density:

In clinical trials in HIV-1-infected adults, tenofovir DF was associated with slightly greater

decreases in bone mineral density (BMD) and increases in biochemical markers of bone

metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid

hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF.

For more information, please consult the VIREAD® prescribing information.

The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term

bone health and future fracture risk are unknown. Assessment of BMD should be considered for

patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or

bone loss. Although the effect of supplementation with calcium and Vitamin D was not studied,

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such supplementation may be beneficial for all patients. If bone abnormalities are suspected then

appropriate consultation should be obtained.

Mineralization Defects:

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or

pain in extremities and which may contribute to fractures, have been reported in association with

the use of tenofovir DF [See Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness

have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and

osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of

renal dysfunction who present with persistent or worsening bone or muscle symptoms while

receiving products containing tenofovir DF [See Warnings and Precautions (5.3)].

5.9 Coadministration with Other Products

Eviplera should not be administered concurrently with other medicinal products containing the

active components emtricitabine or tenofovir DF (ATRIPLA®, EMTRIVA, STRIBILD®,

TRUVADA®, VIREAD), with medicinal products containing lamivudine (Epivir®, Epivir-

HBV®, Epzicom®, Combivir®,

Triumeq®, Trizivir®), or with adefovir dipivoxil (HEPSERA).

EVIPLERA should not be administered with rilpivirine (Edurant) unless needed for dose

adjustment (e.g., with rifabutin) [See Dosage and Administration (2) and Drug Interactions (7.5)].

5.10 Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement

(buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid

appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and

long-term consequences of these events are unknown. A causal relationship has not been

established.

5.11 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination

antiretroviral therapy, including the components of EVIPLERA. During the initial phase of

combination antiretroviral treatment, patients whose immune system responds may develop an

inflammatory response to indolent or residual opportunistic infections [such as

Mycobacterium

avium

infection, cytomegalovirus,

Pneumocystis jirovecii

pneumonia (PCP), or tuberculosis],

which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)

have also been reported to occur in the setting of immune reconstitution, however, the time to

onset is more variable, and can occur many months after initiation of treatment.

5.12 Excipients

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Eviplera 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.

Eviplera contains a colourant called sunset yellow aluminium lake (E110), this may cause allergic

reactions in some people.

5.13

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.

5.14 Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most

pronounced with stavudine, didanosine and zidovudine.

There have been reports of mitochondrial dysfunction in HIV negative infants exposed

in utero

and/or postnatally to nucleoside analogues

these have predominantly concerned treatment with

regimens containing zidovudine.

The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and

metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory.

late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal

behaviour). Whether the 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.

5.15 Effects on ability to drive and use machines

Eviplera has no or negligible influence on the ability to drive and use machines. No studies on the

effects on the ability to drive and use machines have been performed. However, patients should

be informed that fatigue, dizziness and somnolence have been reported during treatment with the

components of Eviplera. This should be considered when assessing a patient’s ability to drive or

operate machinery.

6 ADVERSE REACTIONS

The following adverse drug reactions are discussed in other sections of the labeling:

Lactic Acidosis/Severe Hepatomegaly with Steatosis

[See Boxed Warning,

Warnings and Precautions (5.1)]

Severe Acute Exacerbations of Hepatitis B

[See Boxed Warning, Warnings

and Precautions (5.2)]

Skin and Hypersensitivity Reactions [See Warnings and Precautions (5.3)].

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New Onset or Worsening Renal Impairment

[See Warnings and Precautions

(5.4)]

Depressive Disorders

[See Warnings and Precautions (5.6)].

Hepatotoxicity

[See Warnings and Precautions (5.7)].

Bone Effects of Tenofovir DF

[See Warnings and Precautions (5.8)]

Immune Reconstitution Syndrome

[See Warnings and Precautions (5.11)]

6.1 Adverse Reactions from Clinical Trials Experience in Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of

another drug and may not reflect the rates observed in practice.

In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History

Studies C209 and C215

Treatment-Emergent Adverse Drug Reactions:

The safety assessment of rilpivirine, used in

combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1368

patients in the Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in

antiretroviral treatment-naive HIV-1 infected adult patients. A total of 686 subjects received

rilpivirine in combination with other antiretroviral drugs as background regimen; most (N=550)

received emtricitabine/tenofovir DF as background regimen. The number of subjects randomized

to the control arm efavirenz was 682, of which 546 received emtricitabine/tenofovir DF as

background regimen

[See Clinical Studies (14)]

. The median duration of exposure for subjects in

either treatment arm was 104 weeks.

Adverse drug reactions (ADR) observed at week 96 in subjects who received rilpivirine or

efavirenz plus emtricitabine/tenofovir DF as background regimen are shown in Table 1. No new

types of adverse reactions were identified between Week 48 and Week 96.

The adverse drug

reactions observed in this subset of subjects were generally consistent with those seen for the

overall patient population participating in these studies (refer to the prescribing information for

EDURANT).

The proportion of subjects who discontinued treatment with rilpivirine or efavirenz +

emtricitabine/tenofovir DF due to ADR, regardless of severity, was 2% and 5%, respectively. The

most common ADRs leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in

the rilpivirine + emtricitabine/tenofovir DF arm and 12 (2.2%) subjects in the efavirenz +

emtricitabine/tenofovir DF arm. Rash led to discontinuation in 1 (0.2%) subjects in the rilpivirine

+ emtricitabine/tenofovir DF arm and 10 (1.8%) subjects in the efavirenz +

emtricitabine/tenofovir DF arm.

Common Adverse Drug Reactions

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Clinical ADRs to rilpivirine or efavirenz of at least moderate intensity (≥ Grade 2) reported in at

least 2% of adult subjects are shown in Table 1.

Table 1 :Selected Treatment-Emergent Adverse Drug Reactions

a

(Grades 2-4)

Reported in ≥2% of Subjects Receiving Rilpivirine or Efavirenz in

Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96

analysis)

Rilpivirine+

FTC/TDF

Efavirenz+

FTC/TDF

N=550

N=546

Gastrointestinal Disorder

Nausea

Nervous System Disorders

Headache

Dizziness

Psychiatric Disorders

Depressive disorders

Insomnia

Abnormal dreams

Skin and subcutaneous Tissue

Disorders

Rash

a. Frequencies of adverse reactions are based on all Grades 2-4 treatment-emergent adverse events

assessed to be related to study drug.

b. Includes adverse drug reactions reported as depressed mood, depression, dysphoria, major depression,

mood altered, negative thoughts, suicide attempt, suicide ideation.

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Rilpivirine:

Treatment-emergent adverse drug reactions of at least moderate intensity (≥ Grade 2)

that occurred in less than 2% of subjects treated with rilpivirine plus any of the allowed

background regimen (N=686) in clinical studies C209 and C215 include (grouped by Body

System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis,

cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis

membranous and glomerulonephritis mesangioproliferative, and nephrolithiasis

In Virologically-Suppressed HIV-1-Infected Subjects

No new adverse reactions to EVIPLERA were identified in stable, virologicallysuppressed

subjects switching to EVIPLERA from a regimen containing a ritonavir-boosted protease

inhibitor; however the frequency of adverse reactions increased by 20% (Study 106) after

switching to EVIPLERA.

Emtricitabine and Tenofovir Disoproxil Fumarate:

The most common adverse drug reactions occurred in at least 10% of HIV-1-infected

treatment-

naive adult subjects in a phase 3 clinical trial of emtricitabine and tenofovir DF in combination

with another antiretroviral agent are diarrhea, nausea, fatigue, headache, dizziness, depression,

insomnia, abnormal dreams, and rash. adverse drug reactions that occurred in at least 5% of

treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with

other antiretroviral agents in clinical trials include abdominal pain, dyspepsia, vomiting, fever,

pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back

pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy),

anxiety, increased cough, and rhinitis.

Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects;

it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and

asymptomatic. The mechanism and clinical significance are unknown.

6.2Laboratory Abnormalities in adult subjects:

The percentage of subjects treated with rilpivirine + emtricitabine/tenofovir DF or efavirenz +

emtricitabine/tenofovir DF in studies C209 and C215 with selected treatment-emergent laboratory

abnormalities (Grade 1 to 4), representing worst grade toxicity are presented in Table 2.

Table 2 : Selected Laboratory Abnormalities (Grades 1-4) Reported in Subjects Who Received

Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and

C215 (Week 96 Analysis)

Laboratory

Parameter

Abnormality, (%)

DAIDS Toxicity

Range

Rilpivirine +

FTC/TDF

Efavirenz + FTC/TDF

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N=550

N=546

BIOCHEMISTRY

Increased Creatinine

Grade 1

1.1-1.3 x ULN

Grade 2

>1.3-1.8 x ULN

Grade 3

>1.8-3.4 x ULN

<1%

Grade 4

>3.4 x ULN

<1%

Increased AST

Grade 1

1.25-2.5 x ULN

Grade 2

>2.5-5.0 x ULN

Grade 3

>5.0-10.0 x ULN

Grade 4

>10.0 x ULN

Increased ALT

Grade 1

1.25-2.5 x ULN

Grade 2

>2.5-5.0 x ULN

Grade 3

>5.0-10.0 x ULN

Grade 4

>10.0 x ULN

Increased Total

Bilirubin

Grade 1

1.1-1.5 x ULN

<1%

Grade 2

>1.5-2.5 x ULN

Grade 3

>2.5-5.0 x ULN

<1%

Increased Total

Cholesterol (fasted)

Grade 1

200-239 mg/dL

Grade 2

240-300 mg/dL

Grade 3

>300 mg/dL

<1%

Increased LDL

Cholesterol (fasted)

Grade 1

130-159 mg/dL

Laboratory

Parameter

Abnormality, (%)

DAIDS Toxicity

Range

Rilpivirine +

FTC/TDF

Efavirenz + FTC/TDF

N=550

N=546

Grade 2

160-190 mg/dL

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Grade 3

>190 mg/dL

Increased

Triglycerides (fasted)

Grade 2

500-750 mg/dL

Grade 3

751-1,200 mg/dL

Grade 4

>1,200 mg/dL

N = number of subjects per treatment group

a. ULN = Upper limit of normal value.

Note: Percentages were calculated versus the number of subjects in ITT population with emtricitabine +

tenofovir DF as background regimen

Emtricitabine or Tenofovir Disoproxil Fumarate

: The following Grade 3 or 4 laboratory

abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir

DF with other antiretroviral agents in other clinical trials:

increased pancreatic amylase (>2.0 x ULN), increased serum amylase (>175 U/L), increased

lipase (>3.0 x ULN), increased alkaline phosphatase (>550 U/L), increased or decreased serum

glucose (<40 or >250 mg/dL), increased glycosuria (≥3+), increased creatine kinase

(M: >990 U/L; F: >845 U/L), decreased neutrophils (<750/mm

) and increased hematuria (>75

RBC/HPF) occurred.

Adrenal Function

In the pooled Phase 3 trials of C209 and C215, in subjects treated with rilpivirine plus any of the

allowed background regimens (N=686), at Week 96 there was an overall mean change from

baseline in basal cortisol of –0.69 (−1.12, 0.27) micrograms/dL in the rilpivirine group, and of

−0.02 (−0.48, 0.44) micrograms/dL in the efavirenz group.

In the rilpivirine group, 43/588 (7.3%) of subjects with a normal 250 micrograms ACTH

stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak

cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3.2%) in the efavirenz

group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test

during the trial, 14 subjects in the rilpivirine group and 9 subjects in the efavirenz group had an

abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious

adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal

insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH

stimulation tests in the rilpivirine group is not known.

Serum Creatinine

In the pooled Phase 3 trials of C209 and C215 trials in subjects treated with rilpivirine plus any of

the allowed background regimen (N=686), there was a small increase in serum creatinine over 96

weeks of treatment with rilpivirine. Most of this increase occurred within the first four weeks of

treatment with a mean change of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) observed through

Week 96. In subjects who entered the trial with mild or moderate renal impairment, the serum

creatinine increase observed was similar to that seen in subjects with normal renal function.

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These changes are not considered to be clinically relevant and no subject discontinued treatment

due to increases in serum creatinine. Creatinine increases were comparable by background

N(t)RTIs.

Serum Lipids

Changes from baseline in total cholesterol, LDL-cholesterol and triglycerides are presented in

Table 3.

Table 3: Lipid Values Reported in Subjects Receiving Rilpivirine or Efavirenz in

Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215

a

Pooled Data from the Week 96 Analysis of C209 and C215 Trials

Rilpivirine + FTC/TDF N=550

Efavirenz + FTC/TDF N=546

N

Baseline

Week 96

N

Baseline

Week 96

Mean

Mean

(mg/dL)

Mean

(mg/dL)

Mean

Change

(mg/dL)

Mean

(mg/dL)

Mean

(mg/dL)

Mean

Change

(mg/dL)

Total

Cholesterol

(fasted)

HDL-

cholesterol

(fasted)

LDL-

cholesterol

(fasted)

Triglycerides

(fasted)

N = number of subjects per treatment group

a. Excludes subjects who received lipid lowering agents during the treatment period.

b. The change from baseline is the mean of within-patient changes from baseline for patients with both

baseline and Week 96 values.

Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus

In patients coinfected with hepatitis B or C virus receiving rilpivirine in studies C209 and C215,

the incidence of hepatic enzyme elevation was higher than in subjects receiving rilpivirine who

were not coinfected. The same increase was also observed in the efavirenz arm. The

pharmacokinetic exposure of rilpivirine in coinfected subjects was comparable to that in subjects

without coinfection.

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6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of rilpivirine-or

tenofovir DF-containing regimens. Because postmarketing reactions are reported voluntarily from

a population of uncertain size, it is not always possible to reliably estimate their frequency or

establish a causal relationship to drug exposure.

EVIPLERA:

Metabolism and Nutrition

Disorders weight increased

Skin and Subcutaneous Tissue Disorders severe skin and hypersensitivity reactions including

DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms

Rilpivirine:

Renal and Urinary Disorders

nephrotic syndrome

Emtricitabine:

No postmarketing adverse reactions have been identified for inclusion in this section.

Tenofovir Disoproxil Fumarate:

Immune System Disorders

allergic reaction, including angioedema

Metabolism and Nutrition Disorders

lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

dyspnea

Gastrointestinal Disorders

pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders

hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT) .

Skin and Subcutaneous Tissue Disorders

rash

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures),

muscular weakness, myopathy

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Renal and Urinary Disorders

acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal

tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal

insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

asthenia

The following adverse reactions, listed under the body system headings above, may occur as a

consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia,

muscular weakness, myopathy, hypophosphatemia.

Additional adverse events reaction based on clinical study and post marketing experience

Emtricitabine:

Neutropenia, anemia, allergic reaction, hyperglycemia, hypertriglyceridemia, asthenia.

vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin

discolouration (increased pigmentation)

angioedema

Rilpivirine HCl:

Decreased white blood cell count, decreased haemoglobin, decreased platelet count, immune

reactivation syndrome, increased total cholesterol (sasted), increased LDL cholerterol (fasted),

decreased appetite increased triglycerides (fasted), depression, abnormal dreams, depressed

mood, headaches, dizziness, nausea, increased pancreatic amylase, increased lipase, dry mouth,

rash.

Tenofovir diproxal fumarate:

Flatulence

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.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMe

dic@moh.gov.il

7 DRUG INTERACTIONS

EVIPLERA is a complete regimen for the treatment of HIV-1 infection; therefore, EVIPLERA

should not be administered with other antiretroviral medications. Information regarding potential

drug-drug interactions with other antiretroviral medications is not provided. Please refer to the

EDURANT, VIREAD and EMTRIVA prescribing information as needed.

This section describes clinically relevant drug interactions with EVIPLERA. Drug interaction

studies were conducted with the components of EVIPLERA (emtricitabine, rilpivirine, and

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tenofovir DF as single agents) or with EVIPLERA as a combination product

[See Dosage and

Administration (2), Contraindications (4), and Clinical Pharmacology (12.3)]

7.1 Drugs Inducing or Inhibiting CYP3A Enzymes

Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or

inhibit CYP3A may thus affect the clearance of rilpivirine

[See Clinical Pharmacology (12.3),

Contraindications (4)]

. Coadministration of rilpivirine and drugs that induce CYP3A may result

in decreased plasma concentrations of rilpivirine and loss of virologic response and possible

resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that

inhibit CYP3A may result in increased plasma concentrations of rilpivirine.

Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the

exposure of drugs metabolized by CYP enzymes.

7.2 Drugs Increasing Gastric pH

Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma

concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or

to the class of NNRTIs

[See Table 4].

7.3 Drugs Affecting Renal Function

Because emtricitabine and tenofovir are primarily eliminated by the kidneys through a

combination of glomerular filtration and active tubular secretion, coadministration of EVIPLERA

with drugs that reduce renal function or compete for active tubular secretion may increase serum

concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples

of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir,

adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g.,

gentamicin), and high-dose or multiple NSAIDs [See Warnings and Precautions (5.4)],

amphotericin B, foscarnet, pentamidine, or interleukin-2 (also called aldesleukin).

7.4 QT Prolonging Drugs

There is limited information available on the potential for a pharmacodynamic interaction

between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of

healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily)

have been shown to prolong the QTc interval of the electrocardiogram

[See Clinical

Pharmacology (12.2)]

. EVIPLERA should be used with caution when coadministered with a drug

with a known risk of Torsade de Pointes.

7.5 Established and Other Potentially Significant Drug Interactions

Important drug interaction information for EVIPLERA is summarized in Table 4. The drug

interactions described are based on studies conducted with emtricitabine, rilpivirine, or tenofovir

DF as individual medications or with EVIPLERA as a combination product, or are potential drug

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interactions [for pharmacokinetic data see

Clinical Pharmacology (12.3)

, Tables 6-7 Table 4

includes potentially significant interactions, but is not all inclusive.

Table 4: Established and Other Potentially Significant

a

Drug Interactions: Alteration in

Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted

Interaction

Concomitant Drug Class: Drug

Name

Effect on

Concentration

b

Clinical Comment

Antacids:

antacids (e.g., aluminium,

magnesium hydroxide, or

calcium carbonate)

rilpivirine

(antacids taken at

least 2 hours before

or at least 4 hours

after rilpivirine)

↓ rilpivirine

(concomitant intake)

The combination of EVIPLERA and

antacids should be used with caution as

coadministration may cause significant

decreases in rilpivirine plasma

concentrations (increase in gastric pH).

Antacids should only be administered

either at least 2 hours before or at least

4 hours after EVIPLERA.

Antimycobacterials:

rifabutin

↓ rilpivirine

Concomitant use of EVIPLERA with

rifabutin may cause significant decreases

in rilpivirine plasma concentrations

(induction of CYP3A enzymes). If

EVIPLERA is coadministered with

rifabutin, an additional 25 mg tablet of

rilpivirine (Edurant) once per day is

recommended to be taken concomitantly

with EVIPLERA and with a meal for the

duration of rifabutin coadministration.

Azole Antifungal Agents:

Fluconazole

itraconazole

ketoconazole

posaconazole

voriconazole

rilpivirine

↓ ketoconazole

Concomitant use of EVIPLERA with

azole antifungal agents may cause an

increase in the plasma concentrations

of rilpivirine (inhibition of CYP3A

enzymes). No dose adjustment is

required when EVIPLERA is

coadministered with azole antifungal

agents. Clinically monitor for

breakthrough fungal infections when

azole antifungals are coadministered

with EVIPLERA.

Hepatitis C Antiviral Agents:

ledipasvir/sofosbuvir

↑ tenofovir

Patients receiving EVIPLERA

concomitantly with HARVONI

(ledipasvir/sofosbuvir) should be

monitored for adverse reactions

associated with tenofovir disoproxil

fumarate.

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H

2

-Receptor

Antagonists:

cimetidine

famotidine

nizatidine

ranitidine

↔ rilpivirine

(famotidine taken

12 hours before

rilpivirine or 4 hours

after rilpivirine)

↓ rilpivirine

(famotidine taken 2

hours before

rilpivirine)

The combination of EVIPLERA and H

receptor antagonists should be used with

caution as coadministration may cause

significant decreases in rilpivirine plasma

concentrations (increase in gastric

pH). H

-receptor antagonists should only

administered at least 12 hours before or at

least 4 hours after EVIPLERA .

Macrolide or Ketolide

Antibiotics:

clarithromycin

erythromycin

telithromycin

rilpivirine

↔ clarithromycin

↔ erythromycin

↔ telithromycin

Concomitant use of EVIPLERA with

clarithromycin, erythromycin or

telithromycin may cause an increase in

the plasma concentrations of rilpivirine

(inhibition of CYP3A enzymes).

Where possible, alternatives such as

azithromycin should be considered.

Narcotic Analgesics:

methadone

↓ R(−) methadone

↓ S(+) methadone

↔ rilpivirine

↔ methadone

(when used with

tenofovir)

No dose adjustments are required when

initiating coadministration of methadone

with EVIPLERA. However, clinical

monitoring is recommended as

methadone maintenance therapy may

need to be adjusted in some patients.

ANTICOAGULANTS

Dabigatran etexilate

Interaction not

studied with any of

the components of

Eviplera.

A risk for increases in dabigatran

plasma concentrations

cannot be excluded (inhibition of

intestinal P-glycoprotein).

The combination of Eviplera and

dabigatran should be used with caution

Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)

Didanosine/Emtricitabine

Interaction not studied.

Co-administration of Eviplera and

didanosine is not recommended

Didanosine (400 mg once daily)

/Rilpivirine

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Didanosine:

AUC: ↑ 12%

: NA

: ↔

Rilpivirine:

AUC: ↔

: ↔

: ↔

Didanosine/Tenofovir disoproxil

fumarate

Co-administration of

tenofovir disoproxil

fumarate and

didanosine results in

a 40-60% increase in

systemic exposure to

didanosine that may

increase the risk of

didanosine-related

adverse reactions.

Rarely, pancreatitis

and lactic acidosis,

sometimes fatal,

have been reported.

Co-administration of

tenofovir disoproxil

fumarate and

didanosine at a dose

of 400 mg daily has

been associated with

a significant

decrease in CD4 cell

count, possibly due

to an intracellular

interaction

increasing

phosphorylated (i.e.

active) didanosine.

A decreased dosage

of 250 mg

didanosine co-

administered with

tenofovir disoproxil

fumarate therapy has

been associated with

reports of high rates

of virological failure

within several tested

combinations for the

treatment of HIV-1

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infection.

This table is not all inclusive.

Increase = ↑; Decrease = ↓; No Effect = ↔

The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted.

This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The

dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily.

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.

P-glycoprotein substrates:

Rilpivirine inhibits P-glycoprotein

in vitro

is 9.2 μM). In a

clinical study rilpivirine did not significantly affect the pharmacokinetics of digoxin. However, it

may not be completely excluded that rilpivirine can increase the exposure to other drugs

transported by P-glycoprotein that are more sensitive to intestinal P-glycoprotein inhibition (e.g.

dabigatran etexilate).

7.6 Drugs with No Observed or Predicted Interactions with EVIPLERA

No clinically significant drug interactions have been observed between emtricitabine and the

following medications: famciclovir, edipasvir/sofosbuvir

or tenofovir DF.

no clinically significant drug interactions have been observed between tenofovir DF and the

following medications: entecavir, methadone, oral contraceptives, ribavirin, sofosbuvir or

tacrolimus in studies conducted in healthy subjects.

No clinically significant drug interactions have been observed between rilpivirine and the

following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol,

ledipasvir/sofosbuvir

norethindrone, sildenafil,

simeprevir, sofosbuvir

telaprevir or tenofovir

DF. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or

metformin

No clinically relevant drug-drug interaction is expected when rilpivirine is

coadministered with ribavirin.

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8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Emtricitabine:

The incidence of fetal variations and malformations was not increased in

embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC)

approximately 60 times higher and in rabbits at approximately 120-times higher than human

exposures at the recommended daily dose.

Rilpivirine:

Studies in animals have shown no evidence of embryonic or fetal toxicity or an effect

on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during

pregnancy and lactation, there were no toxicologically significant effects on developmental

endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels in rats and

rabbits were respectively 15 and 70 times higher than the exposure in humans at the

recommended dose of 25 mg once daily.

Tenofovir Disoproxil Fumarate:

Reproduction studies have been performed in rats and rabbits at

doses up to 14 and 19 times the human dose based on body surface area comparisons and

revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal

reproduction studies are not always predictive of human response, EVIPLERA should be used

during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV infected mothers not

breastfeed their infants to avoid risking postnatal transmission of HIV.

Emtricitabine

: Samples of breast milk obtained from five HIV-1-infected mothers show that

emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated

with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other

emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are

unknown.

Rilpivirine:

Studies in lactating rats and their offspring indicate that rilpivirine was present in rat

milk. It is not known whether rilpivirine is secreted in human milk.

Tenofovir Disoproxil Fumarate

: Samples of breast milk obtained from five HIV-1-infected

mothers in the first post-partum week show that tenofovir is excreted in human milk. The impact

of this exposure in breastfed infants is unknown.

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Because of both the potential for HIV transmission and the potential for serious adverse reactions

in nursing infants,

mothers should be instructed not to breastfeed if they are receiving

EVIPLERA.

8.4 Pediatric Use

Eviplera is approved in Israel only for adult patients.

8.5 Geriatric Use

Clinical studies of emtricitabine, rilpivirine, or tenofovir DF did not include sufficient numbers of

subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, dose selection for the elderly patients should be cautious, keeping in mind the greater

frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other

drug therapy

[See Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Because EVIPLERA is a fixed-dose combination, it should not be prescribed for patients

requiring dosage adjustment such as those with moderate, severe or end stage renal impairment

(estimated creatinine clearance below 50 mL per minute) or that require dialysis

[See Warnings

and Precautions (5.4

Clinical Pharmacology (12.3)]

8.7 Hepatic Impairment

There is limited information regarding the use of Eviplera in patients with mild or moderate

hepatic impairment (Child-Pugh-Turcotte (CPT) Score A or B). No dose adjustment of Eviplera

is required in patients with mild or moderate hepatic impairment. Eviplera should be used with

caution in patients with moderate hepatic impairment. Eviplera has not been studied in patients

with severe hepatic impairment (CPT Score C). Therefore, Eviplera is not recommended in

patients with severe hepatic impairment

[See Clinical Pharmacology (12.3)]

10 OVERDOSAGE

If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose

with EVIPLERA consists of general supportive measures including monitoring of vital signs and

ECG (QT interval) as well as observation of the clinical status of the patient.

Emtricitabine:

Limited clinical experience is available at doses higher than the therapeutic dose

of EMTRIVA. In one clinical pharmacology study, single doses of emtricitabine 1200 mg were

administered to 11 subjects. No severe adverse reactions were reported. The effects of higher

doses are not known.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour

dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per

minute and a dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine

can be removed by peritoneal dialysis.

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Rilpivirine:

There is no specific antidote for overdose with rilpivirine. Human experience of

overdose with rilpivirine is limited. Since rilpivirine is highly bound to plasma protein, dialysis is

unlikely to result in significant removal of rilpivirine.

Administration of activated charcoal may also be used to aid in removal of unabsorbed active

substance.

Tenofovir Disoproxil Fumarate

: Limited clinical experience at doses higher than the therapeutic

dose of VIREAD 300 mg is available. In one study, 600 mg tenofovir DF was administered to 8

subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher

doses are not known.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately

54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed

approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

EVIPLERA is a fixed-dose combination tablet containing emtricitabine, rilpivirine hydrochloride,

and tenofovir DF. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog

of cytidine. EDURANT is the brand name for rilpivirine, a non-nucleoside reverse transcriptase

inhibitor. VIREAD is the brand name for tenofovir DF, which is converted in vivo to tenofovir,

an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. VIREAD

and EMTRIVA are the components of TRUVADA.

EVIPLERA tablets are for oral administration. Each tablet contains 200 mg of emtricitabine,

27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of rilpivirine), and 300 mg of tenofovir

DF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the

following inactive ingredients: pregelatinized starch, lactose monohydrate, microcrystalline

cellulose, croscarmellose sodium, magnesium stearate, povidone, polysorbate 20. The tablets are

film-coated with a coating material containing polyethylene glycol, hypromellose, lactose

monohydrate, triacetin, titanium dioxide, iron oxide red, indigo carmine aluminum lake (E132),

sunset yellow aluminum lake (E110)

Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-[(2R,5S)-2(hydroxymethyl)-1,3-

oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which

differs from other cytidine analogs in that it has a fluorine in the 5-position.

It has a molecular formula of C

S and a molecular weight of 247.24. It has the

following structural formula:

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Emtricitabine is a white to off-white crystalline powder with a solubility of approximately

112 mg per mL in water at 25 °C.

Rilpivirine: Rilpivirine is available as the hydrochloride salt. The chemical name for rilpivirine

hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-

2pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C

HCl

and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural

formula:

Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is

practically insoluble in water over a wide pH range.

Tenofovir Disoproxil Fumarate: Tenofovir DF is a fumaric acid salt of the

bisisopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir

DF is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine

fumarate (1:1). It has a molecular formula of C

P C

and a molecular weight of

635.52. It has the following structural formula:

Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg per mL in

water at 25 °C. All dosages are expressed in terms of tenofovir DF except where otherwise noted.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

EVIPLERA is a fixed-dose combination of antiviral drugs emtricitabine, rilpivirine and tenofovir

disoproxil fumarate

[See Microbiology (12.4)].

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12.2 Pharmacodynamics

Effects on Electrocardiogram

The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was

evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled

crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The

maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from

placebo after baseline-correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical

concern).

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine were

studied in healthy adults, the maximum mean time-matched (95% upper confidence bound)

differences in QTcF interval from placebo after baseline-correction were 10.7 (15.3) and 23.3

(28.4) milliseconds, respectively. Steady-state administration of rilpivirine 75 mg once daily and

300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and

6.7-fold,

respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose

of rilpivirine

[See Warnings and Precautions (5.5)]

12.3 Pharmacokinetics

EVIPLERA:

Under fed conditions (total calorie content of the meal was approximately 400 kcal

with approximately 13 grams of fat), rilpivirine, emtricitabine and tenofovir exposures were

bioequivalent when comparing EVIPLERA to EMTRIVA capsules (200 mg) plus EDURANT

tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy

subjects (N=34).

Single-dose administration of EVIPLERA tablet to healthy subjects under fasted conditions

provided approximately 25% higher exposure of rilpivirine compared to administration of

EMTRIVA capsules (200 mg) plus EDURANT tablets (25 mg) plus VIREAD tablets (300 mg),

while exposures of emtricitabine and tenofovir were comparable (N=15).

Emtricitabine:

Following oral administration, emtricitabine is absorbed with peak plasma

concentrations occurring at 1–2 hours post-dose. Following multiple dose oral administration of

EMTRIVA to 20 HIV-1 infected subjects, the mean steady-state plasma emtricitabine Cmax was

1.8 ± 0.7 μg per mL and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 μghr per mL.

The mean steady state plasma trough concentration at 24 hours post-dose was 0.09 μg per

mL. The mean absolute bioavailability of EMTRIVA capsules was 93%. Less than 4% of

emtricitabine binds to human plasma proteins

in vitro

over the range of 0.02 to 200 μg per mL.

Following administration of radiolabelled emtricitabine, recovery was approximately 86% in the

urine, approximately 14% in the feces, and 13% as metabolites in the urine. The metabolites of

emtricitabine include 3′-sulfoxide diastereomers (approximately 9% of the dose) and the

glucuronic acid conjugate (approximately 4% of the dose). Emtricitabine is eliminated by a

combination of glomerular filtration and active tubular secretion with a renal clearance in adults

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Eviplera_Tabs_oct_2016 USPI Feb 2016

with creatinine clearance >80 mL per minute of 213 ± 89 mL per minute (mean ± SD). The

plasma emtricitabine half-life is approximately 10 hours.

Rilpivirine:

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy

subjects and in adult antiretroviral treatment-naive HIV-1 infected subjects

[See Table 5]

Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.

After oral administration, the Cmax of rilpivirine is achieved within 4–5 hours. The absolute

bioavailability of rilpivirine is unknown.

Table 5 : Population Pharmacokinetic Estimates of Rilpivirine 25 mg Once Daily in

Antiretroviral Treatment-Naive HIV-1-infected Adult Subjects (Pooled Data from Phase 3

Trials through Week 96)

Parameter

Rilpivirine 25 mg once daily

N=679

(ngh/mL)

Mean ± Standard Deviation

2235 ± 851

Median (Range)

2096 (198 -7307)

(ng/mL)

Mean ± Standard Deviation

79 ± 35

Median (Range)

73 (2 -288)

Rilpivirine is approximately 99.7% bound to plasma proteins

in vitro

, primarily to albumin.

In

vitro

experiments indicate that rilpivirine primarily undergoes oxidative metabolism by the

cytochrome CYP3A system. The terminal elimination half-life of rilpivirine is approximately 50

hours. After single dose oral administration of

C-rilpivirine, on average 85% and 6.1% of the

radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine

accounted for on average 25% of the administered dose. Only trace amounts of unchanged

rilpivirine (less than 1% of dose) were detected in urine.

Tenofovir Disoproxil Fumarate:

Following oral administration of a single 300 mg dose of

VIREAD to HIV-1 infected subjects in the fasted state, Cmax was achieved in one hour. Cmax

and AUC values were 0.30 ± 0.09 μg per mL and 2.29 ± 0.69 μghr per mL, respectively. The

oral bioavailability of tenofovir from VIREAD in fasted subjects is approximately 25%. Less than

0.7% of tenofovir binds to human plasma proteins

in vitro

over the range of 0.01 to 25 μg per mL.

Approximately 70-80% of the intravenous dose of tenofovir is recovered as unchanged drug in

the urine within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular

filtration and active tubular secretion with a renal clearance in adults with creatinine clearance

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>80 mL per minute of 243.5 ± 33.3 mL per minute (mean ± SD). Following a single oral dose,

the terminal elimination half-life of tenofovir is approximately 17 hours.

Effects of Food on Oral Absorption

The food effect trial for

EVIPLERA

evaluated two types of meals. The trial defined a meal

with 390 kcal containing 12 g fat as a light meal, and a meal with 540 kcal containing 21 g

fat as a standard meal. Relative to fasting conditions, the administration of

EVIPLERA

healthy adult subjects with both types of meals resulted in increased exposures of rilpivirine

and tenofovir. The C

and AUC of rilpivirine increased 34% and 9% with a light meal,

while increasing 26% and 16% with a standard meal, respectively. The C

and AUC of

tenofovir increased 12% and 28% with a light meal, while increasing 32% and 38% with a

standard meal, respectively. Emtricitabine exposures were not affected by food.

The effects on rilpivirine, emtricitabine and tenofovir exposure when

EVIPLERA

administered with a high fat meal were not evaluated.

EVIPLERA

should be taken with food.

Special Populations

Race

Emtricitabine:

No pharmacokinetic differences due to race have been identified following the

administration of EMTRIVA.

Rilpivirine:

Population pharmacokinetic analysis of rilpivirine in HIV-1 infected subjects

indicated that race had no clinically relevant effect on the exposure to rilpivirine.

Tenofovir Disoproxil Fumarate:

There were insufficient numbers from racial and ethnic groups

other than Caucasian to adequately determine potential pharmacokinetic differences among these

populations following the administration of VIREAD.

Gender

No clinically relevant pharmacokinetic differences have been observed between men and women

for emtricitabine, rilpivirine, and tenofovir DF.

Geriatric Patients

Pharmacokinetics of emtricitabine, rilpivirine and tenofovir have not been fully evaluated in the

elderly (65 years of age and older)

[See Use in Specific Populations (8.5)].

Patients with Renal Impairment

Emtricitabine and Tenofovir Disoproxil Fumarate:

The pharmacokinetics of emtricitabine and

tenofovir DF are altered in subjects with renal impairment. In subjects with creatinine clearance

below 50 mL per minute or with end stage renal disease requiring dialysis, Cmax, and AUC of

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Eviplera_Tabs_oct_2016 USPI Feb 2016

emtricitabine and tenofovir were increased

[See Warnings and Precautions (5.4) and Use in

Specific Populations (8.6)]

Rilpivirine:

Population pharmacokinetic analysis indicated that rilpivirine exposure was similar in

HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with

normal renal function. There is limited or no information regarding the pharmacokinetics of

rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal

disease, and rilpivirine concentrations may be increased due to alteration of drug absorption,

distribution, and metabolism secondary to renal dysfunction

[See Use in Specific Populations

(8.6)]

Patients with Hepatic Impairment

No dose adjustment of Eviplera is suggested but caution is advised in patients with moderate

hepatic impairment. Eviplera has not been studied in patients with severe hepatic impairment

(CPT Score C). Therefore, Eviplera is not recommended in patients with severe hepatic

impairment.

The pharmacokinetics of emtricitabine have not been studied in patients with varying degrees of

hepatic insufficiency.

Rilpivirine hydrochloride is primarily metabolised and eliminated by the liver. In a study

comparing 8 patients with mild hepatic impairment (CPT Score A) to 8 matched controls and 8

patients with moderate hepatic impairment (CPT Score 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 (CPT Score C). However, it may not be excluded that the

pharmacologically active, unbound, rilpivirine exposure is significantly increased in moderate

impairment.

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected subjects with

varying degrees of hepatic impairment defined according to CPT classification. Tenofovir

pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting

that no dose adjustment is required in these subjects. The mean (%CV) tenofovir C

and AUC

0-∞

values were 223 (34.8%) ng/mL and 2,050 (50.8%) ngh/mL, respectively, in normal subjects

compared with 289 (46.0%) ng/mL and 2,310 (43.5%) ngh/mL in subjects with moderate hepatic

impairment, and 305 (24.8%) ng/mL and 2,740 (44.0%) ngh/mL in subjects with severe hepatic

impairment.

Hepatitis B and/or Hepatitis C Virus Coinfection

Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in hepatitis B

and/or C virus-coinfected patients. Population pharmacokinetic analysis indicated that hepatitis B

and/or C virus coinfection had no clinically relevant effect on the exposure to rilpivirine.

Drug Interaction Studies

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EVIPLERA is a complete regimen for the treatment of HIV-1 infection; therefore, EVIPLERA

should not be administered with other antiretroviral medications. Information regarding potential

drug-drug interactions with other HIV antiretroviral medications is not provided. Please refer to

the EDURANT, VIREAD and EMTRIVA prescribing information as needed.

The drug interaction studies described were conducted with EVIPLERA as a combination product

or with emtricitabine, rilpivirine, or tenofovir DF as individual agents.

EVIPLERA:

A drug interaction study for EVIPLERA was performed with HARVONI

(ledipasvir/sofosbuvir). No effect on the pharmacokinetic parameters of ledipasvir,

sofosbuvir, and GS-331007 (the predominant circulating metabolite of sofosbuvir) was

observed. There was no effect on the C

, AUC, and C

of emtricitabine or rilpivirine;

tenofovir C

increased by 32% (90% confidence interval [CI]: [↑25% to ↑39%]), tenofovir

AUC increased by 40% (90% CI: [↑31% to ↑50%]), and tenofovir C

increased by 91%

(90% CI: [↑74% to ↑110%])

[See Drug Interactions (7.5)].

Emtricitabine and Tenofovir Disoproxil Fumarate: In vitro

and clinical pharmacokinetic drug-

drug interaction studies have shown that the potential for CYP mediated interactions involving

emtricitabine and tenofovir with other medicinal products is low.

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular

filtration and active tubular secretion. No drug-drug interactions due to competition for renal

excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with

drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine,

tenofovir, and/or the coadministered drug

[See Drug Interactions (7.3, 7.6)]

Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

Drug interaction studies were performed for emtricitabine and the following medications:

tenofovir DF and famciclovir. Tenofovir increased the Cmin of emtricitabine by 20% (90%

confidence interval [CI]: [↑12% to ↑29%]) and had no effect on emtricitabine Cmax and AUC.

Emtricitabine had no effect on the Cmax, AUC and Cmin of tenofovir. Coadministration of

emtricitabine and famciclovir had no effect on the Cmax or AUC of either medication.

Drug interaction studies were performed for tenofovir DF and the following medications:

entecavir, methadone, oral contraceptives (ethinyl estrodiol/norgestimate), ribavirin, and

tacrolimus. Tacrolimus increased the Cmax of tenofovir by 13% (90% CI: [↑1% to ↑27%]) and

had no effect on the tenofovir AUC and Cmin. Tenofovir had no effect on the Cmax, AUC and

Cmin of tacrolimus.

The Cmax, AUC and Cmin of tenofovir were not affected in the presence of entecavir. Tenofovir

increased the AUC of entecavir by 13% (90% CI: [↑11% to ↑15%]) and had no effect on the

entecavir Cmax and Cmin.

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Tenofovir had no effect on the Cmax, AUC and Cmin of methadone, ethinyl or ethinyl

estrodiol/norgestimate or the Cmax and AUC of ribavirin.

Rilpivirine:

Rilpivirine is primarily metabolized by cytochrome CYP3A, and drugs that induce or

inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of EVIPLERA and

drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of

virologic response and possible resistance. Coadministration of EVIPLERA and drugs that inhibit

CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of

EVIPLERA with drugs that increase gastric pH may result in decreased plasma concentrations of

rilpivirine and loss of virologic response and possible resistance to rilpivirine and to the class of

NNRTIs.

Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the

exposure of medicinal products metabolized by CYP enzymes.

The effects of coadministration of other drugs on the AUC, Cmax and Cmin values of rilpivirine

are summarized in Table 7. The effect of coadministration of rilpivirine on the AUC, Cmax and

Cmin values of other drugs are summarized in Table 8. For information regarding clinical

recommendations, see

Drug Interactions (7)

Table 7: Drug Interactions: Changes in Pharmacokinetic Parameters for Rilpivirine in the

Presence of the Coadministered Drugs

Coadministered

Drug

Dose of

Coadministered

Drug (mg)

Dose of

Rilpivirine

N

a

Mean % Change of Rilpivirine

Pharmacokinetic Parameters

b

(90% CI)

C

max

AUC

C

min

Acetaminophen

500 mg single

dose

150 mg once

daily

↑ 9

(↑ 1 to ↑ 18)

↑ 16

(↑ 10 to ↑ 22)

↑ 26

(↑ 16 to ↑ 38)

Atorvastatin

40 mg once

daily

150 mg once

daily

↓ 9

(↓ 21 to ↑ 6)

↓ 10

(↓ 19 to ↓ 1)

↓ 10

(↓ 16 to ↓ 4)

Chlorzoxazone

500 mg single

dose taken 2

hours after

rilpivirine

150 mg once

daily

↑ 17

(↑ 8 to ↑ 27)

↑ 25

(↑ 16 to ↑ 35)

↑ 18

(↑ 9 to ↑ 28)

Ethinyl estradiol/

Norethindrone

0.035 mg once

daily/1 mg once

daily

25 mg once

daily

Famotidine

40 mg single

dose taken 12

hours before

rilpivirine

150 mg single

dose

↓ 1

(↓ 16 to ↑ 16)

↓ 9

(↓ 22 to ↑ 7)

40 mg single

dose taken 2

150 mg single

dose

↓ 85

(↓ 88 to ↓ 81)

↓ 76

(↓ 80 to ↓ 72)

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Eviplera_Tabs_oct_2016 USPI Feb 2016

hours before

rilpivirine

40 mg single

dose taken 4

hours after

rilpivirine

150 mg single

dose

↑ 21

(↑ 6 to ↑ 39)

↑ 13

(↑ 1 to ↑ 27)

Ketoconazole

400 mg once

daily

150 mg once

daily

↑ 30

(↑ 13 to ↑ 48)

↑ 49

(↑ 31 to ↑ 70)

↑ 76

(↑ 57 to ↑ 97)

Methadone

60 -100 mg once

daily

individualized

dose

25 mg once

daily

Omeprazole

20 mg once

daily

150 mg once

daily

↓ 40

(↓ 52 to ↓ 27)

↓ 40

(↓ 49 to ↓ 29)

↓ 33

(↓ 42 to ↓ 22)

Rifabutin

300 mg once

daily

25 mg once

daily

↓ 31

(↓ 38 to ↓ 24)

↓ 42

(↓ 48 to ↓ 35)

↓ 48

(↓ 54 to ↓ 41)

300 mg once

daily

50 mg once

daily

↑ 43

(↑ 30 to ↑ 56)

↑ 16

(↑ 6 to ↑ 26)

↓ 7

(↓ 15 to↑ 1)

Rifampin

600 mg once

daily

150 mg once

daily

↓ 69

(↓ 73 to ↓ 64)

↓ 80

(↓ 82 to ↓ 77)

↓ 89

(↓ 90 to ↓ 87)

Simeprevir

25 mg once

daily

150 mg once

daily

↑ 4

(↓ 5 to ↑ 13)

↑ 12

(↑ 5 to ↑ 19)

↑ 25

(↑ 16 to ↑ 35)

Sildenafil

50 mg single

dose

75 mg once

daily

↓ 8

(↓ 15 to ↓ 1)

↓ 2

(↓ 8 to ↑ 5)

↑ 4

(↓ 2 to ↑ 9)

Telaprevir

750 mg every 8

hours

25 mg once

daily

↑ 49

(↑ 20 to ↑ 84)

↑ 78

(↑ 44 to ↑ 120)

↑ 93

(↑ 55 to ↑ 141)

Tenofovir

Disoproxil

Fumarate

300 mg once

daily

150 mg once

daily

↓4

(↓19 to ↑13)

↑1

(↓13 to ↑18)

↓1

(↓17 to ↑16)

NA = not available

a. N=maximum number of subjects for C

, AUC, or C

b. Increase = ↑; Decrease = ↓; No Effect = ↔

c. The Interaction study has been performed with a dose higher than the recommended dose for rilpivirine

(25 mg once daily) assessing the maximal effect on the coadministered drug.

d. Comparison based on historic controls.

e. Reference arm for comparison was 25 mg q.d. rilpivirine administered alone.

Table 8: Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug

in the Presence of Rilpivirine

Coadministered

Drug

Dose of

Coadministered

Drug (mg)

Dose of

Rilpivirine

N

a

Mean % Change of Coadministered Drug

Pharmacokinetic Parameters

b

(90% CI)

C

max

AUC

C

min

Atorvastatin

40 mg once

150 mg

↑ 35

↑ 4

↓ 15

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Eviplera_Tabs_oct_2016 USPI Feb 2016

daily

once daily

(↑ 8 to ↑ 68)

(↓ 3 to ↑ 12)

(↓ 31 to ↑ 3)

hydroxyatorvastatin

↑ 58

(↑ 33 to ↑ 87)

↑ 39

(↑ 29 to ↑ 50)

↑ 32

(↑ 10 to ↑ 58)

hydroxyatorvastatin

↑ 28

(↑ 15 to ↑ 43)

↑ 23

(↑ 13 to ↑ 33)

Ethinyl estradiol

0.035 mg

once daily

25 mg once

daily

↑ 17

(↑ 6 to ↑ 30)

↑ 14

(↑ 10 to ↑ 19)

↑ 9

(↑ 3 to ↑ 16)

Ketoconazole

400 mg once

daily

150 mg

once daily

↓ 15

(↓ 20 to ↓ 10)

↓ 24

(↓ 30 to ↓ 18)

↓ 66

(↓ 75 to ↓ 54)

R(-) methadone

60-100 mg once

daily

individualized

dose

25 mg once

daily

↓ 14

(↓ 22 to ↓ 5)

↓ 16

(↓ 26 to ↓ 5)

↓ 22

(↓ 33 to ↓ 9)

S(+) methadone

↓ 13

(↓ 22 to ↓ 3)

↓ 16

(↓ 26 to ↓ 4)

↓ 21

(↓ 33 to ↓ 8)

Omeprazole

20 mg once

daily

150 mg

once daily

↓ 14

(↓ 32 to ↑ 9)

↓ 14

(↓ 24 to ↓ 3)

Rifampin

600 mg once

daily

150 mg

once daily

↑ 2

(↓ 7 to ↑ 12)

↓ 1

(↓ 8 to ↑ 7)

desacetylrifampin

(↓ 13 to ↑ 15)

↓ 9

(↓ 23 to ↑ 7)

Telaprevir

750 mg every 8

hours

25 mg once

daily

↓ 3

(↓ 21 to ↑ 21)

↓ 5

(↓ 24 to ↑ 18)

↓ 11

(↓ 33 to ↑

Tenofovir Disoproxil

Fumarate

300 mg once

daily

150 mg once

daily

↑19

(↑6 to ↑34)

↑23

(↑16 to ↑31)

↑24

(↑10 to ↑38)

NA = not available

a. N=maximum number of subjects for C

, AUC, or C

b. Increase = ↑; Decrease = ↓; No Effect = ↔

c. The Interaction study has been performed with a dose higher than the recommended dose for rilpivirine

(25 mg once daily).

No effect on the pharmacokinetic parameters of the following coadministered drugs was

observed with rilpivirine: acetaminophen, chlorzoxazone (administered 2 hours after

rilpivirine), digoxin, ledipasvir, norethindrone, metformin, sildenafil (and its metabolite, N-

desmethyl-sildenafil), and sofosbuvir (and its predominant circulating metabolite,

GS331007).

12.4 Microbiology

Mechanism of Action

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Emtricitabine:

Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by

cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits

the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-

triphosphate and by being incorporated into nascent viral DNA which results in chain

termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA

polymerase α, β, ε, and mitochondrial DNA polymerase γ.

Rilpivirine:

Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase

inhibitor of HIV-1 and inhibits HIV-1 replication 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 Disoproxil Fumarate:

Tenofovir DF is an acyclic nucleoside phosphonate diester

analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for

conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form

tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by

competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation

into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of

mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral Activity

Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate:

The triple combination of

emtricitabine, rilpivirine, and tenofovir was not antagonistic in cell culture.

Emtricitabine:

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

peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for

emtricitabine were in the range of 0.0013–0.64 μM. Emtricitabine displayed antiviral activity

in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from

0.007–0.075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged

from 0.007–1.5 μM). In drug combination studies of emtricitabine with nucleoside reverse

transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-

nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz,nevirapine, and rilpivirine),

and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects

were observed.

Rilpivirine:

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

acutely infected T-cell line with a median EC

value for HIV-1

IIIB

of 0.73 nM. Rilpivirine

demonstrated limited activity in cell culture against HIV-2 with a median EC50 value of

5220 nM (range 2510 to 10830 nM). Rilpivirine 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 and was less active against group O primary isolates

with EC50 values ranging from 2.88 to 8.45 nM. The antiviral activity of rilpivirine was not

antagonistic when combined with the NNRTIs efavirenz, etravirine or nevirapine; the

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N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir or zidovudine;

the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir,

saquinavir or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist

maraviroc or the integrase strand transfer inhibitor raltegravir.

Tenofovir Disoproxil Fumarate:

The antiviral activity of tenofovir against laboratory and

clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary

monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for

tenofovir were in the range of 0.04–8.5 μM. Tenofovir displayed antiviral activity in cell

culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–

2.2 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from

1.6 μM–5.5 μM). In drug combination studies of tenofovir with NRTIs (abacavir, didanosine,

emtricitabine, lamivudine, stavudine, and zidovudine), NNRTIs (delavirdine, efavirenz,

nevirapine, and rilpivirine), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir),

no antagonistic effects were observed.

Resistance

In Cell Culture

Emtricitabine and Tenofovir Disoproxil Fumarate:

HIV-1 isolates with reduced

susceptibility to emtricitabine or tenofovir have been selected in cell culture. Reduced

susceptibility to emtricitabine was associated with M184V/I substitutions in HIV-1 RT.

HIV-1 isolates selected by tenofovir expressed a K65R substitution in HIV-1 RT and

showed a 2

4 fold reduction in susceptibility to tenofovir. In addition, a K70E substitution

in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility

to abacavir, emtricitabine, lamivudine, and tenofovir.

Rilpivirine:

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 frequently

observed amino acid substitutions that emerged and conferred decreased phenotypic

susceptibility to rilpivirine included: L100I, K101E, V106I and A, V108I, E138K and G, Q,

R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C and M230I and L.

In HIV-1-Infected Adult Subjects with No Antiretroviral Treatment History

In the Week 96 pooled resistance analysis for subjects receiving rilpivirine or efavirenz in

combination with emtricitabine/tenofovir DF in the Phase 3 clinical trials C209 and C215, the

emergence of resistance was greater among subjects’ viruses in the rilpivirine plus

emtricitabine/tenofovir DF arm compared to the efavirenz plus emtricitabine/tenofovir DF

arm and was dependent on baseline viral load. In the pooled resistance analysis, 61% (47/77)

of the subjects who qualified for resistance analysis (resistance analysis subjects) in the

rilpivirine plus emtricitabine/tenofovir DF arm had virus with genotypic and/or phenotypic

resistance to rilpivirine compared to 42% (18/43) of the resistance analysis subjects in the

efavirenz plus emtricitabine/tenofovir DF arm who had genotypic and/or phenotypic

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resistance to efavirenz. Moreover, genotypic and/or phenotypic resistance to emtricitabine or

tenofovir emerged in viruses from 57% (44/77) of the resistance analysis subjects in the

rilpivirine arm compared to 26% (11/43) in the efavirenz arm.

Emerging NNRTI substitutions in the rilpivirine resistance analysis of subjects’ viruses

included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L and

M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6-621.

The E138K substitution emerged most frequently during rilpivirine treatment commonly in

combination with the M184I substitution. The emtricitabine and lamivudine resistance-

associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N,

A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the rilpivirine

resistance analysis subjects than in efavirenz resistance analysis subjects (See Table 9).

NNRTI-and NRTI-resistance substitutions emerged less frequently in the resistance analysis

of viruses from subjects with baseline viral loads of ≤100,000 copies/mL compared to viruses

from subjects with baseline viral loads of >100,000 copies/mL: 23% (10/44) compared to

77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of

NRTI-resistance substitutions. This difference was also observed for the individual

emtricitabine/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78%

(32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally,

NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance

analysis of the viruses from subjects with baseline CD4+ cell counts ≥200 cells/mm

compared to the viruses from subjects with baseline CD4+ cell counts <200 cells/mm

: 32%

(14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44)

compared to 73% (32/44) of NRTI-resistance substitutions.

Table 9: Proportion of Frequently Emerging Reverse Transcriptase Substitutions

inthe HIV-1 Virus of Resistance Analysis Subjects

a

Who Received Rilpivirine or

Efavirenz in Combination with Emtricitabine/Tenofovir DF from Pooled Phase 3

TMC278-C209 and TMC278-C215 Trials in the Week 96 Analysis

C209 and C215

N=1096

Rilpivirine

+ FTC/TDF

Efavirenz

+ FTC/TDF

N=550

N=546

Subjects who Qualified for

Resistance Analysis

14% (77/550)

8% (43/546)

Subjects with Evaluable

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Eviplera_Tabs_oct_2016 USPI Feb 2016

Post-Baseline Resistance

Data

Emergent NNRTI Substitutions

b

63% (44/70)

55% (17/31)

V90I

14% (10/70)

K101E/P/T/Q

19% (13/70)

10% (3/31)

K103N

1% (1/70)

39% (12/31)

E138K/A/Q/G

40% (28/70)

E138K+M184I

30% (21/70)

V179I/D

6% (4/70)

10% (3/31)

Y181C/I/S

13% (9/70)

3% (1/31)

V189I

9% (6/70)

H221Y

10% (7/70)

Emergent NRTI Substitutions

d

63% (44/70)

32% (10/31)

M184I/V

59% (41/70)

26% (8/31)

K65R/N

11% (8/70)

6% (2/31)

A62V, D67N/G, K70E, Y115F,

or K219E/R

20% (14/70)

3% (1/31)

a. Subjects who qualified for resistance analysis

b. V90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227, and

M230

c. This combination of NRTI and NNRTI substitutions is a subset of those with the E138K.

d. A62V, K65R/N, D67N/G, K70E, L74I, Y115F, M184V/I, L210F, K219E/R

e. These substitutions emerged in addition to the primary substitutions M184V/I or K65R; A62V (n=2),

D67N/G (n=3), K70E (n=4), Y115F (n=2), K219E/R (n=8) in rilpivirine resistance analysis subjects.

In Virologically-Suppressed HIV-1-Infected Subjects

Study 106: Through Week 48, four subjects who switched to EVIPLERA (4 of 469 subjects,

0.9%) and one subject who maintained their ritonavir-boosted protease inhibitor-based

regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to a

study drug. All four of the subjects who had resistance emergence on EVIPLERA had

evidence of emtricitabine resistance and three of the subjects had evidence of rilpivirine

resistance.

Cross Resistance

Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate:

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Eviplera_Tabs_oct_2016 USPI Feb 2016

In Cell Culture

No significant cross-resistance has been demonstrated between rilpivirine-resistant HIV-1

variants and emtricitabine or tenofovir, or between emtricitabine- or tenofovirresistant variants

and rilpivirine.

Rilpivirine:

Site-Directed NNRTI Mutant Virus

Cross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P,

Y181I and Y181V conferred 52-fold, 15-fold and 12-fold decreased susceptibility to

rilpivirine, respectively. The combination of E138K and M184I showed 6.7-fold reduced

susceptibility to rilpivirine compared to 2.8-fold for E138K alone. The K103N substitution

did not show reduced susceptibility to rilpivirine by himself.

However, 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.

Combinations of 2 or 3 NNRTI resistance-

associated substitutions gave decreased susceptibility to rilpivirine (fold change range of 3.7–

554) in 38% and 66% of mutants, respectively.

In HIV-1-Infected Subjects with No Antiretroviral Treatment History

Considering all of the available cell culture and clinical data, any of the following amino acid

substitutions, when present at baseline, are likely to decrease the antiviral activity of

rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I,

Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I+K103N.

Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and

development of rilpivirine resistance. In a pooled 96-Week analysis for subjects receiving

rilpivirine in combination with emtricitabine/tenofovir DF in the Phase 3 clinical trials

TMC278-C209 and TMC278-C215, 43 of the 70 (61%) rilpivirine resistance analysis

subjects with post-baseline resistance data had virus with decreased susceptibility to

rilpivirine (≥2.5-fold). Of these, 84% (n=36/43) were resistant to efavirenz (≥3.3 fold

change), 88% (n=38/43) were resistant to etravirine (≥3.2 fold change) and 60% (n=26/43)

were resistant to nevirapine (≥6 fold change). In the efavirenz arm, 3 of the 15 (20%)

efavirenz resistance analysis subjects had viruses with resistance to etravirine and rilpivirine,

and 93% (14/15) had resistance to nevirapine. Virus from subjects experiencing virologic

failure on rilpivirine in combination with emtricitabine/tenofovir DF developed more NNRTI

resistance-associated substitutions conferring more cross-resistance to the NNRTI class and

had a higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed

on efavirenz.

Emtricitabine

: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine but

retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs

Page 39 of 44

Eviplera_Tabs_oct_2016 USPI Feb 2016

(delavirdine, efavirenz, nevirapine, and rilpivirine). HIV-1 isolates containing the K65R

substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced

susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced

susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E),

or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the substitutions

associated with NNRTI resistance K103N or rilpivirine-associated substitutions were susceptible

to emtricitabine.

Tenofovir Disoproxil Fumarate:

The K65R and K70E substitutions selected by tenofovir are

also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1

isolates with the K65R and K70E substitutions also showed reduced susceptibility to

emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in

patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20)

whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions

(M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1fold decrease in the

susceptibility to tenofovir

Subjects whose virus expressed an L74V substitution without zidovudine resistance associated

substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients

whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion

(N=4), all of whom had a reduced response.

HIV-1 containing the substitutions associated with NNRTI resistance K103N and Y181C, or

rilpivirine-associated substitutions were susceptible to tenofovir.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Emtricitabine:

In long-term carcinogenicity studies of emtricitabine, no drug-related increases in

tumor incidence were found in mice at doses up to 750 mg per kg per day (26 times the human

systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per

kg per day (31 times the human systemic exposure at the therapeutic dose).

Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse

lymphoma or mouse micronucleus assays.

Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female

mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended

200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth

(in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than

human exposures at the recommended 200 mg daily dose.

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Eviplera_Tabs_oct_2016 USPI Feb 2016

Rilpivirine:

Rilpivirine was evaluated for carcinogenic potential by oral gavage administration to

mice and rats up to 104 weeks. Daily doses of 20, 60 and 160 mg per kg per day were

administered to mice and doses of 40, 200, 500 and 1500 mg per kg per day were administered to

rats. In rats, there were no drug related neoplasms. In mice, rilpivirine was positive for

hepatocellular neoplasms in both males and females. The observed hepatocellular findings in

mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the

systemic exposures (based on AUC) to rilpivirine were 21 fold (mice) and 3 fold (rats), relative to

those observed in humans at the recommended dose (25 mg once daily).

Rilpivirine has tested negative in the absence and presence of a metabolic activation system, in

in vitro

Ames reverse mutation assay and

in vitro

clastogenicity mouse lymphoma assay.

Rilpivirine did not induce chromosomal damage in the

in vivo

micronucleus test in mice

.

In a study conducted in rats, there were no effects on mating or fertility with rilpivirine up to 400

mg per kg per day, a dose of rilpivirine that showed maternal toxicity. This dose is associated

with an exposure that is approximately 40 times higher than the exposure in humans at the

recommended dose of 25 mg once daily.

Tenofovir Disoproxil Fumarate:

Long-term oral carcinogenicity studies of tenofovir DF in mice

and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats)

those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female

mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was

negative for carcinogenic findings at exposures up to 5 times that observed in humans at the

therapeutic dose.

Tenofovir DF was mutagenic in the

in vitro

mouse lymphoma assay and negative in an

in vitro

bacterial mutagenicity test (Ames test). In an

in vivo

mouse micronucleus assay, tenofovir DF

was negative when administered to male mice.

There were no effects on fertility, mating performance or early embryonic development when

tenofovir DF was administered to male rats at a dose equivalent to 10 times the human dose based

on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior

to mating through day seven of gestation. There was, however, an alteration of the estrous cycle

in female rats.

13.2 Animal Toxicology and/or Pharmacology

Tenofovir Disoproxil Fumarate:

Tenofovir and tenofovir DF administered in toxicology studies

to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those

observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as

osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction

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Eviplera_Tabs_oct_2016 USPI Feb 2016

or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone

mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN,

glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were

observed to varying degrees in these animals. These toxicities were noted at exposures (based on

AUCs) 2–20 times higher than those observed in humans. The relationship of the renal

abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

14

CLINICAL STUDIES

In HIV-1-Infected Adult Subjects with No Antiretroviral Treatment History

The efficacy of EVIPLERA is based on the analyses of 48 and 96 week data from two

randomized, double-blind, controlled studies C209 (ECHO) and TRUVADA subset of Study

C215 (THRIVE) in treatment-naive, HIV-1 infected subjects (N=1368). The studies are identical

in design with the exception of the background regimen (BR). Subjects were randomized in a 1:1

ratio to receive either rilpivirine 25 mg (N=686) once daily or efavirenz 600 mg (N=682) once

daily in addition to a BR. In Study C209 (N=690), the BR was emtricitabine/tenofovir DF. In

Study C215 (N=678), the BR consisted of 2 NRTIs: emtricitabine/tenofovir DF (60%, N=406) or

lamivudine/zidovudine (30%, N=204) or abacavir plus lamivudine (10%, N=68).

For subjects who received emtricitabine/tenofovir DF (N=1096) in C209 and C215, the mean age

was 37 years (range 18-78), 78% were male, 62% were White, 24% were Black, and 11% were

Asian. The mean baseline CD4+ cell count was 265 cells/mm

(range 1–888) and 31% had CD4+

cell counts <200 cells/mm

. The median baseline plasma HIV-1 RNA was 5 log

copies/mL

(range 2–7). Subjects were stratified by baseline HIV-1 RNA. Fifty percent of subjects had

baseline viral loads ≤100,000 copies/mL, 39% of subjects had baseline viral load between

100,000 copies/mL to 500,000 copies/mL and 11% of subject had baseline viral load >500,000

copies/mL.

Treatment outcomes through 96 weeks for the subset of subjects receiving

emtricitabine/tenofovir DF in studies C209 and C215 (Table 10) are generally consistent with

treatment outcomes for all participating subjects (presented in the prescribing information for

EDURANT). The incidence of virologic failure was higher in the rilpivirine arm than the

efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly

occurred in the first 48 weeks of treatment.

Table 9 :Virologic Outcome of Randomized Treatment of Studies C209 and C215 (Pooled Data

for Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF)

at Week 96

a

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Eviplera_Tabs_oct_2016 USPI Feb 2016

Rilpivirine + FTC/TDF

Efavirenz + FTC/TDF

N=550

N=546

HIV-1 RNA <50 copies/mL

b

HIV-1 RNA ≥50 copies/mL

c

No virologic data at Week 96

window

Reasons

Discontinued study due to adverse

event or death

Discontinued study for other

reasons

and the last available HIV-

1 RNA <50 copies/mL (or missing)

Missing data during window but on

study

<1%

<1%

HIV-1 RNA <50 copies/mL by

Baseline HIV-1 RNA (copies/mL)

≤100,000

>100,000

HIV-1 RNA ≥50 copies/mL

c

by

Baseline HIV-1 RNA (copies/mL)

≤100,000

>100,000

HIV-1 RNA <50 copies/mL by

Baseline CD4+ Cell Count

(cells/mm

3

)

<200

≥200

HIV-1 RNA ≥50 copies/mL

c

by

Baseline CD4+ Cell Count

(cells/mm

3

)

<200

≥200

a. Analyses were based on the last observed viral load data within the Week 96 window (Week 90-103).

b. Predicted difference (95% CI) of response rate is 0.5% (-4.5% to 5.5%) at Week 96.

c. Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to

lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or

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Eviplera_Tabs_oct_2016 USPI Feb 2016

loss of efficacy and at the time of discontinuation had a viral load value of ≥50 copies/mL, and subjects who

had a switch in background regimen that was not permitted by the protocol.

d. Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment

virologic data in the Week 96 window.

e. Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of

efficacy, e.g., withdrew consent, loss to follow-up, etc.

Based on the pooled data from studies C209 and C215, the mean CD4+ cell count increase from

baseline at Week 96 was 226 cells/mm

for rilpivirine plus emtricitabine/tenofovir DF-treated

subjects and 223 cells/mm

for efavirenz plus emtricitabine/tenofovir DF-treated subjects.

In Virologically-Suppressed HIV-1-Infected subjects

The efficacy and safety of switching from a ritonavir-boosted protease inhibitor in combination

with two NRTIs to EVIPLERA was evaluated in Study 106, a randomized, open-label study in

virologically-suppressed HIV-1-infected adults. Subjects had to be on either their first or second

antiretroviral regimen with no history of virologic failure, have no current or past history of

resistance to any of the three components of EVIPLERA, and must have been suppressed (HIV-1

RNA <50 copies/mL) for at least 6 months prior to screening. Subjects were randomized in a 2:1

ratio to either switch to EVIPLERA at baseline (EVIPLERA arm, N = 317), or stay on their

baseline antiretroviral regimen for 24 weeks (SBR arm, N = 159) and then switch to

EVIPLERA

for an additional 24 weeks (N =152). Subjects had a mean age of 42 years (range 19-73), 88%

were male, 77% were White, 17% were Black, and 17% were Hispanic/Latino. The mean

baseline CD4+ cell count was 584 cells/mm

(range 42–1484). Randomization was stratified by

use of tenofovir DF and/or lopinavir/ritonavir in the baseline regimen.

Treatment outcomes are presented in Table 11.

Table 11 Virologic Outcomes of Randomized Treatment in Study GS-US-264-0106

EVIPLERA

Week 48

a

Stayed on Baseline Regimen

(SBR)

Week 24

b

N = 317

N = 159

HIV-1 RNA <50 copies/mL

c

89% (283/317)

90% (143/159)

HIV-1 RNA ≥50 copies/mL

3% (8/317)

5% (8/159)

No Virologic Data at Week

24 Window

Discontinued Study Drug

Due to AE or Death

2% (7/317)

Discontinued Study Drug

5% (16/317)

3% (5/159)

Page 44 of 44

Eviplera_Tabs_oct_2016 USPI Feb 2016

Due to Other Reasons and

Last Available HIV-1 RNA

<50 copies/mL

Missing Data During

Window but on Study Drug

1% (3/317)

2% (3/159)

a. Week 48 window is between Day 295 and 378 (inclusive).

b. For subjects in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to

EVIPLERA, the Week 24 window is between Day 127 and first dose day on EVIPLERA.

c. Predicted difference (95% CI) of response rate for switching to EVIPLERA at Week 48 compared to

staying on baseline regimen at Week 24 (in absence of Week 48 results from the SBR group by study

design) is -0.7% (-6.4% to 5.1%).

d. Includes subjects who had HIV-1 RNA ≥50 copies/mL in the time window, subjects who discontinued

early due to lack or loss of efficacy, and subjects who discontinued for reasons other than an adverse event

or death and at

the time of discontinuation had a viral load value of ≥50 copies/mL.

e. Includes subjects who discontinued due to adverse event 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 subjects who discontinued for reasons other than an adverse event, death or lack or loss of

efficacy, e.g., withdrew consent, loss to follow-up, etc.

16 HOW SUPPLIED/STORAGE AND HANDLING

EVIPLERA tablets are purplish-pink, capsule-shaped, film-coated, debossed with “GSI” on one

side and plain-faced on the other side. Each bottle contains 30 tablets, a silica gel desiccant,

polyester fiber coil, and is closed with a child-resistant closure.

Do not Store above 25 °C.

Keep container tightly closed in order to protect from moisture

Dispense only in original container

Do not use if seal over bottle opening is broken or missing.

17. MANUFACTURER

Janssen Cilag, Latina, Italy

18. REGISTRATION HOLDER

J-C HealthCare Ltd, Kibbutz Shefayim 6099000, Israel