EDURANT

The format of this leaflet was determined by the Ministry of Health

and its content was checked and approved

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) – 1986

The medicine is dispensed with a doctor’s prescription only

Preparation name, its form and strength

Edurant

®

25 mg, Film-Coated Tablets

Active ingredient and its quantity per dosage unit

Rilpivirine (as HCl) 25 mg per tablet

Inactive and allergenic ingredients in the preparation - see section

6 “Further information”.

Read this leaflet carefully in its entirety before using the medicine.

This leaflet contains concise information about the medicine. If you

have further questions, refer to the doctor or pharmacist.

This medicine has been prescribed for the treatment of your ailment.

Do not pass it on to others. It may harm them even if it seems to

you that their ailment is similar.

The medicine is intended for adults )above the age of 18 years(.

1. WHAT IS THE MEDICINE INTENDED FOR?

Edurant is a medicine intended for the treatment of AIDS )caused

by HIV [human immunodeficiency virus] infection( in adults. This

medicine belongs to a group of HIV medicines called non-nucleoside

reverse transcriptase inhibitors )NNRTIs(. Edurant works by reducing

the amount of HIV in your body. This reduction will lead to an

improved immune system and to a reduction in the risk of developing

diseases that are associated with HIV.

Edurant is intended for adults who were not treated in the past with

other HIV medicines and whose viral load does not exceed 100,000

copies per ml. The doctor will measure your viral load.

Edurant is always given in combination with other HIV medicines.

Your doctor will explain to you which combination of medicines is

best for you.

Edurant does not cure HIV infection or AIDS. See section: "Special

warnings regarding use of the medicine" - how to avoid infecting

others with the virus.

Therapeutic group - HIV treatment from the non-nucleoside reverse

transcriptase inhibitors )NNRTIs( group.

2. BEFORE USING THE MEDICINE:

Do not use the preparation if:

you are sensitive )allergic( to the active ingredient rilpivirine or to

any of the other ingredients of Edurant. For a list of the additional

ingredients, see section 6 "Further information".

you have been treated in the past with other preparations for

the treatment of HIV.

Do not take Edurant in combination with any of the following

medicines, as they may affect the activity of Edurant or

alternatively, Edurant may affect the activity of the medicines:

∘ carbamazepine, oxcarbazepine, phenobarbital, phenytoin

)medicines to treat epilepsy and prevent seizures(

∘ rifampicin and rifapentine )medicines to treat bacterial

infections, such as tuberculosis(

∘ omeprazole, esomeprazole, lansoprazole, pantoprazole,

rabeprazole )medicines from the proton pump inhibitors group

for prevention and treatment of stomach ulcers, heartburn or

acid reflux disease(

∘ dexamethasone )a corticosteroid used in a variety of

conditions, such as inflammations and allergic reactions(,

when taken orally or by injection, except when administered

as a single-dose treatment

∘ preparations that contain St. John’s Wort )Hypericum

perforatum( )a herbal preparation taken in states of

depression(

If you are taking any of the above mentioned medicines, consult

with your doctor about alternatives.

Special warnings regarding use of the medicine:

Edurant does not cure HIV infection. This medicine is part of a

treatment to reduce the amount of virus in the blood. You can

still transmit HIV to others through sexual contact or exposure to

blood carrying HIV.

Avoid doing things that can transmit HIV to others:

- Do not have unprotected sex. Always have protected sex by

using a condom to lower the chance of sexual contact with body

fluids, such as: semen, vaginal secretions, or blood.

- Never reuse needles or use other people’s needles.

- Do not share personal items that may have blood or bodily fluids

on them, such as a toothbrush and razor blades.

People taking Edurant can still develop infections or other illnesses

associated with HIV. You must maintain regular contact with your

doctor.

Edurant is not intended for use in children or adolescents under

18 years of age.

Edurant has only been used by a limited number of patients 65

years of age and older. If you belong to this age group, consult

the doctor about taking this medicine.

Before treatment with Edurant, tell the doctor about your

condition:

Tell your doctor if you suffer, or have suffered in the past, from liver

problems, including hepatitis B and/or C, and/or kidney problems.

Your doctor may evaluate how severe your liver or kidney disease

is before deciding if you can start taking Edurant.

Tell your doctor if you notice changes in body shape or body fat.

A gain, loss or redistribution of body fat may occur if you take

Edurant.

Tell your doctor immediately if you notice any symptoms of an

infection. In some patients with advanced HIV infection and

a history of opportunistic infections, signs and symptoms of

inflammation from previous infections may occur soon after HIV

treatment is started. It is assumed that these signs and symptoms

are due to an improvement in the body’s immune response, which

allows the body to fight existing infections that did not show any

obvious symptom.

In addition to the opportunistic infections, autoimmune disorders

)a condition that occurs when the immune system attacks healthy

body tissue( may also occur after you start taking medicines for

treatment of HIV. Autoimmune disorders may even occur many

months after the start of treatment. If you notice any symptoms

of infection or symptoms such as muscle weakness, weakness

beginning in the hands and feet and moving up towards the trunk

of the body, palpitations, tremor or hyperactivity, inform your

doctor immediately.

Tell your doctor if you have ever suffered from mental health

problems.

If you are taking, or have recently taken, any other medicines,

including non-prescription medicines and nutritional supplements,

tell the doctor or pharmacist.

Edurant is taken together with other HIV medicines. Your doctor

will advise you on which HIV medicines you have to take together

with Edurant. Follow the doctor’s instructions.

Some medicines may affect the levels of Edurant in the blood

when they are taken at the same time as Edurant.

It is not recommended to take Edurant together with other

non-nucleoside reverse transcriptase inhibitors )NNRTIs(, such as:

delavirdine, efavirenz, etravirine and nevirapine.

The effect of Edurant or of other medicines might be changed if

you take Edurant together with any of the following medicines;

consult with your doctor if you are taking:

∘ Rifabutin )a medicine for the treatment of certain bacterial

infections(. If you are taking this medicine during the course

of treatment with Edurant, please carefully read how to take

Edurant in section 3 “How should the medicine be used?”.

∘ Clarithromycin, erythromycin, troleandomycin )antibiotics(.

∘ Cimetidine, famotidine, nizatidine, ranitidine )antihistamines,

-receptor antagonists, used to treat stomach or intestinal

ulcers or to relieve heartburn due to acid reflux(. If you take these

medicines, please carefully read how to take them in section 3

“How should the medicine be used?”.

∘ Antacids )for treatment of diseases related to stomach acidity,

such as aluminium/magnesium hydroxide, calcium carbonate(.

If you take these medicines, please carefully read how to take

them in section 3 “How should the medicine be used?”.

∘ Methadone )used to treat narcotic withdrawal or dependence(.

∘ Dabigatran )anticoagulant(.

∘ Fluconazole, itraconazole, ketoconazole, posaconazole and

voriconazole taken orally or by injection )for treatment of fungal

infections(.

If you take any of the medicines listed above, consult with your

doctor.

Taking Edurant and food

It is very important that Edurant be taken with a meal. A meal is

important in order to absorb the right levels of medicine in your

body.

A nutritional drink alone, rich in proteins, is not considered a

substitute for a meal.

See section 3 “How should the medicine be used?”.

Pregnancy and breastfeeding

Consult with the doctor before taking Edurant if you are planning

to become pregnant.

Tell your doctor immediately if you are pregnant. Pregnant women

must not take Edurant unless specifically directed by the doctor.

Do not breastfeed if you are an HIV carrier, as there is a fear of

infecting the baby via breast milk.

Driving and using machines

Some patients may experience tiredness, dizziness or drowsiness

during treatment with Edurant. Do not drive or operate dangerous

machinery if you feel tired, dizzy or drowsy while taking Edurant.

Important information about some of the ingredients of the

medicine

Edurant contains lactose )approximately 56 mg lactose

monohydrate(.

If you suffer from an intolerance to certain sugars, consult with the

doctor before starting treatment with Edurant.

3. HOW SHOULD THE MEDICINE BE USED?

Always use according to the doctor’s instructions.

Check with the doctor if you are not sure how to use it.

The dosage and treatment regimen will be determined by the doctor

only. The usual dosage is one tablet once a day.

Do not exceed the recommended dose.

Take the tablet with a meal. A meal is important in order to absorb

the right levels of medicine in your body.

A nutritional drink alone, rich in proteins, is not considered

a substitute for a meal.

There is no information regarding the possibility of crushing/halving or

chewing the tablets.

Nonetheless, crushing them is not recommended

as this can cause loss of the substance and, thereby, administration

of an inaccurate dosage.

There are three situations that require special attention:

- If you are taking rifabutin )a medicine for the treatment of certain

bacterial infections(, take two Edurant tablets once a day. When

you cease taking rifabutin, take one Edurant tablet once a day.

Speak to the doctor or pharmacist if you are uncertain.

- If you take antacids )to treat diseases related to stomach acidity,

such as: aluminium/magnesium hydroxide, calcium carbonate(.

Take the antacid either at least 2 hours before or at least 4 hours

after taking Edurant.

- If you take antihistamines, H

-receptor antagonists )to treat

stomach or intestinal ulcers or to relieve heartburn due to acid

reflux(, such as cimetidine, famotidine, nizatidine or ranitidine.

Take the H

-receptor antagonist at least 12 hours before or at least

4 hours after taking Edurant. H

-receptor antagonists should not

be taken in a twice-a-day regimen. Refer to the doctor about an

alternative regimen.

Child-resistant caps have significantly lowered the number of

poisoning cases caused by medicines each year. Yet, if you find it

hard to open the bottle, you can refer to the pharmacist and ask to

remove the safety mechanism from the cap and

turn it into a regular, easy-to-open cap.

Opening instructions: The plastic bottle comes

with a child-resistant cap. Open the cap

according to the following instructions:

Press down on the plastic cap, while turning

counterclockwise

Remove the cap

If you have accidentally taken a higher

dosage. If you took an overdose, or if a child

accidentally swallowed the medicine, refer

immediately to a doctor or to a hospital emergency room and

bring the package of the medicine with you. In case of an overdose,

you may suffer from a headache, nausea, dizziness and/or unusual

dreams.

If you forget to take Edurant: If you notice that you forgot to

take Edurant within 12 hours of the time you usually take it - take

Edurant as soon as you remember. Always take Edurant with a

meal. Afterwards, continue taking Edurant as usual, at the regular

time.

If you notice that you forgot to take Edurant after 12 hours from

the time you usually take it, skip the present dose and continue

taking the rest of the doses at their usual times. Do not take a

double dose to make up for a forgotten dose.

How can you contribute to the success of the treatment?

Comply with the treatment recommended by the doctor.

Even if there is an improvement in your health, do not stop

treatment with Edurant or with the other HIV medicines you are

taking, or change the medicine dosages without consulting the

doctor.

Be sure that you have an adequate supply of Edurant and of the

additional required medicines.

If you stop taking the medicine, even for a short time, you can

bring about an increased virus level in your blood and increase the

risk of the HIV developing resistance. Before stopping treatment

with the medicine, consult the doctor.

Do not take medicines in the dark! Check the label and the dose

each time you take medicine. Wear glasses if you need them.

If you have any further questions regarding use of the medicine,

consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Edurant may cause side effects in some

users. Do not be alarmed when reading the list of side effects. You

may not suffer from any of them.

Edurant may cause the following severe side effects:

- Severe skin rash and allergic reaction. Skin rash is a common

side effect of Edurant. Skin rash can be serious and may need to

be treated in a hospital. Inform your doctor right away if you get

a rash.

If you get a rash with any of the following symptoms, stop taking

Edurant and get medical help right away:

fever, skin blisters, mouth sores, swelling of the face, lips, mouth,

tongue or throat, trouble breathing or swallowing, pain on the right

side of the abdominal area, dark colored urine.

- Depression or mood change. Inform the doctor immediately if you

feel any of the following symptoms: If you feel sad or hopeless, if

you feel restless or anxious, if you have thoughts of hurting yourself

)suicide( or if you have tried to hurt yourself.

- Liver problems may develop in patients taking Edurant. People with

a history of hepatitis B or C or who have certain changes in liver

function test results may have an increased risk of developing new

or worsening liver problems during treatment with Edurant. Liver

problems have also been reported during treatment with Edurant

in patients without history of liver diseases. Your doctor may need

to perform liver function tests before and during treatment with

Edurant.

- Changes in body fat may occur in people taking HIV medicines.

These changes may include an increased amount of fat in the

upper back and neck )“buffalo humps”(, in the breast, and around

the middle of the body. Loss of fat from the legs, arms, and face

may also occur. The exact cause and long-term health effects of

these problems are not known.

- Changes in the immune system may occur at the beginning of

treatment with HIV medicines. Your immune system may get

stronger and begin to fight infections that have been hidden in

your body for a long time. Refer to the doctor immediately if you

notice any symptom of infection after starting use of the HIV

medicines.

Additional side effects:

Side effects occurring frequently:

Effects that appear in more than one user in 10:

An increase in cholesterol and/or in a pancreatic enzyme called

amylase in the blood; change in liver function test results; headache;

depression, depressed mood; insomnia; rash; nausea; dizziness

Effects that appear in less than one user in 10:

Low white blood cell and/or platelet count, decreased hemoglobin

in the blood, increased blood triglycerides; increased blood lipase

and/or bilirubin; decreased appetite; abnormal dreams, sleep

disorders; drowsiness; stomach pain, vomiting, stomach discomfort,

dry mouth; tiredness

Effects that appear infrequently )affect less than 1 user in 100(:

Signs or symptoms of inflammation or infection )immune reactivation

syndrome(.

If one of the side effects worsens, or if you suffer from a side effect

not mentioned in the leaflet, consult with the doctor.

Side effects can be reported to the Ministry of Health by clicking

on the link “Report Side Effects of Drug Treatment” found on the

Ministry of Health homepage )www.health.gov.il( that directs you to

the online form for reporting side effects.

5. HOW SHOULD THE MEDICINE BE STORED?

Avoid poisoning! This medicine and any other medicines, should

be kept in a safe place out of the reach of children and/or infants, in

order to avoid poisoning. Do not induce vomiting unless explicitly

instructed to do so by a doctor.

Do not use the medicine after the expiry date )exp. date( appearing

on the package. The expiry date refers to the last day of that

month.

Do not store the medicine at a temperature above 30°C.

Store the Edurant tablets in their original bottle in order to protect

the medicine from light.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine also contains:

Lactose Monohydrate, Croscarmellose Sodium, Povidone )K30(,

Polysorbate 20, Silicified Microcrystalline Cellulose, Magnesium

Stearate, Hypromellose 2910 6 mPa.s, Titanium Dioxide, Macrogol

3000, Triacetin.

Allergenic ingredients: the medicine contains lactose.

What the medicine looks like and contents of the package:

white to off-white, film-coated, round, biconvex tablet, with “TMC”

imprinted on one side and “25” imprinted on the other side.

The package )plastic bottle( contains 30 tablets.

Registration Holder and address: J-C Health Care Ltd.,

Kibbutz Shefayim 6099000, Israel.

Manufacturer and address: Janssen-Cilag, Latina, Italy.

This leaflet was checked and approved by the Ministry of Health

in May 2016.

Registration number of the medicine in the National Drug Registry

of the Ministry of Health: 148 57 33585 00

Edurant SH

07/16

Edurant SH

07/16

Edurant_SPC_Jul_2020 USPI AUG 2015

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

EDURANT

TM

Rilpivirine 25mg tablets

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

EDURANT™, in combination with other antiretroviral agents, is indicated for the treatment of human

immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve adult patients with

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

This indication is based on safety and efficacy analyses through 96 weeks from 2 randomized, double-

blind, active controlled, Phase 3 trials in treatment-naïve subjects

[see Clinical Studies (14.1)]

The following points should be considered when initiating therapy with EDURANT:

More EDURANT 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 EDURANT

treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [

see Clinical Studies (14.1)

Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with

CD4+ cell count less than 200 cells/mm

experienced virologic failure compared to

EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm

[see Clinical Studies (14.1)]

The observed virologic failure rate in EDURANT treated subjects conferred a higher rate of

overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz [

see

Clinical Pharmacology (12.4)

More subjects treated with EDURANT developed lamivudine/emtricitabine associated

resistance compared to efavirenz [

see Clinical Pharmacology (12.4)

EDURANT is not recommended for patients less than 18 years of age

[see Use In Specific

Populations (8.4)]

2 DOSAGE AND ADMINISTRATION

The recommended dose of EDURANT is one 25 mg tablet once daily taken orally with a meal [

see

Clinical Pharmacology (12.3)

Rifabutin Co-administration:

For patients concomitantly receiving rifabutin, the

EDURANT dose should be increased to 50 mg (two tablets of 25 mg each) once daily,

taken with a meal. When rifabutin co-administration is stopped, the EDURANT dose

should be decreased to 25 mg once daily, taken with a meal

[see Drug Interactions (7),

Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

25 mg white to off-white, film-coated, round, biconvex, tablet of 6.4 mm, debossed with “TMC” on

one side and “25” on the other side. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is

equivalent to 25 mg of rilpivirine.

Edurant_SPC_Jul_2020 USPI AUG 2015

4 CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients.

EDURANT should not be co-administered 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 EDURANT or to the class of

NNRTIs [

see also Drug Interactions (7) and Clinical Pharmacology (12.3)

the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin

the antimycobacterials rifabutin, rifampin, rifapentine

proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole,

rabeprazole

the glucocorticoid systemic dexamethasone (more than a single dose)

St John’s wort (

Hypericum perforatum

5 WARNINGS AND PRECAUTIONS

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce

the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission

should be taken in accordance with national guidelines.

5.1 Drug Interactions

Caution should be given to prescribing EDURANT 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)

]. EDURANT should be used with caution when co-administered with a

drug with a known risk of Torsade de Pointes.

5.2 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 3% of subjects receiving EDURANT. No grade 4 rash

was reported. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of

therapy [see Adverse Reactions (6 and 6.2)]. Discontinue EDURANT 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.

5.3 Depressive Disorders

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

mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with EDURANT.

Patients with severe depressive symptoms should seek immediate medical evaluation to assess the

Edurant_SPC_Jul_2020 USPI AUG 2015

possibility that the symptoms are related to EDURANT, 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 EDURANT (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 EDURANT and efavirenz. The

incidence of discontinuation due to depressive disorders among EDURANT 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 EDURANT arm.

During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N = 36) receiving

EDURANT through 48 weeks, the incidence of depressive disorders (regardless of causality, severity)

was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4

depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due

to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.

5.4 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 transaminases prior to treatment may

be at increased risk for worsening or development of transaminase elevations with use of EDURANT.

A few cases of hepatic toxicity have been reported in 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 EDURANT is

recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with

marked elevations in transaminases prior to treatment initiation. Liver enzyme monitoring should also

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

5.5 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 currently unknown. A causal relationship has not been established.

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral

therapy, including EDURANT. 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

jiroveci

pneumonia 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.

Important information about some of the ingredients of EDURANT

EDURANT contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp

lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

6 ADVERSE REACTIONS

The following adverse drug reaction (ADR) is discussed in greater detail in other sections of the

package insert:

Edurant_SPC_Jul_2020 USPI AUG 2015

Skin and Hypersensitivity Reactions [

see Warnings and Precautions (5.2)]

Depressive Disorders [

see Warnings and Precautions (5.3)

Hepatotoxicity [

see Warnings and Precautions (5.4

6.1 Clinical Trials Experience

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 clinical practice.

The safety assessment is based on the Week 96 pooled data from 1368 patients in the Phase 3

controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-

naïve HIV-1 infected adult patients, 686 of whom received EDURANT (25 mg once daily) [

see

Clinical Studies (14.1)

]. The median duration of exposure for patients in the EDURANT arm and

efavirenz arm was 104.3 and 104.1 weeks, respectively. Most ADRs occurred in the first 48 weeks of

treatment.The proportion of subjects who discontinued treatment with EDURANT or efavirenz due to

ADR, regardless of severity, was 2% and 4%, respectively. The most common ADRs leading to

discontinuation were psychiatric disorders: 10 (1%) subjects in the EDURANT arm and 11 (2%)

subjects in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the EDURANT arm

and 10 (1.5%) subjects in the efavirenz arm.

Common Adverse Drug Reactions

Clinical ADRs of at least moderate intensity (≥ Grade 2) reported in at least 2% of adult subjects are

presented in Table 1. Selected treatment-emergent laboratory abnormalities are included in Table 2.

Table 1: Selected Treatment-Emergent Adverse Drug Reactions of at least Moderate

Intensity*(Grade 2-4) Occurring in at Least 2% of Antiretroviral Treatment-Naïve HIV-1

Infected Adult Subjects (week 96 analysis)

System Organ Class,

Preferred Term,

%

Pooled Data from the TMC278-C209

and TMC278-C215 Trials

EDURANT+BR

N=686

Efavirenz+BR

N=682

Gastrointestinal Disorders

Nausea

Abdominal pain

Vomiting

General Disorders and Administration Site Conditions

Fatigue

Nervous System Disorders

Edurant_SPC_Jul_2020 USPI AUG 2015

Headache

Dizziness

Psychiatric Disorders

Depressive disorders†

Insomnia

Abnormal Dreams

Skin and Subcutaneous Tissue Disorders

Rash

N=total number of subjects per treatment group, BR=background regimen

* Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual

activity); Severe (incapacitating with inability to work or do usual activity).

includes adverse drug reactions reported as depressed mood, depression, dysphoria, major

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

No new ADR terms were identified in adult subjects in the Phase 3 TMC278-C209 and TMC278-C215

trials between 48 weeks and 96 weeks nor in the Phase 2b TMC278-C204 trial through 240 weeks. The

incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials

through 96 weeks.

Less Common Adverse Drug Reactions

Treatment-emergent ADRs of at least moderate intensity (≥ Grade 2) occurring in less than 2% of

antiretroviral treatment-naïve subjects receiving EDURANT are listed below by Body System. Some of

these events have been included because of investigator’s assessment of potential causal relationship

and were considered serious or have been reported in more than 1 subject treated with EDURANT.

Gastrointestinal Disorders

: diarrhea, abdominal discomfort

Hepatobiliary Disorders

: cholecystitis, cholelithiasis

Metabolism and Nutrition Disorders

: decreased appetite

Nervous System

: somnolence

Psychiatric Disorder

: sleep disorders, anxiety

Renal and Urinary Disorders

: glomerulonephritis membranous, glomerulonephritis

mesangioproliferative, nephrolithiasis

Laboratory Abnormalities in Treatment-Naïve Subjects

The percentage of subjects treated with EDURANT or efavirenz in the Phase 3 trials with selected

treatment-emergent clinical laboratory abnormalities (Grades 1 to 4), representing worst Grade toxicity

are shown in Table 2.

Table 2: Selected Treatment-Emergent Changes in Laboratory Parameters (Grades 1 to 4)

Observed in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (week 96 analysis)

Laboratory Parameter

DAIDS Toxicity

Pooled Data from the phase 3

Edurant_SPC_Jul_2020 USPI AUG 2015

Abnormality, (%)

Range

TMC278-C209 and TMC278C215

Trials

EDURANT + BR

N=686

Efavirenz + BR

N=682

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%

Grade 4

> 5.0 x ULN

Increased Total Cholesterol

(fasted)

Grade 1

5.18-6.19 mmol/L

200-239 mg/dL

Grade 2

6.20-7.77 mmol/L

240-300 mg/dL

Grade 3

> 7.77 mmol/L

> 300 mg/dL

<1%

Increased LDL Cholesterol

(fasted)

Edurant_SPC_Jul_2020 USPI AUG 2015

Grade 1

3.37-4.12 mmol/L

130-159 mg/dL

Grade 2

4.13-4.90 mmol/L

160-190 mg/dL

Grade 3

> 4.91 mmol/L

> 191 mg/dL

Increased Triglycerides (fasted)

Grade 2

5.65-8.48 mmol/L

500-750 mg/dL

Grade

8.49-13.56 mmol/L

751-1,200 mg/dL

Grade

> 13.56 mmol/L

> 1,200 mg/dL

BR = background regimen; ULN = upper limit of normal

N = number of subjects per treatment group

Note: Percentages were calculated versus the number of subjects in ITT.

Adrenal Function

In the pooled Phase 3 trials, 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 EDURANT group and of -0.02 (-0.48, 0.44)

micrograms/dL in the efavirenz group.

In the EDURANT 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, fourteen subjects

in the EDURANT group and nine 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 EDURANT group is not

known.

Serum Creatinine

In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of

treatment with EDURANT. 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 after 96 weeks of

treatment. 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. These

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

increases in serum creatinine. Serum creatinine increases occurred regardless of the background

N(t)RTI regimen.

Serum Lipids

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

presented in Table 3. The clinical benefit of these findings has not been demonstrated.

Table 3: Lipid Values, Mean Change from Baseline*

Pooled data from the Week 96 analysis of the pahse 3 TMC278-C209 and TMC278-

C215 trials

EDURANT+BR

Efavirenz+BR

N

Baseline

Week 96

N

Baseline

Week 96

Edurant_SPC_Jul_2020 USPI AUG 2015

Mean

(95% CI)

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

* Excludes subjects who received lipid lowering agents during the treatment period

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

baseline and Week 96 values

Subjects co-infected with hepatitis B and/or hepatitis C virus

In subjects co-infected with hepatitis B or C virus receiving EDURANT, the incidence of hepatic

enzyme elevation was higher than in subjects receiving EDURANT who were not co-infected. This

observation was the same in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in co-

infected subjects was comparable to that in subjects without co-infection.

Immune reactivation syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of combination

antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic

infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported;

however, the reported time to onset is more variable and these events can occur many months after

initiation of treatment .

Additional adverse events

Gastrointestinal disorders

Dry mouth (common)

increased lipase (common)

Blood and lymphatic systemdisorders

decreased white blood cell count (common)

decreased haemoglobin (common)

decreased platelet count (common)

Immune system disorders

immune reactivation syndrome (uncommon)

6.1 Postmarketing Experience

Adverse reactions have been identified during post-marketing in patients receiving a rilpivirine

containing regimen. Because these reactions are reported voluntarily from a population of unknown

size, it is not always possible to reliably estimate their frequency or establish a causal relationship to

drug exposure.

Edurant_SPC_Jul_2020 USPI AUG 2015

Renal and Genitourinary Disorders

: nephrotic syndrome

Skin and Subcutaneous Tissue Disorders

:

Severe skin and hypersensitivity reactions including DRESS

(Drug Reaction with Eosinophilia and Systemic Symptoms)

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

7 DRUG INTERACTIONS

See also Dosage and administrations (2), Contraindications (4) and Clinical Pharmacology (12.3).

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

CYP3A may thus affect the clearance of rilpivirine. Co-administration of EDURANT 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. Co-administration of

EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.

Co-administration of EDURANT with drugs that increase gastric pH may result in decreased plasma

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

the class of NNRTIs.

EDURANT 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.

Table 4 shows the established and other potentially significant drug interactions based on which

alterations in dose or regimen of EDURANT and/or co-administered drug may be recommended.

Drugs that are not recommended for co-administration with EDURANT are also included in Table 4.

Table 4: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or

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

See Clinical Pharmacology (12.3)

Concomitant Drug Class:

Drug Name

Effect on

Concentration of

Rilpivirine or

Concomitant Drug

Clinical Comment

HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

didanosine*

rilpivirine

didanosine

No dose adjustment is required when EDURANT is

coadministered with didanosine. Didanosine is to be

administered on an empty stomach and at least two

hours before or at least four hours after EDURANT

(which should be administered with a meal).

HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

NNRTI (delavirdine)

Other NNRTIs (efavirenz,

etravirine, nevirapine)

rilpivirine

delavirdine

rilpivirine

other

NNRTIs

It is not recommended to co-administer EDURANT

with delavirdine and other NNRTIs.

Edurant_SPC_Jul_2020 USPI AUG 2015

HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose

ritonavir) or Unboosted (i.e., without co-administration of low-dose ritonavir)

darunavir/ritonavir*

rilpivirine

boosted darunavir

Concomitant use of EDURANT with

darunavir/ritonavir may cause an increase in the plasma

concentrations of rilpivirine (inhibition of CYP3A

enzymes). No dose adjustment is required when

EDURANT is co-administered with

darunavir/ritonavir.

lopinavir/ritonavir*

rilpivirine

boosted lopinavir

Concomitant use of EDURANT with

lopinavir/ritonavir may cause an increase in the plasma

concentrations of rilpivirine (inhibition of CYP3A

enzymes). No dose adjustment is required when

EDURANT is co-administered with lopinavir/ritonavir.

other boosted PIs

(atazanavir/ritonavir,

fosamprenavir/ritonavir,

saquinavir/ritonavir,

tipranavir/ritonavir)

rilpivirine

boosted PI

Concomitant use of EDURANT with boosted PIs may

cause an increase in the plasma concentrations of

rilpivirine (inhibition of CYP3A enzymes). EDURANT

is not expected to affect the plasma concentrations of

co-administered PIs.

unboosted PIs (atazanavir,

fosamprenavir, indinavir,

nelfinavir)

rilpivirine

unboosted PI

Concomitant use of EDURANT with unboosted PIs

may cause an increase in the plasma concentrations of

rilpivirine (inhibition of CYP3A enzymes). EDURANT

is not expected to affect the plasma concentrations of

co-administered PIs.

Other Agents

Antacids:

antacids (e.g.,

aluminum or magnesium

hydroxide, calcium

carbonate)

rilpivirine

(antacids taken at

least 2 hours before

or at least 4 hours

after rilpivirine)

rilpivirine

(concomitant intake)

The combination of EDURANT and antacids should be

used with caution as co-administration 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 EDURANT.

Antimycobacterials:

Rifabutin*

rilpivirine

Concomitant use of EDURANT with rifabutin may

cause a decrease in the plasma concentrations of

rilpivirine (induction of CYP3A enzymes). Throughout

administration of EDURANT with rifabutin, the

EDURANT dose should be increased from 25 mg once

daily to 50 mg once daily. When rifabutin co-

administration is stopped, the EDURANT dose should

be decreased to 25 mg once daily.

Azole Antifungal

Agents

fluconazole

itraconazole

ketoconazole*

posaconazole

voriconazole

rilpivirine

ketoconazole

Concomitant use of EDURANT with azole antifungal

agents may cause an increase in the plasma

concentrations of rilpivirine (inhibition of CYP3A

enzymes). No rilpivirine dose adjustment is

required when EDURANT is co-administered with

azole antifungal agents. Clinically monitor for

breakthrough fungal infections when azole antifungals

are co-administered with EDURANT.

H

2

-Receptor

Antagonists

cimetidine

famotidine*

nizatidine

ranitidine

rilpivirine

(famotidine taken

12 hours before

rilpivirine or 4 hours

after rilpivirine)

rilpivirine

The combination of EDURANT and H

-receptor

antagonists should be used with caution as co-

administration may cause significant decreases in

rilpivirine plasma concentrations (increase in gastric

pH). H

-receptor antagonists should only be

administered at least 12 hours before or at least 4 hours

after EDURANT.

Edurant_SPC_Jul_2020 USPI AUG 2015

(famotidine taken 2

hours before

rilpivirine)

Antacids:

Antacids (e.g.,

aluminium or

magnesium

hydroxide, calcium

carbonate)

Not studied.

Significant

decreases

in rilpivirine plasma

concentrations

are expected.

(reduced absorption

due to gastric

pH increase)

The combination of EDURANT and

antacids should be used with particular

caution. Antacids should only be

administered either at least 2 hours

before or at least 4 hours after

EDURANT.

Macrolide antibiotics

clarithromycin,

erythromycin,

telithromycin

rilpivirine

clarithromycin

erythromycin

telithromycin

Concomitant use of EDURANT 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

No dose adjustments are required when initiating co-

administration of methadone with EDURANT.

However, clinical monitoring is recommended as

methadone maintenance therapy may need to be

adjusted in some patients.

↑ = increase, ↓ = decrease, ↔ = no change

* The interaction between EDURANT and the drug 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 EDURANT

assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the

recommended dose of EDURANT 25 mg once daily

In addition to the drugs included in Table 4, the interaction between EDURANT and the following

drugs was evaluated in clinical studies and no dose adjustment is needed for either drug [

see Clinical

Pharmacology (12.3)

]: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone,

raltegravir, sildenafil, telaprevir and tenofovir disoproxil fumarate.

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

No clinically relevant drug-drug interaction is expected when EDURANT is co-administered with

maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine.

Additional information :

Dabigatran (ANTICOAGULANTS)- Not studied. A risk for increases in dabigatran plasma

concentrations cannot be excluded.

(inhibition of intestinal P-gp).The combination of EDURANT and dabigatran should be used with

caution.

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)

EDURANT should be used with caution when coadministered with a drug with a known risk of

Torsade de Pointes.

Edurant_SPC_Jul_2020 USPI AUG 2015

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

No adequate and well-controlled or pharmacokinetic studies of EDURANT use in pregnant women

have been conducted. Studies in animals have shown no evidence of relevant 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

(NOAELs) 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. EDURANT 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.

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. Because of both the potential for HIV transmission and the potential for

adverse reactions in nursing infants,

mothers should be instructed not to breastfeed if they are

receiving EDURANT

8.4 Pediatric Use

The safety, efficacy and pharmacokinetics of EDURANT were evaluated in a single arm, open-label,

Phase 2 trial that enrolled 36 antiretroviral treatment-naïve, HIV-1 infected pediatric subjects 12 to less

than 18 years of age and weighing at least 32 kg .

Safety and effectiveness in pediatric patients less than 12 years of age have not been established.

In Israel Edurat is approved for use only in adult patient.

8.5 Geriatric Use

Clinical studies of EDURANT did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. In general, caution should be

exercised in the administration and monitoring of EDURANT in elderly patients reflecting the greater

frequency of decreased renal and hepatic function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

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

hepatic

impairment (Child-Pugh score A or B). No dose adjustment of EDURANT is required in

patients with

mild or moderate hepatic impairment. EDURANT should be used with caution in patients with

moderate hepatic impairment. EDURANT has not been studied in patients with severe

hepatic

impairment (Child-Pugh score C). Therefore, EDURANT is not recommended in patients with

severe

hepatic impairment

8.7 Renal Impairment

No dose adjustment is required in patients with mild or moderate renal impairment. However, in

patients with severe renal impairment or end-stage renal disease ,rilpivirine should be used with caution

and with increased monitoring for adverse effects, as rilpivirine concentrations may be increased due to

alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. As

rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by

hemodialysis or peritoneal dialysis [

see Clinical Pharmacology (12.3)

Edurant_SPC_Jul_2020 USPI AUG 2015

In patients with severe renal impairment or end-stage renal disease, the combination of

EDURANT with a strong CYP3A inhibitor (e.g., ritonavir-boosted HIV protease inhibitor)

should only be used if the benefit outweighs the risk.

8.8 Effects on ability to drive and use machines

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

effects of EDURANT on the ability to drive and use machines have been performed. Fatigue,

dizziness and somnolence have been reported in some patients taking EDURANT and should be

considered when assessing a patient’s ability to drive or operate machinery.

10 OVERDOSAGE

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

EDURANT is limited. Treatment of overdose with EDURANT 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. Administration of activated charcoal may be used to aid in removal of unabsorbed active

substance. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant

removal of the active substance.

11 DESCRIPTION

EDURANT

(rilpivirine)

non-nucleoside

reverse

transcriptase

inhibitor

(NNRTI)

human

immunodeficiency virus type 1 (HIV-1). EDURANT is available as a white to off-white, film-coated,

round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine

hydrochloride, which is equivalent to 25 mg of rilpivirine.

The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-

dimethylphenyl]amino]2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is

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.

Each EDURANT tablet also contains the inactive ingredients croscarmellose sodium, magnesium

stearate, lactose monohydrate, povidone K30, polysorbate 20 and silicified microcrystalline cellulose.

The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, PEG 3000, titanium

dioxide and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rilpivirine is an antiviral drug [

see Clinical Pharmacology (12.4)

Edurant_SPC_Jul_2020 USPI AUG 2015

12.2 Pharmacodynamics

Effects on Electrocardiogram

The effect of EDURANT 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 EDURANT 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 EDURANT 75 mg once daily and 300 mg once daily

resulted in a mean steady-state C

approximately 2.6-fold and 6.7-fold, respectively, higher than the

mean C

observed with the recommended 25 mg once daily dose of EDURANT [

see Warnings and

Precautions (5.1)

12.3 Pharmacokinetics

Pharmacokinetics in Adults

The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult

antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in

HIV-1 infected subjects than in healthy subjects.

Table 5: Population Pharmacokinetic Estimates of Rilpivirine 25 mg once daily in Antiretroviral

Treatment-Naïve HIV-1-Infected 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)

Absorption and Bioavailability

After oral administration, the maximum plasma concentration of rilpivirine is generally achieved

within 4-5 hours. The absolute bioavailability of EDURANT is unknown.

Effects of Food on Oral Absorption

The exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted

condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal).

When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than

when taken with a meal.

Distribution

Rilpivirine is approximately 99.7% bound to plasma proteins

in vitro

, primarily to albumin. The

distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract

secretions) has not been evaluated in humans.

Metabolism

Edurant_SPC_Jul_2020 USPI AUG 2015

In vitro

experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the

cytochrome P450 (CYP) 3A system.

Elimination

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 (< 1% of dose) were detected in urine.

Special Populations

Hepatic Impairment

Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with

mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate

hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of

rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with

moderate hepatic impairment.

No dose adjustment is suggested but caution is advised in patients with moderate hepatic impairment.

EDURANT has not been studied in patients with severe hepatic impairment (Child-Pugh score C).

Therefore, EDURANT is not recommended in patients with severe hepatic impairment

see Use in Specific Populations (8.6)

Hepatitis B and/or Hepatitis C Virus Co-infection

Population pharmacokinetic analysis indicated that hepatitis B and/or C virus co-infection had no

clinically relevant effect on the exposure to rilpivirine.

Renal Impairment

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. No

dose adjustment is required in patients with mild renal impairment. 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. The potential impact

is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment,

and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with

increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal

disease. In patients with severe renal impairment or end-stage renal disease, the combination of

EDURANT with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk.

As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by

hemodialysis or peritoneal dialysis

[see Use in Specific Populations (8.7)]

Gender

No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between

men and women.

Race

Population pharmacokinetic analysis of rilpivirine in HIV-infected patients indicated that race had no

clinically relevant effect on the exposure to rilpivirine.

Pediatric Patients

The pharmacokinetics and dosing recommendations of rilpivirine in pediatric patients less than

years have not been established [

see Use in Specific Populations (8.4)

In Israel Edurat is approved for use only in adult patient.

Drug Interactions

See Contraindications (4) and Drug Interactions (7)

Edurant_SPC_Jul_2020 USPI AUG 2015

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

CYP3A may thus affect the clearance of rilpivirine. Co-administration of EDURANT and drugs that

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

response and possible resistance. Co-administration of EDURANT and drugs that inhibit CYP3A may

result in increased plasma concentrations of rilpivirine. Co-administration of EDURANT 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.

EDURANT at a dose of 25 mg q.d. is not likely to have a clinically relevant effect on the exposure of

medicinal products metabolised by CYP enzymes.

Drug interaction studies were performed with EDURANT and other drugs likely to be co-administered

or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other

drugs on the Cmax, AUC, and Cmin values of rilpivirine are summarized in Table 6 (effect of other

drugs on EDURANT). The effect of co-administration of EDURANT on the Cmax, AUC, and Cmin

values of other drugs are summarized in Table 7 (effect of EDURANT on other drugs). For information

regarding clinical recommendations, [

see Drug Interactions (7)]

Table 6: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Co-administered

Drugs

Co-

administered

Drug

Dose/Schedule

N

Mean Ratio of Rilpivirine Pharmacokinetic

Parameters With/Without Co-administered

Drug (90% CI); No Effect = 1.00

Co-administered

Drug

Rilpivirine

C

max

AUC

C

min

Co-Administration With Protease Inhibitors (PIs)

Darunavir/

ritonavir

800/100 mg q.d.

150 mg q.d.

1.79

(1.56-2.06)

2.30

(1.98-2.67)

2.78

(2.39-3.24)

Lopinavir/

ritonavir (soft gel

capsule)

400/100 mg b.i.d.

150 mg q.d.

1.29

(1.18-1.40)

1.52

(1.36-1.70)

1.74

(1.46-2.08)

Co-Administration With Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)

Didanosine

400 mg q.d.

delayed release

capsules taken 2

hours before

rilpivirine

150 mg q.d.

1.00

(0.90-1.10)

1.00

(0.95-1.06)

1.00

(0.92-1.09)

Tenofovir

disoproxil

fumarate

300 mg q.d.

150 mg q.d.

0.96

(0.81-1.13)

1.01

(0.87-1.18)

0.99

(0.83-1.16)

Co-Administration With HIV Integrase Strand Transfer Inhibitors

Raltegravir

400 mg b.i.d.

25 mg q.d.

1.12

(1.04-1.20)

1.12

(1.05-1.19)

1.03

(0.96-1.12)

Co-Administration With other Antivirals

Telaprevir

750mg q8h

25 mg q.d.

1.49

(1.20-1.84)

1.78

(1.44-2.20)

1.93

(1.55-2.41)

Co-Administration With Drugs other than Antiretrovirals

Acetaminophen

500 mg single

dose

150 mg q.d.

1.09

(1.01-1.18)

1.16

(1.10-1.22)

1.26

(1.16-1.38)

Atorvastatin

40 mg q.d.

150 mg q.d.

0.91

(0.79-1.06)

0.90

(0.81-0.99)

0.90

(0.84-0.96)

Chlorzoxazone

500 mg single

dose taken 2

hours after

rilpivirine

150 mg q.d.

1.17

(1.08-1.27)

1.25

(1.16-1.35)

1.18

(1.09-1.28)

Edurant_SPC_Jul_2020 USPI AUG 2015

Ethinylestradiol/

Norethindrone

0.035 mg q.d./ 1

mg q.d.

25 mg q.d.







Famotidine

40 mg single dose

taken 12 hours

before rilpivirine

150 mg single

dose

0.99

(0.84-1.16)

0.91

(0.78-1.07)

N.A.

Famotidine

40 mg single dose

taken 2 hours

before rilpivirine

150 mg single

dose

0.15

(0.12-0.19)

0.24

(0.20-0.28)

N.A.

Famotidine

40 mg single dose

taken 4 hours after

rilpivirine

150 mg single

dose

1.21

(1.06-1.39)

1.13

(1.01-1.27)

N.A.

Ketoconazole

400 mg q.d.

150 mg q.d.

1.30

(1.13-1.48)

1.49

(1.31-1.70)

1.76

(1.57-1.97)

Methadone

60-100 mg q.d.

Individualized

dose

25 mg q.d.







Omeprazole

20 mg q.d.

150 mg q.d.

0.60

(0.48-0.73)

0.60

(0.51-0.71)

0.67

(0.58-0.78)

Rifabutin

300 mg q.d.

25 mg q.d.

0.69

(0.62-0.76)

0.58

(0.52-0.65)

0.52

(0.46-0.59)

Rifabutin

300 mg q.d.

50 mg q.d.

1.43

(1.30-1.56)

1.16

(1.06-1.26)

0.93

(0.85-1.01)

(reference arm for comparison was 25 mg q.d.

rilpivirine administered alone)

Rifampin

600 mg q.d.

150 mg q.d.

0.31

(0.27-0.36)

0.20

(0.18-0.23)

0.11

(0.10-0.13)

Sildenafil

50 mg single dose

75 mg q.d.

0.92

(0.85-0.99)

0.98

(0.92-1.05)

1.04

(0.98-1.09)

CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease;

↔ = no change; q.d. = once daily; b.i.d. = twice daily

* comparison based on historic controls

† This interaction study has been performed with a dose higher than the recommended dose for EDURANT

(25 mg once daily) assessing the maximal effect on the co-administered drug.

Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of

EDURANT

Co-

administered

Drug

Dose/Schedule

N

Mean Ratio of Co-administered Drugs

Pharmacokinetic Parameters With/Without

EDURANT (90% CI); No Effect = 1.00

Co-administered

Drug

Rilpivirine

C

max

AUC

C

min

Co-Administration With Protease Inhibitors (PIs)

Darunavir/

ritonavir

800/100 mg q.d.

150 mg q.d.

0.90

(0.81-1.00)

0.89

(0.81-0.99)

0.89

(0.68-1.16)

Edurant_SPC_Jul_2020 USPI AUG 2015

Lopinavir/

ritonavir (soft gel

capsule)

400/100 mg b.i.d.

150 mg q.d.

0.96

(0.88-1.05)

0.99

(0.89-1.10)

0.89

(0.73-1.08)

Co-Administration With Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)

Didanosine

400 mg q.d.

delayed release

capsules taken 2

hours before

rilpivirine

150 mg q.d.

0.96

(0.80-1.14)

1.12

(0.99-1.27)

N.A.

Tenofovir

disoproxil

fumarate

300 mg q.d.

150 mg q.d.

1.19

(1.06-1.34)

1.23

(1.16-1.31)

1.24

(1.10-1.38)

Co-Administration With HIV Integrase Strand Transfer Inhibitors

Raltegravir

400 mg b.i.d.

25 mg q.d.

1.10

(0.77-1.58)

1.09

(0.81-1.47)

1.27

(1.01-1.60)

Co-Administration With other Antivirals

Telaprevir

750 mg q8h

25 mg q.d.

0.97

(0.79-1.21)

0.95

(0.76-1.18)

0.89

(0.67-1.18)

Co-Administration With Drugs other than Antiretrovirals

Acetaminophen

500 mg single

dose

150 mg q.d.

0.97

(0.86-1.10)

0.91

(0.86-0.97)

N.A.

Atorvastatin

2-hydroxy-

atorvastatin

4-hydroxy-

atorvastatin

40 mg q.d.

150 mg q.d.

1.35

(1.08-1.68)

1.58

(1.33-1.87)

1.28

(1.15-1.43)

1.04

(0.97-1.12)

1.39

(1.29-1.50)

1.23

(1.13-1.33)

0.85

(0.69-1.03)

1.32

(1.10-1.58)

N.A.

Chlorzoxazone

500 mg single

dose taken 2

hours after

rilpivirine

150 mg q.d.

0.98

(0.85-1.13)

1.03

(0.95-1.13)

N.A.

Digoxin

0.5 mg single

dose

25 mg q.d.

1.06

(0.97-1.17)

0.98

(0.93-1.04)#

N.A.

Ethinylestradiol

Norethindrone

0.035 mg q.d.

1 mg q.d.

25 mg q.d.

1.17

(1.06-1.30)

0.94

(0.83-1.06)

1.14

(1.10-1.19)

0.89

(0.84-0.94)

1.09

(1.03-1.16)

0.99

(0.90-1.08)

Ketoconazole

400 mg q.d.

150 mg q.d.

0.85

(0.80-0.90)

0.76

(0.70-0.82)

0.34

(0.25-0.46)

R(-) methadone

S(+) methadone

60-100 mg q.d.

Individualized

dose

25 mg q.d.

0.86

(0.78-0.95)

0.87

(0.78-0.97)

0.84

(0.74-0.95)

0.84

(0.74-0.96)

0.78

(0.67-0.91)

0.79

(0.67-0.92)

Metformin

850 mg single

dose

25 mg q.d.

1.02

(0.95-1.10)

0.97

(0.90-1.06)

N.A.

Edurant_SPC_Jul_2020 USPI AUG 2015

Omeprazole

20 mg q.d.

150 mg q.d.

0.86

(0.68-1.09)

0.86

(0.76-0.97)

N.A.

Rifampin

desacetylrifampin

600 mg q.d.

150 mg q.d.

1.02

(0.93-1.12)

1.00

(0.87-1.15)

0.99

(0.92-1.07)

0.91

(0.77-1.07)

N.A.

N.A.

Sildenafil

N-desmethyl-

sildenafil

50 mg single dose

75 mg q.d.

0.93

(0.80-1.08)

0.90

(0.80-1.02)

0.97

(0.87-1.08)

0.92

(0.85-0.99)

N.A.

N.A.

CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ =

no change; q.d. = once daily ; b.i.d. = twice daily

† This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg

once daily) assessing the maximal effect on the co-administered drug.

# AUC

(0-last)

^ N (maximum number of subjects with data) for AUC

(0-∞)

= 15

12.4 Microbiology

Mechanism of Action

Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of human

immunodeficiency virus type 1 (HIV-1) and inhibits HIV-1 replication by non-competitive inhibition

of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the

human cellular DNA polymerases α, β and γ.

Antiviral Activity in Cell Culture

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

line with a median EC50 value for HIV-1IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated

limited activity in cell culture against HIV-2 with a median EC50 value of 5220 nM (range 2510 to

10830 nM) (920 to 3970 ng/mL).

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 (0.03 to

0.37 ng/ml) and was less active against group O primary isolates with EC50 values ranging from

2.88 to 8.45 nM (1.06 to 3.10 ng/ml).

The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz,

etravirine or nevirapine; the 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.

Resistance

In Cell Culture

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.

Edurant_SPC_Jul_2020 USPI AUG 2015

In Treatment-Naïve Subjects

In the Week 96 pooled resistance analysis of the Phase 3 trials C209 and C215, the emergence of

resistance was greater among subjects’ viruses in the EDURANT arm compared to the efavirenz arm,

and was dependent on baseline viral load. In the pooled resistance analysis, 58% (57/98) of the subjects

who qualified for resistance analysis (resistance analysis subjects) in the EDURANT arm had virus

with genotypic and/or phenotypic resistance to rilpivirine compared to 45% (25/56) of the resistance

analysis subjects in the efavirenz arm who had genotypic and/or phenotypic resistance to efavirenz.

Moreover, genotypic and/or phenotypic resistance to a background drug (emtricitabine, lamivudine,

tenofovir, abacavir or zidovudine) emerged in viruses from 52% (51/98) of the resistance analysis

subjects in the rilpivirine arm compared to 23% (13/56) 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, T215S/T, or

K219E/R) emerged more frequently in rilpivirine resistance analysis subjects compared to efavirenz

resistance analysis subjects (see Table 8).

NNRTI-and NRTI-resistance substitutions emerged less frequently in resistance analysis of viruses

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

baseline viral load of > 100,000 copies/mL: 26% (14/54) compared to 74% (40/54) of NNRTI-

resistance substitutions and 22% (11/50) compared to 78% (39/50) of NRTI-resistance substitutions.

This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance

substitutions: 23% (11/47) compared to 77% (36/47) for M184I/V and 0% (0/8) compared to 100%

(8/8) for K65R/N. Additionally, NNRTI-and NRTI-resistance substitutions emerged less frequently in

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

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

: 37% (20/54)

compared to 63% (34/54) of NNRTI-resistance substitutions and 28% (14/50) compared to 72%

(36/50) of NRTI-resistance substitutions.

Table 8. Proportion of Resistance Analysis Subjects* with Frequently Emerging Reverse

Transcriptase Substitutions from the Pooled Phase 3 TMC278-C209 and TMC278-C215 Trials

in the Week 96 Analysis

C209 and C215

N = 1368

Rilpivirine

N = 686

EFV Control

N = 682

Subjects who Qualified for

Resistance Analysis

(15%) 98/652

(9%) 56/604

Subjects with Evaluable Post-

Baseline Resistance Data

Emerging NNRTI Substitutions†

62% (54/87)

53% (23/43)

V90I

13% (11/87)

2% (1/43)

K101E/P/T/Q

20% (17/87)

9% (4/43)

K103N

1% (1/87)

40% (17/43)

E138K/A/Q/G

40% (35/87)

2% (1/43)

E138K+ M184I‡

25% (22/87)

V179I/L/D

6% (5/87)

7% (3/43)

Y181C/I/S

10% (9/87)

2% (1/43)

V189I

8% (7/87)

2% (1/43)

H221Y

9% (8/87)

Edurant_SPC_Jul_2020 USPI AUG 2015

Emerging NRTI Substitutions

§

57% (50/87)

30% (13/43)

M184I/V

54% (47/87)

26% (11/43)

K65R/N

9% (8/87)

5% (2/43)

A62V, D67N/G, K70E,

Y115F, T215S/T or K219E/R¶

21% (18/87)

2% (1/43)

BR = background regimen

* Subjects who qualified for resistance analysis.

† V90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221,

P225, F227 or M230

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

§ A62V, K65R/N, D67N/G, K70E, L74I, V75I, Y115F, M184I/V, L210F, T215S/T,

K219E/R

¶ These substitutions emerged in addition to the primary substitutions M184V/I or

K65R/N; A62V (n=3), D67N/G

(n=3), K70E (n=4), Y115F (n=2), T215S/T (n=1), K219E/R (n=8) in rilpivirine resistance

analysis subjects.

Cross-Resistance

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 result in reduced susceptibility to

rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7-fold reduced

susceptibility to rilpivirine. Combinations of 2 or 3 NNRTI resistance-associated substitutions had

decreased susceptibility to rilpivirine (fold change range of 3.7 -554) in 38% and 66% of mutants

analyzed, respectively.

Treatment-naïve HIV

1

infected subjects

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 or M230L.

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

development of rilpivirine resistance. In the Week 96 pooled analyses of the Phase 3 TMC278-C209

and TMC278-C215 clinical trials, 50 of the 87 (57%) rilpivirine resistance analysis subjects with post-

baseline resistance data had virus with decreased susceptibility to rilpivirine (≥ 2.5 fold change). Of

these, 86% (n= 43/50) were resistant to efavirenz (≥ 3.3 fold change), 90% (n= 45/50) were resistant to

etravirine (≥ 3.2 fold change) and 62% (n= 31/50) were resistant to nevirapine (≥ 6 fold change). In the

efavirenz arm, 3 of the 21 (14%) efavirenz resistance analysis subjects’ viruses were resistant to

etravirine and rilpivirine, and 95% (n= 20/21) were resistant to nevirapine. Virus from subjects

experiencing virologic failure on EDURANT 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 compared to virus from subjects who failed on efavirenz.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

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/kg/day were administered to mice and doses of 40,

Edurant_SPC_Jul_2020 USPI AUG 2015

200, 500 and 1500 mg/kg/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 q.d.).

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

in

vitro

Ames reverse mutation assay and the

in vitro

clastogenicity mouse lymphoma assay. Rilpivirine

did not induce chromosomal damage in the

in vivo

micronucleus test in mice.

Impairment of Fertility

No human data on the effect of rilpivirine on fertility are available. In a study conducted in rats, there

were no effects on mating or fertility with rilpivirine up to 400 mg/kg/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.

14 CLINICAL STUDIES

14.1 Treatment-Naïve Subjects

The evidence of efficacy of EDURANT is based on the analyses of 48-and 96-week data from 2

randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-

C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected

subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥ 5000 copies/mL and were screened

for susceptibility to N(t)RTIs and for absence of specific NNRTI RAMs. The Phase 3 trials were

identical in design, with the exception of the background regimen (BR). In TMC278-C209, the BR was

fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR

consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or

zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by

screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR.

In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline

characteristics were balanced between the EDURANT arm and the efavirenz arm. Table 9 displays

selected demographic and baseline disease characteristics of the subjects in the EDURANT and

efavirenz arms.

Table 9: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Naïve

HIV-1Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis)

Pooled Data from the TMC278-C209 and TMC278-C215 Trials

EDURANT + BR

N=686

Efavirenz + BR

N=682

Demographic Characteristics

Median Age, years (range)

36 (18-78)

36 (19-69)

Male

Female

Race

White

Edurant_SPC_Jul_2020 USPI AUG 2015

Black/African American

Asian

Other

Not allowed to ask per local

regulations

Baseline Disease Characteristics

Median Baseline Plasma HIV-1

RNA (range), log

copies/mL

5.0 (2-7)

5.0 (3-7)

Percentage of Patients with

Baseline Plasma Viral Load:

≤ 100,000

> 100,000 to ≤ 500,000

> 500,000

Median Baseline CD4+ Cell

Count (range), cells/mm

249 (1-888)

260 (1-1137)

Percentage of Subjects with:

Hepatitis B/C Virus Co-infection

Percentage of Patients with the

following background regimens:

tenofovir disoproxil fumarate plus

emtricitabine zidovudine plus

lamivudine abacavir plus

lamivudine

BR=background regimen

Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled

analysis are shown in Table 10. The incidence of virologic failure was higher in the EDURANT 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 10: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215

(Pooled Data) at Week 96

EDURANT + BR

N=686

Efavirenz + BR

N=682

HIV-1 RNA < 50 copies/mL*

HIV-1 RNA < 50 copies/mL

†

No virologic data at Week 96

window

Reasons

Discontinued study due to adverse

event or death

Discontinued study for other reasons

and last available HIV-1 RNA < 50

copies/mL (or missing)

Missing data during window but on

study

<1%

< 1%

Edurant_SPC_Jul_2020 USPI AUG 2015

HIV-1 RNA < 50 copies/mL by

Baseline HIV-1 RNA (copies/ml)

(copies/mL)

≤ 100,000

> 100,000

HIV-1 RNA ≥ 50 copies/mL

†

by

Baseline HIV-1 RNA (copies/ml)

(copies/mL)

≤ 100,000

> 100,000

HIV-1 RNA < 50 copies/mL by

CD4+ cell count (cells/mm

3

)

<200

≥200

HIV-1 RNA ≥ 50 copies/mL

†

by

CD4+ cell count (cells/mm

3

)

<200

≥200

N = total number of subjects per treatment group; BR = background regimen.

* CI = Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96.

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

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

‡ 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.

§ 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.

Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90-103),

respectively.

At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm

for EDURANT-

treated subjects and 219 cells/mm

for efavirenz-treated subjects in the pooled analysis of the TMC278-

C209 and TMC278-C215 trials.

Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-

naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-

finding part [EDURANT doses blinded] followed by a long-term, open-label part. After Week 96,

subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 25 mg once

daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both

parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or

tenofovir disoproxil fumarate plus emtricitabine.

Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma

HIV-1 RNA ≥ 5000 copies/ml, previously received ≤ 2 weeks of treatment with an N(t)RTI or protease

Edurant_SPC_Jul_2020 USPI AUG 2015

inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence

of specific NNRTI RAMs.

At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/ml receiving EDURANT 25 mg

(N = 93) compared to subjects receiving efavirenz (N = 89) was 76% and 71%, respectively. The mean

increase from baseline in CD4+ counts was 146 cells/mm

in subjects receiving EDURANT 25 mg and

160 cells/mm

in subjects receiving efavirenz.

At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA <

50 copies/mL compared to 57% (51/89) of subjects in the control group.

16 HOW SUPPLIED/STORAGE AND HANDLING

EDURANT (rilpivirine) tablets are supplied as white to off-white, film-coated, round, biconvex, 6.4

mm tablets. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of

rilpivirine. Each tablet is debossed with “TMC” on one side and “25” on the other side.

EDURANT tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30.

Store EDURANT tablets in the original bottle in order to protect from light.

After first opening the package, Edurant should be used within 8 weeks, but no later than the expiry

date.

Do not Store EDURANT tablets above 30°C.

Manufacturer:

Janssen-Cilag S.p.A, Latina, Italy

Registration Holder:

J-C Health Care, Ltd.

Revised in July 2020.