DARUNAVIR 400 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

Available from:
Teva B.V.
Dosage:
400 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Authorization status:
Authorised
Authorization number:
PA1986/015/001
Authorization date:
2017-06-02

Read the complete document

Package leaflet: Information for the user

Darunavir Teva 400 mg Film-coated Tablets

darunavir

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. See Section 4.

What is in this leaflet

What Darunavir Teva is and what it is used for

What you need to know before you take Darunavir Teva

How to take Darunavir Teva

Possible side effects

How to store Darunavir Teva

Contents of the pack and other information

1.

What Darunavir Teva is and what it is used for

What is Darunavir Teva?

Darunavir Teva contains the active substance darunavir. Darunavir Teva is an antiretroviral medicine

used in the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of

medicines called protease inhibitors. Darunavir Teva works by reducing the amount of HIV in your body.

This will improve your immune system and reduces the risk of developing illnesses linked to HIV

infection.

What it is used for?

Darunavir Teva 400 milligram is used to treat adults and children (3 years of age and above, at least 40

kilograms body weight) who are infected by HIV and

who have not used antiretroviral medicines before.

in certain patients who have used antiretroviral medicines before (your doctor will determine this).

Darunavir Teva must be taken in combination with a low dose of ritonavir and other anti-HIV medicines.

Your doctor will discuss with you which combination of medicines is best for you.

2.

What you need to know before you take Darunavir Teva

Do not take Darunavir Teva:

if you are allergic to darunavir or any of the other ingredients of this medicine (listed in section 6)

or to ritonavir.

if you have severe liver problems. Ask your doctor if you are unsure about the severity of your

liver disease. Some additional tests might be necessary.

Do not combine Darunavir Teva with any of the following medicines

If you are taking any of these, ask your doctor about switching to another medicine.

Medicine

Purpose of the medicine

Avanafil

to treat erectile dysfunction

Astemizole or terfenadine

to treat allergy symptoms

Triazolam and oral (taken by mouth) midazolam

to help you sleep and/or relieve anxiety

Cisapride

to treat some stomach conditions

Colchicine (if you have kidney and/or liver

problems)

to treat gout

Pimozide, quetiapine or sertindole

to treat psychiatric conditions

Ergot alkaloids like ergotamine,

dihydroergotamine, ergometrine and

methylergonovine

to treat migraine and headaches

Amiodarone, bepridil, dronedarone, quinidine,

ranolazine and systemic lidocaine

to treat certain heart disorders e.g. abnormal heart

beat

Lovastatin and simvastatin

to lower cholesterol levels

Rifampicin

to treat some infections such as tuberculosis

The combination product lopinavir/ritonavir

this anti-HIV medicine belongs to the same class as

Darunavir Teva

Alfuzosin

to treat enlarged prostate

Sildenafil

to treat high blood pressure in the pulmonary

circulation

Ticagrelor

to help stop the clumping of platelets in the

treatment of patients with a history of a heart attack

Do not combine Darunavir Teva with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Darunavir Teva

Darunavir Teva is not a cure for HIV infection. You can still pass on HIV when taking this medicine,

although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the

precautions needed to avoid infecting other people.

People taking Darunavir Teva may still develop infections or other illnesses associated with HIV

infection. You must keep in regular contact with your doctor.

People taking Darunavir Teva may develop a skin rash. Infrequently a rash may become severe or

potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking Darunavir Teva and raltegravir (for HIV infection), rashes (generally mild or moderate)

may occur more frequently than in patients taking either medicine separately.

Darunavir Teva has only been used in limited numbers of patients 65 years or older. If you belong to this

age group, please discuss with your doctor if you can use Darunavir Teva.

Tell your doctor about your situation BEFORE and DURING your treatment

Make sure that you check the following points and tell your doctor if any of these apply to you.

Tell your doctor if you have had problems with your liver before, including hepatitis B or C.Your

doctor may evaluate how severe your liver disease is before deciding if you can take Darunavir

Teva.

Tell your doctor if you have diabetes. Darunavir Teva might increase sugar levels in the blood.

Tell your doctor immediately if you notice any symptoms of infection (for example enlarged

lymph nodes and fever). In some patients with advanced HIV infection and a history of

opportunistic infection, signs and symptoms of inflammation from previous infections may occur

soon after anti-HIV treatment is started. It is believed that these symptoms are due to an

improvement in the body’s immune response, enabling the body to fight infections that may have

been present with no obvious symptoms.

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 the

treatment of your HIV infection. Autoimmune disorders may occur many months after the start of

treatment. If you notice any symptoms of infection or other 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, please inform your doctor immediately to seek necessary

treatment.

Tell your doctor if you have haemophilia. Darunavir Teva, might increase the risk of bleeding.

Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).

Tell your doctor if you notice any musculoskeletal problems. Some patients taking combination

antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused

by loss of blood supply to the bone). The length of combination antiretroviral therapy,

corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index,

among others, may be some of the many risk factors for developing this disease. Signs of

osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and shoulder) and

difficulty in movement. If you notice any of these symptoms please inform your doctor.

Use in Children and adolescents

Darunavir Teva is not for use in children younger than 3 years of age or weighing less than 15 kilograms.

Other medicines and Darunavir Teva

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

There are some medicines that you must not combine with Darunavir Teva. These are mentioned

above under the heading ‘Do not combine Darunavir Teva with any of the following medicines:’

In most cases, Darunavir Teva can be combined with anti-HIV medicines belonging to another class

[e.g. NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase

inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. Darunavir Teva with ritonavir has not been

tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some cases dosage

of other medicines might need to be changed. Therefore always tell your doctor if you take other anti-

HIV medicines and follow your doctor’s instruction carefully on which medicines can be combined.

The effects of Darunavir Teva might be reduced if you take any of the following products. Tell

your doctor if you take:

-

Phenobarbital, phenytoin (to prevent seizures)

-

Dexamethasone (corticosteroid)

-

Efavirenz (HIV infection)

-

Telaprevir, boceprevir (hepatitis C virus infection)

Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)

Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take Darunavir Teva. Tell your doctor if

you take:

-

Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, metoprolol, mexiletine,

nifedipine, nicardipine, propafenone, timolol, verapamil (for heart disease) as the therapeutic

effect or side effects of these medicines may be increased.

-

Apixaban, dabigatran etexilate, rivaroxaban, warfarin (to reduce clotting of the blood) as

their therapeutic effect or side effects may be altered; your doctor may have to check your

blood.

Oestrogen-based hormonal contraceptives and hormonal replacement therapy. Darunavir Teva

might reduce its effectiveness. When used for birth control, alternative methods of non-hormonal

contraception are recommended.

-

Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle tissue

disorder might be increased. Your doctor will evaluate which cholesterol lowering regimen is

best for your specific situation.

-

Clarithromycin (antibiotic)

-

Ciclosporin, everolimus, tacrolimus, sirolimus (to treat your immune system) as the therapeutic

effect or side effects of these medicines might be increased. Your doctor might want to do some

additional tests.

-

Fluticasone, budesonide (to control asthma). Its use should only take place after medical

evaluation and under close monitoring by your doctor for corticosteroid side effects.

-

Buprenorphine/naloxone (medicines to treat opiate dependence)

-

Salmeterol (medicine to treat asthma)

-

Artemether/lumefantrine (a combination medicine to treat malaria).

Dasatinib, everolimus, nilotinib, vinblastine, vincristine (to treat cancer)

Prednisone (corticosteroid)

Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder called

pulmonary arterial hypertension).

The dosage of other medicines might need to be changed since either their own or Darunavir Teva’s

therapeutic effect or side effects may be influenced when combined.

Tell your doctor if you take:

Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)

Digoxin (to treat certain heart disorders)

Clarithromycin (antibiotic)

-

Ketoconazole, itraconazole, fluconazole, posaconazole, clotrimazole (to treat fungal infections).

Voriconazole should only be taken after medical evaluation.

-

Rifabutin (against bacterial infections)

-

Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary

circulation)

-

Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat

depression and anxiety)

-

Maraviroc (to treat HIV infection)

-

Methadone (to treat opiate dependance)

-

Carbamazepine (to prevent seizures or to treat certain types of nerve pain)

-

Colchicine (to treat gout)

-

Bosentan (to treat high blood pressure in the pulmonary circulation)

Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam that is not taken orally,

zoldipem (sedative agents)

Perphenazine, risperidone, thioridazine (to treat psychiatric conditions)

Metformin (to treat type 2 diabetes).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are

taking.

Darunavir Teva with food and drink

See section 3 “How to take Darunavir Teva”.

Pregnancy and breast-feeding

Tell your doctor immediately if you are pregnant or if you are breast-feeding. Pregnant or breast-feeding

mothers must not take Darunavir Teva unless specifically directed by the doctor. It is recommended that

HIV infected women must not breast-feed their infants because of both the possibility of your baby

becoming infected with HIV through your breast milk and because of the unknown effects of the

medicine on your baby.

Driving and using machines

Do not operate machines or drive if you feel dizzy after taking Darunavir Teva.

3.

How to take Darunavir Teva

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has

told you. Check with your doctor, pharmacist or nurse if you are not sure. Even if you feel better, do not

stop taking Darunavir Teva and ritonavir without talking to your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be

stopped without instruction of the doctor.

Darunavir Teva

400 milligram tablets are only to be used to construct the once daily 800 milligram

regimen.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine

this)

The usual dose of Darunavir Teva is 800 milligram (2 tablets containing 400 milligram of

Darunavir Teva

once daily.

You must take Darunavir Teva every day and always in combination with 100 milligram of ritonavir and

with food.

Darunavir Teva

cannot work properly without ritonavir and food. You must eat a meal or a

snack within 30 minutes prior to taking your Darunavir Teva and ritonavir. The type of food is not

important. Even if you feel better, do not stop taking Darunavir Teva and ritonavir without talking to your

doctor.

Instructions for adults

Take two 400 milligram tablets at the same time, once a day, every day.

Take Darunavir Teva always together with 100 milligram of ritonavir.

Take Darunavir Teva with food.

Swallow the tablets with a drink such as water or milk.

Take your other HIV medicines used in combination with Darunavir Teva and ritonavir as

recommended by your doctor.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this)

The dose is either:

800 milligram Darunavir Teva (2 tablets containing 400 milligram of Darunavir Teva) together

with 100 milligram ritonavir once daily. OR

600 milligram Darunavir Teva (2 tablets containing 300 milligram of Darunavir Teva or 1 tablet

containing 600 milligram of Darunavir Teva) together with 100 milligram ritonavir twice daily.

Please discuss with your doctor which dose is right for you.

Dose for children 3 years of age and above, weighing more than 40 kilograms who have not taken

antiretroviral medicines before (your child’s doctor will determine this)

The usual dose of Darunavir Teva is 800 milligram (2 tablets containing 400 milligram of

Darunavir Teva) together with 100 milligram ritonavir once daily.

Dose for children 3 years of age and above, weighing more than 40 kilograms who have taken

antiretroviral medicines before (your child’s doctor will determine this)

The dose is either:

800 milligram Darunavir Teva (2 tablets containing 400 milligram of Darunavir Teva) together

with 100 milligram ritonavir once daily. OR

600 milligram Darunavir Teva (2 tablets containing 300 milligram of Darunavir Teva or 1 tablet

containing 600 milligram of Darunavir Teva) together with 100 milligram ritonavir twice daily.

Please discuss with your doctor which dose is right for you.

Instructions for children 3 years of age and above, weighing more than 40 kilograms

Take 800 milligram Darunavir Teva (2 tablets containing 400 milligram of Darunavir Teva) at the

same time, once a day, every day.

Take Darunavir Teva always together with 100 milligram of ritonavir.

Take Darunavir Teva with food.

Swallow the tablets with a drink such as water or milk.

Take your other HIV medicines used in combination with Darunavir Teva and ritonavir as

recommended by your doctor.

If you take more Darunavir Teva than you should

Contact your doctor, pharmacist or nurse immediately.

If you forget to take Darunavir Teva

If you notice within 12 hours, you must take the tablets immediately. Always take with ritonavir and

food. If you notice after 12 hours, then skip the intake and take the next doses as usual. Do not take a

double dose to make up for a forgotten dose.

Do not stop taking Darunavir Teva without talking to your doctor first

HIV therapy may increase your sense of well-being. Even when you feel better, do not stop taking

Darunavir Teva. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4.

Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This is

partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV

medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you develop any of the following side effects.

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests

prior to initiating Darunavir Teva. If you have chronic hepatitis B or C infection, your doctor should

check your blood tests more often because you have an increased chance of developing liver problems.

Talk to your doctor about the signs and symptoms of liver problems. These may include yellowing of your

skin or whites of your eyes, dark (tea colored) urine, pale colored stools (bowel movements), nausea,

vomiting, loss of appetite, or pain, aching, or sensitivity on your right side below your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to

moderate. A skin rash might also be a symptom of a rare severe situation. It is therefore important to

contact your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms or

whether Darunavir Teva must be stopped.

Other clinically relevant severe side effects were diabetes (common) and inflammation of the pancreas

(uncommon).

Very common side effects (may affect more than 1 in 10 people)

diarrhoea.

Common side effects (may affect up to 1 in 10 people)

vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence

headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)

chest pain, changes in electrocardiogram, rapid heart beating

decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory,

problems with your balance

difficulty breathing, cough, nosebleed, throat irritation

inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the abdomen,

constipation, belching

kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of urine,

sometimes at night

urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema,

excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails

muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis

slowing down of the thyroid gland function. This can be seen in a blood test.

high blood pressure, flushing

red or dry eyes

fever, swelling of lower limbs due to fluids, malaise, irritability, pain

symptoms of infection, herpes simplex

erectile dysfunction, enlargement of breasts

sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)

a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of the

face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver,kidney or

lung]

heart attack, slow heart beating, palpitations

visual disturbance

chills, feeling abnormal

a feeling of confusion or disorientation, altered mood, restlessness

fainting, epileptic fits, changes or loss of taste

mouth sores, vomiting blood, inflammation of the lips, dry lips, coated tongue

running nose

skin lesions, dry skin

stiffness of muscles or joints, joint pain with or without inflammation

changes in some values of your blood cells or chemistry. These can be seen in the results of blood

and/or urine tests. Your doctor will explain these to you. Examples are: increase in some white

blood cells.

Some side effects are typical for anti-HIV medicines in the same family as Darunavir Teva. These are:

muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been serious.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via:

Ireland

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1

6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Darunavir Teva

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the outer carton, blister and bottle after

EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Darunavir Teva contains

The active substance is darunavir. Each tablet contains 400 milligram of darunavir.

The other ingredients are

Tablet core: microcrystalline cellulose, colloidal anhydrous silica, crospovidone and magnesium

stearate.

Tablet coating: poly (vinyl alcohol) partially hydrolysed, titanium dioxide (E171), macrogol 3350,

talc, iron oxide yellow (E172), iron oxide red (E172) and iron oxide black (E172).

What Darunavir Teva looks like and contents of the pack

Darunavir Teva 400 mg are orange, film-coated, oval shaped tablets, debossed with "400" on one side and

plain on the other side with dimension of about 18.8 mm x 9.2 mm.

Darunavir Teva 400 mg is available in pack sizes of 20, 20x1, 60, 60x1, 200, 200x1, 240 or 240x1 film-

coated tablets in blisters and in HDPE bottles containing 60, 180 (60x3) and 200 film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturers

Marketing Authorisation Holder

Teva B.V.

Swensweg 5

2031GA Haarlem

Netherlands

Manufacturers

Teva Operations Poland Sp. z.o.o

ul. Mogilska 80., Krakow

31-546

Poland

Merckle GmbH

Ludwig-Merckle-Straße 3, Blaubeuren

89143

Germany

Teva Pharma B.V.

Swensweg 5, Haarlem

2031 GA

The Netherlands

PLIVA Hrvatska d.o.o. (PLIVA Croatia Ltd.)

Prilaz baruna Filipovica 25, Zagreb

10000

Croatia

This medicinal product is authorised in the Member States of the EEA under the following names:

Belgium

Darunavir Teva 400 mg filmomhulde tabletten/comprimés

pelliculés/Filmtabletten

Croatia

Darunavir Pliva 400 mg filmom obložene tablete

Cyprus

Darunavir/Teva 400 mg Επικαλυμμένα με λεπτό υμένιο δισκία

Czech Republic Darunavir Teva 400 mg potahované tablet

Denmark

Darunavir Teva

Estonia

Darunavir Teva

France

DARUNAVIR TEVA 400 mg comprimé pelliculé

Germany

Darunavir-ratiopharm 400 mg Filmtabletten

Greece

Darunavir/Teva 400 mg Επικαλυμμένα με λεπτό υμένιο δισκία

Ireland

Darunavir Teva 400 mg Film-coated Tablets

Italy

DARUNAVIR TEVA

Latvia

Darunavir Teva 400 mg apvalkotās tablets

Lithuania

Darunavir Teva 400 mg plėvele dengtos tabletės

Malta

Darunavir Teva 400 mg Film-coated Tablets

Netherlands

Darunavir Teva 400 mg, filmomhulde tabletten

Poland

Darunavir Teva

Portugal

Darunavir Teva

Romania

DARUNAVIR TEVA 400 mg comprimate filmate

This leaflet was last revised in May 2017.

Read the complete document

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Darunavir Teva 400 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 400 mg of darunavir

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Darunavir Teva 400 mg are orange, film coated, oval shaped tablet, debossed with "400" on one side and plain on the

other side with dimension of about 18.6-19.1 mm X 9.1-9.6 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Darunavir Teva, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal

products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.

Darunavir Teva,

is indicated in combination with other antiretroviral medicinal products for the treatment of human

immunodeficiency virus (HIV-1) infection in adult patients (see section 4.2).

Darunavir Teva 400 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in

adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:

antiretroviral therapy (ART)-naïve (see section 4.2).

ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1

RNA < 100,000 copies/ml and CD4+ cell count

100 cells x 10

/l. In deciding to initiate treatment with

Darunavir Teva in such ART-experienced patients, genotypic testing should guide the use of Darunavir Teva (see

sections 4.2, 4.3, 4.4 and 5.1).

4.2 Posology and method of administration

Therapy should be initiated by a health care provider experienced in the management of HIV infection. After therapy

with Darunavir Teva has been initiated, patients should be advised not to alter the dosage, dose form or discontinue

therapy without discussing with their health care provider.

The interaction profile of darunavir depends on whether ritonavir is used as pharmacokinetic enhancer. Darunavir may

therefore have different contraindications and recommendations for concomitant medications depending on whether the

compound is boosted with ritonavir (see sections 4.3, 4.4 and 4.5).

Posology

Darunavir Teva must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in combination

with other antiretroviral medicinal products. The Summary of Product Characteristics of ritonavir as appropriate, must

therefore be consulted prior to initiation of therapy with Darunavir Teva.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

ART-naïve adult patients

The recommended dose regimen is 800 mg once daily ritonavir 100 mg once daily taken with food. Darunavir Teva

400 mg tablets can be used to construct the once daily 800 mg regimen.

ART-experienced adult patients

The recommended dose regimens are as follows:

In ART-experienced patients with no darunavir resistance associated mutations (DRV-RAMs)* and who have

plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count

100 cells x 10

/l (see section 4.1) a regimen of

800 mg once daily ritonavir 100 mg once daily taken with food may be used. Darunavir Teva 400 mg tablets can

be used to construct the once daily 800 mg regimen.

In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose

regimen is 600 mg twice daily taken with ritonavir 100 mg twice daily taken with food. See the Summary of

Product Characteristics for Darunavir Teva 150 mg, 300 mg or 600 mg film-coated tablets.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

ART-naïve paediatric patients (3 to 17 years of age and weighing at least 40 kg)

The recommended dose regimen is 800 mg once daily with ritonavir 100 mg once daily taken with food.

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)

The recommended dose regimens are as follows:

In ART-experienced patients without DRV-RAMs* and who have plasma HIV-1 RNA < 100,000 copies/ml and

CD4+ cell count

100 cells x 10

/l (see section 4.1) a regimen of 800 mg once daily with ritonavir 100 mg once

daily taken with food may be used. Darunavir Teva 400 mg tablets can be used to construct the once daily 800

mg regimen.

In all other ART-experienced patients or if HIV-1 genotype testing is not available, the recommended dose

regimen described in the Summary of Product Characteristics for Darunavir Teva 150 mg, 300 mg or 600 mg

film-coated tablets.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, and L89V

Advice on missed doses

If a once daily dose of Darunavir Teva and/or ritonavir is missed within 12 hours of the time it is usually taken, patients

should be instructed to take the prescribed dose of Darunavir Teva and ritonavir with food as soon as possible. If this is

noticed later than 12 hours after the time it is usually taken, the missed dose should not be taken and the patient should

resume the usual dosing schedule.

This guidance is based on the half-life of darunavir in the presence of ritonavir and the recommended dosing interval of

approximately 24 hours.

Special populations

Elderly

Limited information is available in this population, and therefore, Darunavir Teva should be used with caution in this

age group (see sections 4.4 and 5.2).

Hepatic impairment

Darunavir is metabolised by the hepatic system. No dose adjustment is recommended in patients with mild (Child-Pugh

Class A) or moderate (Child-Pugh Class B) hepatic impairment, however, Darunavir Teva should be used with caution

in these patients. No pharmacokinetic data are available in patients with severe hepatic impairment. Severe hepatic

impairment could result in an increase of darunavir exposure and a worsening of its safety profile. Therefore, Darunavir

Teva must not be used in patients with severe hepatic impairment (Child-Pugh Class C) (see sections 4.3, 4.4 and 5.2).

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

Renal impairment

No dose adjustment is required for darunavir/ritonavir in patients with renal impairment (see sections 4.4 and 5.2).

Paediatric population

Darunavir should not be used in paediatric patients below 3 years of age or less than 15 kg body weight (see sections

4.4 and 5.3).

ART-naïve paediatric patients (less than 3 years of age or less than 15 kg body weight)

No recommendations on posology can be made in this population.

ART-experienced paediatric patients (3 to 17 years of age and weighing at least 40 kg)

Darunavir exposures in treatment-naïve adolescents 12 to 17 years weighing at least 40 kg receiving darunavir/ritonavir

800/100 mg once daily have been determined and were found to be within the therapeutic range as has been established

in adults receiving darunavir/ritonavir 800/100 mg once daily. As a consequence, since Darunavir Teva /ritonavir

800/100 mg once daily has also been registered for use in treatment-experienced adults without darunavir resistance

associated mutations (DRV-RAMs)* and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count

100 cells x 10

/l, the same indication of Darunavir Teva 800 mg once daily applies to treatment-experienced children 3

to 17 years weighing at least 40 kg.

* DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

For dosage recommendations in children see the Summary of Product Characteristics for Darunavir Teva 150 mg, 300

mg and 600 mg film-coated tablets.

Darunavir should not be used in children less than 15 kg body weight as the dose for this population has not been

established in a sufficient number of patients. Darunavir should not be used in children below 3 years of age because of

safety concerns.

Pregnancy and postpartum

No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. Darunavir should be used

during pregnancy only if the potential benefit justifies the potential risk (see sections 4.4, 4.6 and 5.2).

Method of administration

Patients should be instructed to take Darunavir Teva with low dose ritonavir within 30 minutes after completion of a

meal. The type of food does not affect the exposure to darunavir (see sections 4.4, 4.5 and 5.2).

4.3 Contraindications

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

Use in patients with severe (Child-Pugh Class C) hepatic impairment.

Concomitant treatment with any of the following medicinal products is contraindicated given the expected decrease in

plasma concentrations of darunavir and ritonavir and the potential for loss of therapeutic effect (see sections 4.4 and

4.5).

Applicable to darunavir boosted with ritonavir:

The combination product lopinavir/ritonavir (see section 4.5).

The strong CYP3A inducers rifampicin and herbal preparations containing St John’s wort (Hypericum perforatum).

Co-administration is expected to reduce plasma concentrations of darunavir and ritonavir, which could lead to loss of

therapeutic effect and possible development of resistance (see sections 4.4 and 4.5).

Darunavir boosted with ritonavir inhibits the elimination of active substances that are highly dependent on CYP3A for

clearance, which results in increased exposure to the co-administered medicinal product. Therefore, concomitant

treatment with such medicinal products for which elevated plasma concentrations are associated with serious and/or

life-threatening events is contraindicated (applies to darunavir boosted with ritonavir). These active substances include

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

3

e.g.:

- alfuzosin (alpha 1-adrenoreceptor antagonist)

- amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine (antiarrhythmics/antianginals)

- astemizole, terfenadine (antihistamines)

- colchicine when used in patients with renal and/or hepatic impairment (antigout) (see section 4.5)

- ergot derivatives (e.g. dihydroergotamine, ergometrine, ergotamine, methylergonovine)

- cisapride (gastrointestinal motility agents)

- pimozide, quetiapine, sertindole (antipsychotics/neuroleptics) (see section 4.5)

- triazolam, midazolam administered orally (sedatives/hypnotics) (for caution on parenterally administered midazolam,

see section 4.5)

- sildenafil - when used for the treatment of pulmonary arterial hypertension, avanafil (PDE-5 inhibitors)

- simvastatin and lovastatin (HMG-CoA reductase inhibitors) (see section 4.5)

- ticagrelor (antiplatelets) (see section 4.5).

4.4 Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual

transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance

with national guidelines.

Regular assessment of virological response is advised. In the setting of lack or loss of virological response, resistance

testing should be performed.

Darunavir

must always be given orally with low dose ritonavir as a pharmacokinetic enhancer and in combination

with other antiretroviral medicinal products (see section 5.2). The Summary of Product Characteristics of

ritonavir,

must therefore be consulted prior to initiation of therapy with darunavir.

Increasing the dose of ritonavir from that recommended in section 4.2 did not significantly affect darunavir

concentrations. It is not recommended to alter the dose of ritonavir.

Darunavir binds predominantly to

-acid glycoprotein. This protein binding is concentration-dependent indicative for

saturation of binding. Therefore, protein displacement of medicinal products highly bound to

-acid glycoprotein

cannot be ruled out (see section 4.5).

ART-experienced patients – once daily dosing

Darunavir used in combination with low dose ritonavir once daily in ART-experienced patients should not be used in

patients with one or more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA

100,000 copies/ml

or CD4+ cell count < 100 cells x 10

/l (see section 4.2). Combinations with optimised background regimen (OBRs)

other than

2 NRTIs have not been studied in this population. Limited data are available in patients with HIV-1 clades

other than B (see section 5.1).

Paediatric population

Darunavir is not recommended for use in paediatric patients below 3 years of age or less than 15 kg body weight (see

sections 4.2 and 5.3).

Pregnancy

Darunavir should be used during pregnancy only if the potential benefit justifies the potential risk. Caution should be

used in pregnant women with concomitant medications which may further decrease darunavir exposure (see sections

4.5 and 5.2).

Elderly

As limited information is available on the use of darunavir in patients aged 65 and over, caution should be exercised in

the administration of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function and of

concomitant disease or other therapy (see sections 4.2 and 5.2).

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

4

Severe skin reactions

During the darunavir/ritonavir clinical development program (N=3,063), severe skin reactions, which may be

accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug

Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson Syndrome has been rarely (< 0.1%) reported,

and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have

been reported. Darunavir/ritonavir should be discontinued immediately if signs or symptoms of severe skin reactions

develop. These can include, but are not limited to, severe rash or rash accompanied by fever, general malaise, fatigue,

muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.

Rash occurred more commonly in treatment-experienced patients receiving regimens containing darunavir/ritonavir +

raltegravir compared to patients receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir (see

section 4.8).

Darunavir contains a sulphonamide moiety. Darunavir should be used with caution in patients with a known

sulphonamide allergy.

Hepatotoxicity

Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir. During the

darunavir/ritonavir clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving

combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including

chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially

fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant

product information for these medicinal products.

Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir used in combination with

low dose ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be

considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of

transaminases, especially during the first several months of darunavir used in combination with low dose ritonavir

treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes

and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients

using darunavir used in combination with low dose ritonavir, interruption or discontinuation of treatment should be

considered promptly.

Patients with coexisting conditions

Hepatic impairment

The safety and efficacy of darunavir have not been established in patients with severe underlying liver disorders and

darunavir is therefore contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound

darunavir plasma concentrations, darunavir should be used with caution in patients with mild or moderate hepatic

impairment (see sections 4.2, 4.3 and 5.2).

Renal impairment

No special precautions or dose adjustments for darunavir/ritonavir are required in patients with renal impairment. As

darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by

haemodialysis or peritoneal dialysis. Therefore, no special precautions or dose adjustments are required in these

patients (see sections 4.2 and 5.2).

Haemophiliac patients

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients

with haemophilia type A and B treated with PIs. In some patients additional factor VIII was given. In more than half of

the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal

relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients

should, therefore, be made aware of the possibility of increased bleeding.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

5

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral

therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in

some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating

this to any particular treatment. For monitoring of blood lipids and glucose reference is made to

established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

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 combination antiretroviral therapy (CART). Patients should be

advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune reconstitution inflammatory 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 pathogens may arise and cause serious

clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or

months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial

infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any

inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of

herpes simplex and herpes zoster has been observed in clinical studies with darunavir co-administered with low dose

ritonavir.

Autoimmune disorders (such as Graves'

disease) have also been reported to occur in the setting of immune reactivation;

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

treatment (see section 4.8).

Interactions with medicinal products

Pharmacokinetic enhancer and concomitant medications

Concomitant use of darunavir/ritonavir with lopinavir/ritonavir, rifampicin and herbal products containing St John’s

wort, Hypericum perforatum, is contraindicated (see section 4.5).

Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If

efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen

should be used. See the Summary of Product Characteristics for Darunavir Teva 150 mg, 300 mg or 600 mg film-

coated tablets (see section 4.5).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors

of CYP3A and P-glycoprotein (P-gp; see sections 4.3 and 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

The interaction profile of darunavir may differ depending on whether ritonavir is used as pharmacoenhancer. The

recommendations given for concomitant use of darunavir and other medicinal products may therefore differ depending

on whether darunavir is boosted with ritonavir (see sections 4.3 and 4.4), and caution is also required during the first

time of treatment if switching the pharmacoenhancer from ritonavir (see section 4.4).

Medicinal products that affect darunavir exposure (ritonavir as pharmacoenhancer)

Darunavir and ritonavir are metabolised by CYP3A. Medicinal products that induce CYP3A activity would be expected

to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of these compounds and

consequently that of darunavir, leading to loss of therapeutic effect and possible development of resistance (see

sections 4.3 and 4.4). CYP3A inducers that are contraindicated include rifampicin, St John’s wort and lopinavir.

Co-administration of darunavir and ritonavir with other medicinal products that inhibit CYP3A may decrease the

clearance of darunavir and ritonavir, which may result in increased plasma concentrations of darunavir and ritonavir.

Co-administration with strong CYP3A4 inhibitors is not recommended and caution is warranted, these interactions are

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

6

described in the interaction table below (e.g. indinavir, systemic azoles like ketoconazole and clotrimazole).

Medicinal products that may be affected by darunavir boosted with ritonavir

Darunavir and ritonavir are inhibitors of CYP3A, CYP2D6 and P-gp. Co-administration of darunavir/ritonavir with

medicinal products primarily metabolised by CYP3A and/or CYP2D6 or transported by P-gp may result in increased

systemic exposure to such medicinal products, which could increase or prolong their therapeutic effect and adverse

reactions.

Darunavir co-administered with low dose ritonavir must not be combined with medicinal products that are highly

dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-

threatening events (narrow therapeutic index) (see section 4.3).

The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic

exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100

mg twice daily. Therefore, darunavir must only be used in combination with a pharmacokinetic enhancer (see section

5.2).

A clinical study utilising a cocktail of medicinal products that are metabolised by cytochromes CYP2C9, CYP2C19

and CYP2D6 demonstrated an increase in CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the

presence of darunavir/ritonavir, which may be attributed to the presence of low dose ritonavir. Co-administration of

darunavir and ritonavir with medicinal products which are primarily metabolised by CYP2D6 (such as flecainide,

propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could

increase or prolong their therapeutic effect and adverse reactions. Co-administration of darunavir and ritonavir and

medicinal products primarily metabolised by CYP2C9 (such as warfarin) and CYP2C19 (such as methadone) may

result in decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic

effect.

Although the effect on CYP2C8 has only been studied in vitro, co-administration of darunavir and ritonavir and

medicinal products primarily metabolised by CYP2C8 (such as paclitaxel, rosiglitazone, repaglinide) may result in

decreased systemic exposure to such medicinal products, which could decrease or shorten their therapeutic effect.

Ritonavir inhibits the transporters P-glycoprotein, OATP1B1 and OATP1B3, and co-administration with substrates of

these transporters can result in increased plasma concentrations of these compounds (e.g. dabigatran etexilate, digoxin,

statins and bosentan; see the Interaction table below).

Interaction table

Interaction studies have only been performed in adults.

Several of the interaction studies (indicated by

in the table below) have been performed at lower than recommended

doses of darunavir or with a different dosing regimen (see section 4.2 Posology). The effects on co-administered

medicinal products may thus be underestimated and clinical monitoring of safety may be indicated.

The interaction profile of darunavir depends on whether ritonavir is used as pharmacokinetic enhancer. Darunavir may

therefore have different recommendations for concomitant medications depending on whether the compound is boosted

with ritonavir.

Interactions between darunavir/ritonavir and antiretroviral and non-antiretroviral medicinal products are listed in the

table below (not determined as “ND”). The direction of the arrow for each pharmacokinetic parameter is based on the

90% confidence interval of the geometric mean ratio being within (

), below (

) or above (

) the 80-125% range.

In the table below the specific pharmacokinetic enhancer is specified when recommendations differ. When the

recommendation is the same for Darunavir Teva when co-administered with a low dose ritonavir, the term “boosted

Darunavir Teva” is used.

INTERACTIONS AND DOSE RECOMMENDATIONS WITH OTHER MEDICINAL

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

7

PRODUCTS

Medicinal

products by

therapeutic areas

Interaction

Geometric mean change (%)

Recommendations

concerning co-

administration

HIV ANTIRETROVIRALS

Integrase strand transfer inhibitors

Dolutegravir

dolutegravir AUC

dolutegravir C24h 38%

dolutegravir Cmax

darunavir

* Using cross-study

comparisons to historical

pharmacokinetic data

Boosted darunavir and

dolutegravir can be used

without dose adjustment.

Elvitegravir

elvitegravir AUC

elvitegravir Cmin

elvitegravir Cmax

darunavir AUC

darunavir Cmin 17%

darunavir Cmax

When darunavir co-

administered with low dose

ritonavir (600/100 mg twice

daily) is used in combination

with elvitegravir, the dose of

elvitegravir should be 150 mg

once daily.

The pharmacokinetics and

dosing recommendations for

other doses of darunavir with

elvitegravir have not been

established. Therefore, co-

administration of darunavir

with low dose ritonavir in

doses other than 600/100 mg

twice daily and elvitegravir is

not recommended.

Raltegravir

Some clinical studies suggest

raltegravir may cause a modest

decrease in darunavir plasma

concentrations.

At present the effect of

raltegravir on darunavir

plasma concentrations does

not appear to be clinically

relevant. Boosted darunavir

and raltegravir can be used

without dose adjustments.

Nucleo(s/t)ide reverse transcriptase inhibitors (NRTIs)

Didanosine

400 mg once daily

didanosine AUC

didanosine Cmin ND

Boosted darunavir and

didanosine can be used

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

8

didanosine Cmax

darunavir AUC

darunavir Cmin

darunavir Cmax

without dose adjustments.

Didanosine is to be

administered on an empty

stomach, thus it should be

administered 1 hour before or

2 hours after boosted

darunavir given with food.

Tenofovir

disoproxil fumarate

300 mg once daily

tenofovir AUC

tenofovir Cmin

tenofovir Cmax

#darunavir AUC

#darunavir Cmin

#darunavir Cmax

tenofovir from effect on

MDR-1 transport in the renal

tubules)

Monitoring of renal function

may be indicated when

boosted darunavir is given in

combination with tenofovir,

particularly in patients with

underlying systemic or renal

disease, or in patients taking

nephrotoxic agents.

Refer to section 4.4 if

creatinine clearance is used

for dose adjustment of

tenofovir.

Abacavir

Emtricitabine

Lamivudine

Stavudine

Zidovudine

Not studied. Based on the

different elimination pathways

of the other NRTIs zidovudine,

emtricitabine, stavudine,

lamivudine, that are primarily

renally excreted, and abacavir

for which metabolism is not

mediated by CYP450, no

interactions are expected for

these medicinal compounds

and boosted darunavir.

Boosted darunavir can be

used with these NRTIs

without dose adjustment.

Refer to section 4.4 if

creatinine clearance is used

for dose adjustment of

emtricitabine or lamivudine.

Non-nucleo(s/t)ide reverse transcriptase inhibitors (NNRTIs)

Efavirenz

600 mg once daily

efavirenz AUC

efavirenz Cmin

efavirenz Cmax

#darunavir AUC

#darunavir Cmin

#darunavir Cmax

efavirenz from CYP3A

inhibition)

darunavir from CYP3A

induction)

Clinical monitoring for central

nervous system toxicity

associated with increased

exposure to efavirenz may be

indicated when darunavir co-

administered with low dose

ritonavir is given in

combination with efavirenz.

Efavirenz in combination with

darunavir/ritonavir 800/100

mg once daily may result in

sub-optimal darunavir C

If efavirenz is to be used in

combination with

darunavir/ritonavir, the

darunavir/ritonavir 600/100

mg twice daily regimen

should be used (see section

4.4).

Etravirine

100 mg twice daily

etravirine AUC

etravirine Cmin

Darunavir co-administered

with low dose ritonavir and

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

9

etravirine Cmax

darunavir AUC

darunavir Cmin

darunavir Cmax

etravirine 200 mg twice daily

can be used without dose

adjustments.

Nevirapine

200 mg twice daily

nevirapine AUC

nevirapine Cmin

nevirapine Cmax

#darunavir: concentrations

were consistent with historical

data

nevirapine from CYP3A

inhibition)

Darunavir co-administered

with low dose ritonavir and

nevirapine can be used

without dose adjustments.

Rilpivirine

150 mg once daily

rilpivirine AUC

130%

rilpivirine Cmin

178%

rilpivirine Cmax

darunavir AUC

darunavir Cmin

darunavir Cmax

Boosted darunavir and

rilpivirine can be used without

dose adjustments.

HIV Protease inhibitors (PIs) - without additional co-administration of low dose ritonavir

Atazanavir

300 mg once daily

atazanavir AUC

atazanavir Cmin

atazanavir Cmax

#darunavir AUC

#darunavir Cmin

#darunavir Cmax

Atazanavir: comparison of

atazanavir/ritonavir 300/100

mg once daily vs. atazanavir

300 mg once daily in

combination with

darunavir/ritonavir 400/100 mg

twice daily.

Darunavir: comparison of

darunavir/ritonavir 400/100 mg

twice daily vs.

darunavir/ritonavir 400/100 mg

twice daily in combination with

atazanavir 300 mg once daily.

Darunavir co-administered

with low dose ritonavir and

atazanavir can be used

without dose adjustments.

Indinavir

800 mg twice daily

indinavir AUC

indinavir C

125%

indinavir C

darunavir C

Indinavir: comparison of

indinavir/ritonavir 800/100 mg

twice daily vs.

indinavir/darunavir/ritonavir

800/400/100 mg twice daily.

When used in combination

with darunavir co-

administered with low dose

ritonavir, dose adjustment of

indinavir from 800 mg twice

daily to 600 mg twice daily

may be warranted in case of

intolerance.

darunavir AUC

darunavir C

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

0

Darunavir: comparison of

darunavir/ritonavir 400/100 mg

twice daily vs.

darunavir/ritonavir 400/100 mg

in combination with indinavir

800 mg twice daily.

Saquinavir

1,000 mg twice

daily

#darunavir AUC

#darunavir Cmin

#darunavir Cmax

saquinavir AUC

saquinavir Cmin

saquinavir Cmax

Saquinavir: comparison of

saquinavir/ritonavir 1,000/100

mg twice daily vs.

saquinavir/darunavir/ritonavir

1,000/400/100 mg twice daily

Darunavir: comparison of

darunavir/ritonavir 400/100 mg

twice daily vs.

darunavir/ritonavir 400/100 mg

in combination with saquinavir

1,000 mg twice daily.

It is not recommended to

combine darunavir co-

administered with low dose

ritonavir with saquinavir.

HIV Protease inhibitors (PIs) - with co-administration of low dose ritonavir

Lopinavir/ritonavir

400/100 mg twice

daily

Lopinavir/ritonavir

533/133.3 mg twice

daily

lopinavir AUC

lopinavir Cmin

lopinavir Cmax

darunavir AUC

38%‡

darunavir Cmin

51%‡

darunavir Cmax

21%‡

lopinavir AUC

lopinavir Cmin

lopinavir Cmax

darunavir AUC

darunavir Cmin

darunavir Cmax

‡ based upon non dose

normalised values

Due to a decrease in the

exposure (AUC) of darunavir

by 40%, appropriate doses of

the combination have not

been established. Hence,

concomitant use of boosted

darunavir and the combination

product lopinavir/ritonavir is

contraindicated (see section

4.3).

CCR5 ANTAGONIST

Maraviroc

150 mg twice daily

maraviroc AUC

305%

maraviroc Cmin ND

maraviroc Cmax

129%

darunavir, ritonavir

concentrations were consistent

with historical data

The maraviroc dose should be

150 mg twice daily when co-

administered with boosted

darunavir.

ANAESTHETIC

Alfentanil

Not studied. The metabolism of

alfentanil is mediated via

The concomitant use with

boosted darunavir may require

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

1

CYP3A, and may as such be

inhibited by boosted darunavir.

to lower the dose of alfentanil

and requires monitoring for

risks of prolonged or delayed

respiratory depression.

ANTIANGINA/ANTIARRHYTHMIC

Disopyramide

Flecainide

Mexiletine

Propafenone

Amiodarone

Bepridil

Dronedarone

Lidocaine

(systemic)

Quinidine

Ranolazine

Not studied. Boosted darunavir

is expected to increase these

antiarrhythmic plasma

concentrations.

(CYP3A inhibition)

Caution is warranted and

therapeutic concentration

monitoring, if available, is

recommended for these

antiarrhythmics when co-

administered with boosted

darunavir.

Boosted darunavir and

amiodarone, bepridil,

dronedarone, systemic

lidocaine, quinidine, or

ranolazine is contraindicated

(see section 4.3).

Digoxin

0.4 mg single dose

digoxin AUC

digoxin Cmin ND

digoxin Cmax

digoxin from probable

inhibition of P-gp)

Given that digoxin has a

narrow therapeutic index, it is

recommended that the lowest

possible dose of digoxin

should initially be prescribed

in case digoxin is given to

patients on boosted darunavir

therapy. The digoxin dose

should be carefully titrated to

obtain the desired clinical

effect while assessing the

overall clinical state of the

subject.

ANTIBIOTIC

Clarithromycin

500 mg twice daily

clarithromycin AUC

clarithromycin Cmin

174%

clarithromycin Cmax

#darunavir AUC

#darunavir Cmin

#darunavir Cmax

14-OH-clarithromycin concentrations

were not detectable when combined

with darunavir/ritonavir.

clarithromycin from CYP3A

inhibition and possible P-gp inhibition)

Caution should be

exercised when

clarithromycin is

combined with boosted

darunavir.

For patients with renal

impairment the

Summary of Product

Characteristics for

clarithromycin should

be consulted for the

recommended dose.

ANTICOAGULANTS

Apixaban

Dabigatran etexilate

Rivaroxaban

Not studied. Co-administration of

boosted darunavir with these

anticoagulants may increase

concentrations of the anticoagulant.

(CYP3A and/or P-gp inhibition)

The use of boosted

darunavir and these

anticoagulants is not

recommended.

Warfarin

Not studied. Warfarin concentrations

It is recommended that

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

2

may be affected when co-administered

with boosted darunavir.

the international

normalised ratio (INR)

be monitored when

warfarin is combined

with boosted darunavir.

ANTICONVULSANTS

Phenobarbital

Phenytoin

Not studied. Phenobarbital and

phenytoin are expected to decrease

plasma concentrations of darunavir

and its pharmacoenhancer.

(induction of CYP450 enzymes)

Darunavir co-

administered with low

dose ritonavir should

not be used in

combination with these

medicines.

Carbamazepine

200 mg twice daily

carbamazepine AUC

carbamazepine Cmin

carbamazepine Cmax

darunavir AUC

darunavir Cmin

darunavir Cmax

No dose adjustment for

darunavir/ritonavir is

recommended. If there

is a need to combine

darunavir/ritonavir and

carbamazepine, patients

should be monitored for

potential

carbamazepine-related

adverse events.

Carbamazepine

concentrations should

be monitored and its

dose should be titrated

for adequate response.

Based upon the

findings, the

carbamazepine dose

may need to be reduced

by 25% to 50% in the

presence of

darunavir/ritonavir.

ANTIDEPRESSANTS

Paroxetine

20 mg once daily

Sertraline

50 mg once daily

paroxetine AUC

paroxetine Cmin

paroxetine Cmax

#darunavir AUC

#darunavir C min

#darunavir C max

sertraline AUC

sertraline Cmin

sertraline Cmax

#darunavir AUC

#darunavir C min

#darunavir C max

If antidepressants are

co-administered with

boosted darunavir, the

recommended approach

is a dose titration of the

antidepressant based on

a clinical assessment of

antidepressant

response. In addition,

patients on a stable

dose of these

antidepressants who

start treatment with

boosted darunavir

should be monitored for

antidepressant

response.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

3

Amitriptyline

Desipramine

Imipramine

Nortriptyline

Trazodone

Concomitant use of boosted darunavir

and these antidepressants may increase

concentrations of the antidepressant.

(CYP2D6 and/or CYP3A inhibition).

Clinical monitoring is

recommended when co-

administering boosted

darunavir with these

antidepressants and a

dose adjustment of the

antidepressant may be

needed.

ANTI-DIABETICS

Metformin

Not studied.

(not applicable for

darunavir co-

administered with

ritonavir)

ANTIFUNGALS

Voriconazole

Not studied. Ritonavir may decrease

plasma concentrations of voriconazole.

(induction of CYP450 enzymes)

(inhibition of CYP450 enzymes)

Voriconazole should

not be combined with

boosted darunavir

unless an assessment of

the benefit/risk ratio

justifies the use of

voriconazole.

Ketoconazole

200 mg twice daily

ketoconazole AUC

212%

ketoconazole Cmin

868%

ketoconazole Cmax

111%

#darunavir AUC

#darunavir Cmin

#darunavir Cmax

(CYP3A inhibition)

Caution is warranted

and clinical monitoring

is recommended when

combined with boosted

darunavir. When co-

administration is

required the daily dose

of ketoconazole should

not exceed 200 mg.

Fluconazole

Posaconazole

Not studied. Boosted darunavir may

increase antifungal plasma

concentrations (P-gp inhibition) and

posaconazole or fluconazole may

increase darunavir concentrations.

(CYP3A inhibition)

Caution is warranted

and clinical monitoring

is recommended.

Itraconazole

Not studied. Concomitant systemic use

of itraconazole and boosted darunavir

may increase plasma concentrations of

darunavir and itraconazole.

(CYP3A inhibition)

Caution is warranted

and clinical monitoring

is recommended when

combined with boosted

darunavir. When co-

administration is

required the daily dose

of itraconazole should

not exceed 200 mg.

Clotrimazole

Not studied. Concomitant systemic use

of clotrimazole and boosted darunavir

may increase plasma concentrations of

darunavir and/or clotrimazole.

Caution is warranted

and clinical monitoring

is recommended, when

co-administration of

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

4

darunavir AUC24h

33% (based on

population pharmacokinetic model)

clotrimazole is

required.

ANTIGOUT MEDICINES

Colchicine

Not studied. Concomitant use of

colchicine and boosted darunavir may

increase the exposure to colchicine.

(CYP3A and/ or P-glycoprotein

inhibition)

A reduction in

colchicine dosage or an

interruption of

colchicine treatment is

recommended in

patients with normal

renal or hepatic

function if treatment

with boosted darunavir

is required. For patients

with renal or hepatic

impairment colchicine

with boosted darunavir

is contraindicated (see

section 4.3).

ANTIMALARIALS

Artemether/Lumefantrine

80/480 mg, 6 doses

at 0, 8, 24, 36, 48,

and 60 hours

artemether AUC

artemether Cmin

artemether Cmax

dihydroartemisinin AUC

dihydroartemisinin Cmin

dihydroartemisinin Cmax

lumefantrine AUC

175%

lumefantrine Cmin

126%

lumefantrine Cmax

darunavir AUC

darunavir Cmin

darunavir Cmax

The combination of

boosted darunavir and

artemether/lumefantrine

can be used without

dose adjustments;

however, due to the

increase in lumefantrine

exposure, the

combination should be

used with caution.

ANTIMYCOBACTERIALS

Rifampicin

Rifapentine

Not studied. Rifapentine and rifampicin

are strong CYP3A inducers and have

been shown to cause profound

decreases in concentrations of other

protease inhibitors, which can result in

virological failure and resistance

development (CYP450 enzyme

induction). During attempts to

overcome the decreased exposure by

increasing the dose of other protease

inhibitors with low dose ritonavir, a

high frequency of liver reactions was

seen with rifampicin.

The combination of

rifapentine and boosted

darunavir is not

recommended.

The combination of

rifampicin and boosted

darunavir is

contraindicated (see

section 4.3).

Rifabutin

150 mg once every

other day

rifabutin AUC**

rifabutin Cmin **

rifabutin Cmax **

darunavir AUC

darunavir Cmin

A dosage reduction of

rifabutin by 75% of the

usual dose of 300

mg/day (i.e. rifabutin

150 mg once every

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

5

darunavir Cmax

** sum of active moieties of rifabutin

(parent drug + 25-O-desacetyl

metabolite)

The interaction trial showed a

comparable daily systemic exposure

for rifabutin between treatment at 300

mg once daily alone and 150 mg once

every other day in combination with

darunavir/ritonavir (600/100 mg twice

daily) with an about 10-fold increase

in the daily exposure to the active

metabolite 25-O-desacetylrifabutin.

Furthermore, AUC of the sum of

active moieties of rifabutin (parent

drug + 25-O-desacetyl metabolite) was

increased 1.6-fold, while Cmax

remained comparable.

Data on comparison with a 150 mg

once daily reference dose is lacking.

(Rifabutin is an inducer and substrate

of CYP3A.) An increase of systemic

exposure to darunavir was observed

when darunavir co-administered with

100 mg ritonavir was co-administered

with rifabutin (150 mg once every

other day).

other day) and

increased monitoring

for rifabutin related

adverse events is

warranted in patients

receiving the

combination with

darunavir co-

administered with

ritonavir. In case of

safety issues, a further

increase of the dosing

interval for rifabutin

and/or monitoring of

rifabutin levels should

be considered.

Consideration should

be given to official

guidance on the

appropriate treatment of

tuberculosis in HIV

infected patients.

Based upon the safety

profile of

darunavir/ritonavir, the

increase in darunavir

exposure in the

presence of rifabutin

does not warrant a dose

adjustment for

darunavir/ritonavir.

Based on

pharmacokinetic

modeling, this dosage

reduction of 75% is

also applicable if

patients receive

rifabutin at doses other

than 300 mg/day.

ANTINEOPLASTICS

Dasatinib

Nilotinib

Vinblastine

Vincristine

Everolimus

Not studied. Boosted darunavir is

expected to increase these

antineoplastic plasma concentrations.

(CYP3A inhibition)

Concentrations of these

medicinal products may

be increased when co-

administered with

boosted darunavir

resulting in the

potential for increased

adverse events usually

associated with these

agents.

Caution should be

exercised when

combining one of these

antineoplastic agents

with boosted darunavir.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

6

Concominant use of

everolimus and boosted

darunavir is not

recommended.

ANTIPLATELETS

Ticagrelor

Not studied. Co-administration with

boosted darunavir may lead to a

substantial increase in exposure to

ticagrelor.

Concomitant

administration of

boosted darunavir with

ticagrelor is

contraindicated.

Use of other

antiplatelets not

affected by CYP

inhibition or induction

(e.g. prasugrel) is

recommended.

ANTIPSYCHOTICS/NEUROLEPTICS

Quetiapine

Not studied. Boosted darunavir is

expected to increase these

antipsychotic plasma

concentrations.

(CYP3A inhibition)

Concomitant administration

of boosted darunavir and

quetiapine is

contraindicated as it may

increase quetiapine-related

toxicity. Increased

concentrations of quetiapine

may lead to coma.

Perphenazine

Risperidone

Thioridazine

Pimozide

Sertindole

Not studied. Boosted darunavir is

expected to increase these

antipsychotic plasma

concentrations.

(CYP2D6 inhibition and/or P-gp)

A dose decrease may be

needed for these drugs when

co-administered with

boosted darunavir.

Concominant administration

of boosted darunavir and

pimozide or sertindole is

contraindicated.

-BLOCKERS

Carvedilol

Metoprolol

Timolol

Not studied. Boosted darunavir is

expected to increase these

-blocker

plasma concentrations.

(CYP2D6 inhibition)

Clinical monitoring is

recommended when co-

administering boosted

darunavir with

-blockers.

A lower dose of the

blocker should be

considered.

CALCIUM CHANNEL BLOCKERS

Amlodipine

Diltiazem

Felodipine

Nicardipine

Nifedipine

Verapamil

Not studied. Boosted darunavir can

be expected to increase the plasma

concentrations of calcium channel

blockers.

(CYP3A and/or CYP2D6

inhibition)

Clinical monitoring of

therapeutic and adverse

effects is recommended

when these medicines are

concomitantly administered

with boosted darunavir.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

7

CORTICOSTEROIDS

Fluticasone

Budesonide

In a clinical study where ritonavir

100 mg capsules twice daily were

co-administered with 50 µg

intranasal fluticasone propionate (4

times daily) for 7 days in healthy

subjects, fluticasone propionate

plasma concentrations increased

significantly, whereas the intrinsic

cortisol levels decreased by

approximately 86% (90% CI 82-

89%). Greater effects may be

expected when fluticasone is

inhaled. Systemic corticosteroid

effects including Cushing’s

syndrome and adrenal suppression

have been reported in patients

receiving ritonavir and inhaled or

intranasally administered

fluticasone; this could also occur

with other corticosteroids

metabolised via the P4503A

pathway, e.g., budesonide. The

effects of high fluticasone systemic

exposure on ritonavir plasma levels

are unknown.

Concomitant administration

of boosted darunavir and

these glucocorticoids is not

recommended unless the

potential benefit of

treatment outweighs the risk

of systemic corticosteroid

effects. A dose reduction of

the glucocorticoid should be

considered with close

monitoring of local and

systemic effects or a switch

to a glucocorticoid which is

not a substrate for CYP3A

(e.g., beclomethasone).

Moreover, in case of

withdrawal of

glucocorticoids, progressive

dose reduction may have to

be performed over a longer

period.

Dexamethasone

(systemic)

Not studied. Dexamethasone may

decrease plasma concentrations of

darunavir.

(CYP3A induction)

Systemic dexamethasone

should be used with caution

when combined with

boosted darunavir.

Prednisone

Not studied. Boosted darunavir may

increase plasma concentrations of

prednisone.

(CYP3A inhibition)

Concomitant use of boosted

darunavir with low dose

ritonavir and prednisone

may increase the risk for

development of systemic

corticosteroid effects,

including Cushing’s

syndrome and adrenal

suppression. Clinical

monitoring is recommended

when co-administering

boosted darunavir with

corticosteroids.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan

Not studied. Concomitant use of

bosentan and boosted darunavir

may increase plasma concentrations

of bosentan. Bosentan is expected

to decrease plasma concentrations

of darunavir and/or its

pharmacoenhancer.

(CYP3A induction)

When administered

concomitantly with

darunavir and low dose

ritonavir, the patient’s

tolerability of bosentan

should be monitored.

HEPATITIS C VIRUS (HCV) DIRECT-ACTING ANTIVIRALS

NS3-4A protease inhibitors

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

8

Telaprevir

750 mg every 8

hours

telaprevir AUC

telaprevir Cmin

telaprevir Cmax

darunavir AUC12

darunavir Cmin

darunavir Cmax

It is not recommended to

co-administer boosted

darunavir and telaprevir.

Boceprevir

800 mg three times

daily

boceprevir AUC

boceprevir Cmin

boceprevir Cmax

darunavir AUC

darunavir Cmin

darunavir Cmax

It is not recommended to

co-administer boosted

darunavir and boceprevir.

Simeprevir

simeprevir AUC

159%

simeprevir C

358%

simeprevir C

darunavir AUC

darunavir C

darunavir C

The dose of simeprevir in this

interaction study was 50 mg when

co-administered in combination

with darunavir/ritonavir, compared

to 150 mg in the simeprevir alone

treatment group.

It is not recommended to

co-administer boosted

darunavir and simeprevir.

HERBAL PRODUCTS

St John's wort

(Hypericum

perforatum)

Not studied. St John’s wort is

expected to decrease the plasma

concentrations of darunavir or its

pharmacoenhancers. (CYP450

induction)

Boosted darunavir must not

be used concomitantly with

products containing St

John’s wort (Hypericum

perforatum) (see section

4.3). If a patient is already

taking St John’s wort, stop

St John’s wort and if

possible check viral levels.

Darunavir exposure (and

also ritonavir exposure)

may increase on stopping St

John’s wort. The inducing

effect may persist for at

least 2 weeks after cessation

of treatment with St John’s

wort.

HMG CO-A REDUCTASE INHIBITORS

Lovastatin

Simvastatin

Not studied. Lovastatin and

simvastatin are expected to have

markedly increased plasma

concentrations when co-

administered with boosted

darunavir.

(CYP3A inhibition)

Increased plasma

concentrations of lovastatin

or simvastatin may cause

myopathy, including

rhabdomyolysis.

Concomitant use of boosted

darunavir with lovastatin

and simvastatin is therefore

contraindicated (see section

4.3).

Atorvastatin

10 mg once daily

atorvastatin AUC

3-4 fold

atorvastatin Cmin

5.5-10 fold

When administration of

atorvastatin and boosted

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

1

9

atorvastatin Cmax

2 fold

#darunavir

darunavir is desired, it is

recommended to start with

an atorvastatin dose of 10

mg once daily. A gradual

dose increase of atorvastatin

may be tailored to the

clinical response.

Pravastatin

40 mg single dose

pravastatin AUC

81%¶

pravastatin Cmin ND

pravastatin Cmax

¶ an up to five-fold increase was

seen in a limited subset of subjects

When administration of

pravastatin and boosted

darunavir is required, it is

recommended to start with

the lowest possible dose of

pravastatin and titrate up to

the desired clinical effect

while monitoring for safety.

Rosuvastatin

10 mg once daily

rosuvastatin AUC

rosuvastatin Cmax

144%

based on published data

When administration of

rosuvastatin and boosted

darunavir is required, it is

recommended to start with

the lowest possible dose of

rosuvastatin and titrate up to

the desired clinical effect

while monitoring for safety.

H -RECEPTOR ANTAGONISTS

Ranitidine

150 mg twice daily

#darunavir AUC

#darunavir Cmin

#darunavir C max

Boosted darunavir can be

co-administered with H2-

receptor antagonists without

dose adjustments.

IMMUNOSUPPRESSANTS

Ciclosporin

Sirolimus

Tacrolimus

Everolimus

Not studied. Exposure to these

immunosuppressants will be

increased when co-administered

with boosted darunavir.

(CYP3A inhibition)

Therapeutic drug

monitoring of the

immunosuppressive agent

must be done when co-

administration occurs.

Concomitant use of

everolimus and boosted

darunavir is not

recommended.

INHALED BETA AGONISTS

Salmeterol

Not studied. Concomitant use of

salmeterol and boosted darunavir

may increase plasma concentrations

of salmeterol.

Concomitant use of

salmeterol and boosted

darunavir is not

recommended. The

combination may result in

increased risk of

cardiovascular adverse

event with salmeterol,

including QT prolongation,

palpitations and sinus

tachycardia.

NARCOTIC ANALGESICS / TREATMENT OF OPIOID DEPENDENCE

2

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

0

Methadone

individual dose

ranging from 55 mg

to 150 mg once

daily

R(-) methadone AUC

R(-) methadone Cmin

R(-) methadone Cmax

No adjustment of

methadone dosage is

required when initiating co-

administration with boosted

darunavir. However,

adjustment of the

methadone dose may be

necessary when

concomitantly administered

for a longer period of time.

Therefore, clinical

monitoring is

recommended, as

maintenance therapy may

need to be adjusted in some

patients.

Buprenorphine/naloxone

8/2 mg–16/4 mg

once daily

buprenorphine AUC

buprenorphine Cmin

buprenorphine Cmax

norbuprenorphine AUC

norbuprenorphine Cmin

norbuprenorphine Cmax

naloxone AUC

naloxone Cmin ND

naloxone Cmax

The clinical relevance of the

increase in

norbuprenorphine

pharmacokinetic parameters

has not been established.

Dose adjustment for

buprenorphine may not be

necessary when co-

administered with boosted

darunavir but a careful

clinical monitoring for signs

of opiate toxicity are

recommended.

OESTROGEN-BASED CONTRACEPTIVES

Ethinylestradiol

Norethindrone

35 µg /1 mg once

daily

ethinylestradiol AUC

ethinylestradiol Cmin

ethinylestradiol Cmax

norethindrone AUC

norethindrone Cmin

norethindrone Cmax

Alternative or additional

contraceptive measures are

recommended when

oestrogen-based

contraceptives are co-

administered with boosted

darunavir. Patients using

oestrogens as hormone

replacement therapy should

be clinically monitored for

signs of oestrogen

deficiency.

PHOSPHODIESTERASE, TYPE 5 (PDE-5) INHIBITORS

For the treatment of

erectile dysfunction

Avanafil

Sildenafil

Tadalafil

Vardenafil

In an interaction study #, a

comparable systemic exposure to

sildenafil was observed for a single

intake of 100 mg sildenafil alone

and a single intake of 25 mg

sildenafil co-administered with

darunavir and low dose ritonavir.

The combination of avanafil

and boosted darunavir is

contraindicated (see section

4.3). Concomitant use of

other PDE-5 inhibitors for

the treatment of erectile

dysfunction with boosted

darunavir should be done

with caution. If concomitant

use of boosted darunavir

with sildenafil, vardenafil or

tadalafil is indicated,

sildenafil at a single dose

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

1

not exceeding 25 mg in 48

hours, vardenafil at a single

dose not exceeding 2.5 mg

in 72 hours or tadalafil at a

single dose not exceeding

10 mg in 72 hours is

recommended.

For the treatment of

pulmonary arterial

hypertension

Sildenafil

Tadalafil

Not studied. Concomitant use of

sildenafil or tadalafil for the

treatment of pulmonary arterial

hypertension and boosted darunavir

may increase plasma concentrations

of sildenafil or tadalafil. (CYP3A

inhibition)

A safe and effective dose of

sildenafil for the treatment

of pulmonary arterial

hypertension co-

administered with boosted

darunavir has not been

established. There is an

increased potential for

sildenafil-associated

adverse events (including

visual disturbances,

hypotension, prolonged

erection and syncope).

Therefore, co-

administration of boosted

darunavir and sildenafil

when used for the treatment

of pulmonary arterial

hypertension is

contraindicated (see section

4.3). Co-administration of

tadalafil for the treatment of

pulmonary arterial

hypertension with boosted

darunavir is not

recommended.

PROTON PUMP INHIBITORS

Omeprazole

20 mg once daily

#darunavir AUC

#darunavir Cmin

#darunavir Cmax

Boosted darunavir can be

co-administered with proton

pump inhibitors without

dose adjustments.

SEDATIVES/HYPNOTICS

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Midazolam

(parenteral)

Zoldipem

Not studied. Sedative/hypnotics are

extensively metabolised by

CYP3A. Co-administration with

boosted darunavir may cause a

large increase in the concentration

of these medicines.

If parenteral midazolam is co-

administered with boosted

darunavir it may cause a large

increase in the concentration of this

benzodiazepine. Data from

concomitant use of parenteral

midazolam with other protease

inhibitors suggest a possible 3-4

Clinical monitoring is

recommended when co-

administering boosted

darunavir with these

sedatives/hypnotics and a

lower dose of the

sedatives/hypnotics should

be considered.

If parenteral midazolam is

co-administered with

boosted darunavir, it should

be done in an intensive care

unit (ICU) or similar

setting, which ensures close

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

2

tipranavir) has not been established in HIV patients. According to current treatment guidelines, dual

therapy with protease inhibitors is generally not recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and

consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical

experience in pregnant women should be taken into account.

There are no adequate and well controlled studies on pregnancy outcome with darunavir in pregnant women. Studies in

animals do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or

postnatal development (see section 5.3).

Darunavir co-administered with low dose ritonavir should be used during pregnancy only if the potential benefit

justifies the potential risk.

Breast-feeding

It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is

excreted in milk and at high levels (1,000 mg/kg/day) resulted in toxicity. Because of both the potential for HIV

transmission and the potential for adverse reactions in breast-fed infants, mothers should be instructed not to breast-

feed under any circumstances if they are receiving darunavir.

Fertility

No human data on the effect of darunavir on fertility are available. There was no effect on mating or fertility with

darunavir treatment in rats (see section 5.3).

4.7 Effects on ability to drive and use machines

Darunavir in combination with ritonavir has no or negligible influence on the ability to drive and use machines.

However, dizziness has been reported in some patients during treatment with regimens containing darunavir co-

administered with low dose ritonavir and should be borne in mind when considering a patient’s ability to drive or

operate machinery (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

During the clinical development program (N=2,613 treatment-experienced subjects who initiated therapy with

Midazolam (oral)

Triazolam

fold increase in midazolam plasma

levels.

clinical monitoring and

appropriate medical

management in case of

respiratory depression

and/or prolonged sedation.

Dose adjustment for

midazolam should be

considered, especially if

more than a single dose of

midazolam is administered.

Boosted darunavir with

triazolam or oral midazolam

is contraindicated (see

section 4.3)

The efficacy and safety of the use of darunavir with 100 mg ritonavir and any other HIV PI (e.g. (fos)amprenavir,

nelfinavir and

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

3

darunavir/ritonavir 600/100 mg twice daily), 51.3% of subjects experienced at least one adverse reaction. The

total mean treatment duration for subjects was 95.3 weeks. The most frequent adverse reactions reported in

clinical trials and as spontaneous reports are diarrhoea, nausea, rash, headache and vomiting. The most frequent

serious reactions are acute renal failure, myocardial infarction, immune reconstitution inflammatory syndrome,

thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and pyrexia.

In the 96 week analysis, the safety profile of darunavir/ritonavir 800/100 mg once daily in treatment-naïve subjects

was similar to that seen with darunavir/ritonavir 600/100 mg twice daily in treatment-experienced subjects except for

nausea which was observed more frequently in treatment-naïve subjects. This was driven by mild intensity nausea. No

new safety findings were identified in the 192 week analysis of the treatment-naïve subjects in which the mean

treatment duration of darunavir/ritonavir 800/100 mg once daily was 162.5 weeks.

Tabulated list of adverse reactions

Adverse reactions are listed by system organ class (SOC) and frequency category. Within each frequency category,

adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as follows:

very common (

1/10), common (

1/100 to < 1/10), uncommon (

1/1,000 to < 1/100), rare (

1/10,000 to <

1/1,000) and not known (frequency cannot be estimated from the available data).

Adverse reactions observed with darunavir/ritonavir in clinical trials and post-marketing

MedDRA system organ class

Frequency category

Adverse reaction

Infections and infestations

uncommon

herpes simplex

Blood and lymphatic system disorders

uncommon

rare

thrombocytopenia, neutropenia, anaemia,

leukopenia

increased eosinophil count

Immune system disorders

uncommon

immune reconstitution inflammatory syndrome,

(drug) hypersensitivity

Endocrine disorders

uncommon

hypothyroidism, increased blood thyroid

stimulating hormone

Metabolism and nutrition disorders

common

uncommon

diabetes mellitus, hypertriglyceridaemia,

hypercholesterolaemia, hyperlipidaemia

gout, anorexia, decreased appetite,

decreased weight, increased weight,

hyperglycaemia, insulin resistance,

decreased high density lipoprotein,

increased appetite, polydipsia, increased

blood lactate dehydrogenase

Psychiatric disorders

common

uncommon

insomnia

depression, disorientation, anxiety, sleep

disorder, abnormal dreams, nightmare,

decreased libido

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

4

rare

confusional state, altered mood, restlessness

Nervous system disorders

common

uncommon

rare

headache, peripheral neuropathy, dizziness

lethargy, paraesthesia, hypoaesthesia,

dysgeusia, disturbance in attention, memory

impairment, somnolence

syncope, convulsion, ageusia, sleep phase

rhythm disturbance

Eye disorders

uncommon

rare

conjunctival hyperaemia, dry eye

visual disturbance

Ear and labyrinth disorders

uncommon

vertigo

Cardiac disorders

uncommon

rare

myocardial infarction, angina pectoris,

prolonged electrocardiogram QT, tachycardia

acute myocardial infarction, sinus

bradycardia, palpitations

Vascular disorders

uncommon

hypertension, flushing

Respiratory, thoracic and mediastinal disorders

uncommon

rare

dyspnoea, cough, epistaxis, throat irritation

rhinorrhoea

Gastrointestinal disorders

very common

common

uncommon

rare

diarrhoea

vomiting, nausea, abdominal pain, increased

blood amylase, dyspepsia, abdominal

distension, flatulence

pancreatitis, gastritis, gastrooesophageal reflux

disease, aphthous stomatitis, retching, dry

mouth, abdominal discomfort, constipation,

increased lipase, eructation, oral dysaesthesia

stomatitis, haematemesis, cheilitis, dry lip,

coated tongue

Hepatobiliary disorders

common

uncommon

increased alanine aminotransferase

hepatitis, cytolytic hepatitis, hepatic steatosis,

hepatomegaly, increased transaminase,

increased aspartate aminotransferase,

increased blood bilirubin, increased blood

alkaline phosphatase, increased gamma-

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

5

Description of selected adverse reactions

Rash

In clinical trials, rash was mostly mild to moderate, often occurring within the first four weeks of treatment and

resolving with continued dosing. In cases of severe skin reaction see the warning in section 4.4.

During the clinical development program of raltegravir in treatment-experienced patients, rash, irrespective of

causality, was more commonly observed with regimens containing darunavir/ritonavir + raltegravir compared to those

containing darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. Rash considered by the

investigator to be drug-related occurred at similar rates. The exposure-adjusted rates of rash (all causality) were 10.9,

glutamyltransferase

Skin and subcutaneous tissue disorders

common

uncommon

rare

not known

rash (including macular, maculopapular,

papular, erythematous and pruritic rash),

pruritus

angioedema, generalised rash, allergic

dermatitis, urticaria, eczema, erythema,

hyperhidrosis, night sweats, alopecia, acne, dry

skin, nail pigmentation

DRESS, Stevens-Johnson syndrome, erythema

multiforme, dermatitis, seborrhoeic dermatitis,

skin lesion, xeroderma

toxic epidermal necrolysis, acute

generalised exanthematous pustulosis

Musculoskeletal and connective tissue disorders

uncommon

rare

myalgia, osteonecrosis, muscle spasms,

muscular weakness, arthralgia, pain in

extremity, osteoporosis, increased blood

creatine phosphokinase

musculoskeletal stiffness, arthritis, joint

stiffness

Renal and urinary disorders

uncommon

rare

acute renal failure, renal failure, nephrolithiasis,

increased blood creatinine, proteinuria,

bilirubinuria, dysuria, nocturia, pollakiuria

decreased creatinine renal clearance

Reproductive system and breast disorders

uncommon

erectile dysfunction, gynaecomastia

General disorders and administration site conditions

common

uncommon

rare

asthenia, fatigue

pyrexia, chest pain, peripheral oedema, malaise,

feeling hot, irritability, pain

chills, abnormal feeling, xerosis

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

6

4.2, and 3.8 per 100 patient-years (PYR), respectively; and for drug-related rash were 2.4, 1.1, and 2.3 per 100 PYR,

respectively. The rashes observed in clinical studies were mild to moderate in severity and did not result in

discontinuation of therapy (see section 4.4).

Metabolic parameters

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

Musculoskeletal abnormalities

Increased CPK, myalgia, myositis and rarely, rhabdomyolysis have been reported with the use of protease inhibitors,

particularly in combination with NRTIs.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced

HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown

(see section 4.4).

Immune reconstitution inflammatory 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 (see section 4.4).

Bleeding in haemophiliac patients

There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease

inhibitors (see section 4.4).

Paediatric population

The safety assessment in paediatric patients is based on the 48-week analysis of safety data from three Phase II trials.

The following patient populations were evaluated (see section 5.1):

80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at least 20 kg who

received darunavir tablets with low dose ritonavir twice daily in combination with other antiretroviral agents.

21 ART-experienced HIV-1 infected paediatric patients aged from 3 to < 6 years and weighing 10 kg to < 20 kg

(16 participants from 15 kg to < 20 kg) who received darunavir oral suspension with low dose ritonavir twice

daily in combination with other antiretroviral agents.

12 ART-naïve HIV-1 infected paediatric patients aged from 12 to 17 years and weighing at least 40 kg who

received darunavir tablets with low dose ritonavir once daily in combination with other antiretroviral agents (see

section 5.1).

Overall, the safety profile in these paediatric patients was similar to that observed in the adult population.

Other special populations

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

Among 1,968 treatment-experienced patients receiving darunavir co-administered with ritonavir 600/100 mg twice

daily, 236 patients were co-infected with hepatitis B or C. Co-infected patients were more likely to have baseline and

treatment emergent hepatic transaminase elevations than those without chronic viral hepatitis (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal

product

is important.

allows continued

monitoring of

the benefit/risk balance of

the medicinal

product.

Healthcare professionals are asked to report

suspected adverse reactions via HPRA Pharmacovigilance,

Earlsfort

Terrace,

IRL - Dublin 2;

Tel:

+353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

Human experience of acute overdose with darunavir co-administered with low dose ritonavir is limited. Single doses up

to 3,200 mg of darunavir as oral solution alone and up to 1,600 mg of the tablet formulation of darunavir in

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

7

combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.

There is no specific antidote for overdose with darunavir. Treatment of overdose with darunavir consists of general

supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If

indicated, elimination of unabsorbed active substance is to be achieved by emesis.

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

darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, protease inhibitors ATC code: J05AE10.

Mechanism of action

Darunavir is an inhibitor of the dimerisation and of the catalytic activity of the HIV-1 protease (KD of 4.5 x 10

M). It

selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus infected cells, thereby preventing the

formation of mature infectious virus particles.

Antiviral activity in vitro

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in

acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with

median EC

values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/ml). Darunavir demonstrates antiviral activity in vitro

against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC

values ranging

from < 0.1 to 4.3 nM.

These EC

values are well below the 50% cellular toxicity concentration range of 87 µM to > 100 µM.

Resistance

In vitro selection of darunavir-resistant virus from wild type HIV-1 was lengthy (> 3 years). The selected viruses were

unable to grow in the presence of darunavir concentrations above 400 nM. Viruses selected in these conditions and

showing decreased susceptibility to darunavir (range: 23-50-fold) harboured 2 to 4 amino acid substitutions in the

protease gene. The decreased susceptibility to darunavir of the emerging viruses in the selection experiment could not

be explained by the emergence of these protease mutations.

The clinical trial data from ART-experienced patients (TITAN trial and the pooled analysis of the POWER 1, 2 and 3

and DUET 1 and 2 trials) showed that virologic response to darunavir co-administered with low dose ritonavir was

decreased when 3 or more darunavir RAMs (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V)

were present at baseline or when these mutations developed during treatment.

Increasing baseline darunavir fold change in EC

(FC) was associated with decreasing virologic response. A lower

and upper clinical cut-off of 10 and 40 were identified. Isolates with baseline FC

10 are susceptible; isolates with FC

> 10 to 40 have decreased susceptibility; isolates with FC > 40 are resistant (see Clinical results).

Viruses isolated from patients on darunavir/ritonavir 600/100 mg twice daily experiencing virologic failure by rebound

that were susceptible to tipranavir at baseline remained susceptible to tipranavir after treatment in the vast majority of

cases.

The lowest rates of developing resistant HIV virus are observed in ART-naïve patients who are treated for the first time

with darunavir in combination with other ART.

The table below shows the development of HIV-1 protease mutations and loss of susceptibility to PIs in virologic

failures at endpoint in the ARTEMIS, ODIN and TITAN trials.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

8

Cross-resistance

Darunavir FC was less than 10 for 90% of 3,309 clinical isolates resistant to amprenavir, atazanavir, indinavir,

lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to most PIs remain

susceptible to darunavir.

In the virologic failures of the ARTEMIS trial no cross-resistance with other PIs was observed. In the virologic failures

of the GS-US-216-130 trial no cross-resistance with other HIV PIs was observed.

Clinical results

All clinical trials were performed with Darunavir co-administered with low dose ritonavir.

Adult patients

Efficacy of Darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-naïve patients

ARTEMIS

Week

ODIN

Week 48

TITAN

Week 48

Darunavir/

ritonavir

800/100 mg

once daily

N=343

Darunavir/

ritonavir

800/100 mg

once daily

N=294

Darunavir/

ritonavir

600/100 mg

twice daily

N=296

Darunavir/

ritonavir

600/100 mg

twice daily

N=298

Total number of

virologic failures , n

Rebounders

Never

suppressed

subjects

55 (16.0%)

39 (11.4%)

16 (4.7%)

65 (22.1%)

11 (3.7%)

54 (18.4%)

54 (18.2%)

11 (3.7%)

43 (14.5%)

31 (10.4%)

16 (5.4%)

15 (5.0%)

Number of subjects with virologic failure and paired baseline/endpoint genotypes,

developing mutations

at endpoint, n/N

Primary (major) PI

mutations

PI RAMs

0/43

4/43

1/60

7/60

0/42

4/42

6/28

10/28

Number of subjects with virologic failure and paired baseline/endpoint phenotypes,

showing loss of susceptibility to PIs at endpoint compared to baseline, n/N

darunavir

amprenavir

atazanavir

indinavir

lopinavir

saquinavir

tipranavir

0/39

0/39

0/39

0/39

0/39

0/39

0/39

1/58

1/58

2/56

2/57

1/58

0/56

0/58

0/41

0/40

0/40

0/40

0/40

0/40

0/41

3/26

0/22

0/22

1/24

0/23

0/22

1/25

TLOVR non-VF censored algorithm based on HIV-1 RNA < 50 copies/ml, except for TITAN (HIV-1 RNA < 400 copies/ml)

IAS-USA lists

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

2

9

The evidence of efficacy of darunavir/ritonavir 800/100 mg once daily is based on the analyses of 192 week data from

the randomised, controlled, open-label Phase III trial ARTEMIS in antiretroviral treatment-naïve HIV-1 infected

patients comparing darunavir/ritonavir 800/100 mg once daily with lopinavir/ritonavir 800/200 mg per day (given as a

twice-daily or as a once-daily regimen). Both arms used a fixed background regimen consisting of tenofovir disoproxil

fumarate 300 mg once daily and emtricitabine 200 mg once daily.

The table below shows the efficacy data of the 48 week and 96 week analyses from the ARTEMIS trial:

Data based on analyses at week 48

Data based on analyses at week 96

Imputations according to the TLOVR algorithm

Based on normal approximation to the difference in % response

Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0

Non-inferiority in virologic response to the darunavir/ritonavir treatment, defined as the percentage of patients with

plasma HIV-1 RNA level < 50 copies/ml, was demonstrated (at the pre-defined 12% non-inferiority margin) for both

Intent-To-Treat (ITT) and On Protocol (OP) populations in the 48 week analysis. These results were confirmed in the

analyses of data at 96 weeks of treatment in the ARTEMIS trial. These results were sustained up to 192 weeks of

treatment in the ARTEMIS trial.

Efficacy of darunavir 800 mg once daily co-administered with 100 mg ritonavir once daily in ART-experienced patients

ODIN is a Phase III, randomised, open-label trial comparing darunavir/ritonavir 800/100 mg once daily versus

darunavir/ritonavir 600/100 mg twice daily in ART-experienced HIV-1 infected patients with screening genotype

resistance testing showing no darunavir RAMs (i.e. V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V,

L89V) and a screening HIV-1 RNA > 1,000 copies/ml. Efficacy analysis is based on 48 weeks of treatment (see table

ARTEMIS

Week 48

Week 96

Outcomes

Darunavir/

Lopinavir/

Treatment

Darunavir/

Lopinavir/

Treatment

ritonavir

ritonavir

difference

ritonavir

ritonavir

difference

800/100 mg

once daily

800/200 mg

per day

(95% CI of

difference)

800/100 mg

once daily

800/200 mg

per day

(95% CI of

difference)

N=343

N=346

N=343

N=346

HIV-1 RNA

< 50 copies/ml

All patients

83.7%

78.3%

5.3%

79.0%

70.8%

8.2%

(287)

(271)

(-0.5; 11.2)

(271)

(245)

(1.7; 14.7)

With baseline

85.8%

84.5%

1.3%

80.5%

75.2%

5.3%

HIV-RNA

< 100,000

(194/226)

(191/226)

(-5.2; 7.9)

(182/226)

(170/226)

(-2.3; 13.0)

With baseline

79.5%

66.7%

12.8%

76.1%

62.5%

13.6%

HIV-RNA

100,000

(93/117)

(80/120)

(1.6; 24.1)

(89/117)

(75/120)

(1.9; 25.3)

With baseline

79.4%

70.3%

9.2%

78.7%

64.9%

13.9%

CD4+ cell

count < 200

(112/141)

(104/148)

(-0.8; 19.2)

(111/141)

(96/148)

(3.5; 24.2)

With baseline

86.6%

84.3%

2.3%

79.2%

75.3%

4.0%

CD4+ cell

count

(175/202)

(167/198)

(-4.6; 9.2)

(160/202)

(149/198)

(-4.3; 12.2)

median CD4+

cell

count change

from

baseline (x 10

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

3

0

below). Both arms used an optimised background regimen (OBR) of

2 NRTIs.

Imputations according to the TLOVR algorithm

Based on a normal approximation of the difference in % response

Clades A1, D, F1, G, K, CRF02_AG, CRF12_BF, and CRF06_CPX

Difference in means

Last Observation Carried Forward imputation

At 48 weeks, virologic response, defined as the percentage of patients with plasma HIV-1 RNA level < 50 copies/ml,

with darunavir/ritonavir 800/100 mg once daily treatment was demonstrated to be non-inferior (at the pre-defined 12%

non-inferiority margin) compared to darunavir/ritonavir 600/100 mg twice daily for both ITT and OP populations.

Darunavir/ritonavir 800/100 mg once daily in ART-experienced patients should not be used in patients with one or

more darunavir resistance associated mutations (DRV-RAMs) or HIV-1 RNA

100,000 copies/ml or CD4+ cell count

< 100 cells x 10

/l (see section 4.2 and 4.4). Limited data is available in patients with HIV-1 clades other than B.

Paediatric patients

ART-naïve paediatric patients from the age of 12 years to < 18 years, and weighing at least 40 kg

DIONE is an open-label, Phase II trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of darunavir

with low dose ritonavir in 12 ART-naïve HIV-1 infected paediatric patients aged 12 to less than 18 years and weighing

at least 40 kg. These patients received darunavir/ritonavir 800/100 mg once daily in combination with other

antiretroviral agents. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0

versus baseline.

ODIN

Outcomes

Darunavir/ritonavir

800/100 mg once

daily + OBR

N=294

Darunavir/ritonavir

600/100 mg twice

daily + OBR N=296

Treatment

difference (95% CI

of difference)

HIV-1 RNA < 50

copies/ml

With Baseline

HIV-1 RNA

(copies/ml)

72.1% (212)

70.9% (210)

1.2% (-6.1; 8.5)

< 100,000

77.6% (198/255)

73.2% (194/265)

4.4% (-3.0; 11.9)

100,000

With Baseline

CD4+ cell count

(x 10

35.9% (14/39)

51.6% (16/31)

-15.7% (-39.2; 7.7)

75.1% (184/245)

72.5% (187/258)

2.6% (-5.1; 10.3)

< 100

With HIV-1 clade

57.1% (28/49)

60.5% (23/38)

-3.4% (-24.5; 17.8)

Type B

70.4% (126/179)

64.3% (128/199)

6.1% (-3.4; 15.6)

Type AE

90.5% (38/42)

91.2% (31/34)

-0.7% (-14.0; 12.6)

Type C

72.7% (32/44)

78.8% (26/33)

-6.1% (-2.6; 13.7)

Other

55.2% (16/29)

83.3% (25/30)

-28.2% (-51.0; -5.3)

mean CD4+ cell

count change from

baseline

(x 10

(-25; 16)

DIONE

Outcomes at week 48

Darunavir/ritonavir

N=12

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

3

1

Imputations according to the TLOVR algorithm.

Non-completer is failure imputation: patients who discontinued prematurely are imputed with a change equal to 0.

For additional clinical study results in ART-experienced adults and paediatric patients, refer to the Summary of Product

Characteristics for Darunavir Teva 150 mg, 300 mg or 600 mg film-coated tablets.

Pregnancy and postpartum

Darunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was

evaluated in a clinical trial of 34 pregnant women (17 in each arm) during the second and third trimesters, and

postpartum. Virologic response was preserved throughout the study period in both arms. No mother to child

transmission occurred in the infants born to the 29 subjects who stayed on the antiretroviral treatment through delivery.

There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in

HIV-1 infected adults (see sections 4.2, 4.4 and 5.2).

5.2 Pharmacokinetic properties

The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult

volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy

subjects. The increased exposure to darunavir in HIV-1 infected patients compared to healthy subjects may be

explained by the higher concentrations of

1-acid glycoprotein (AAG) in HIV-1 infected patients, resulting in higher

darunavir binding to plasma AAG and, therefore, higher plasma concentrations.

Darunavir is primarily metabolised by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma

concentrations of darunavir considerably.

Absorption

Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the

presence of low dose ritonavir is generally achieved within 2.5-4.0 hours.

The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to

approximately 82% in the presence of 100 mg twice daily ritonavir. The overall pharmacokinetic enhancement effect

by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg

darunavir was given orally in combination with ritonavir at 100 mg twice daily (see section 4.4).

When administered without food, the relative bioavailability of darunavir in the presence of low dose ritonavir is lower

as compared to intake with food. Therefore, darunavir tablets should be taken with ritonavir and with food. The type of

food does not affect exposure to darunavir.

Distribution

Darunavir is approximately 95% bound to plasma protein. Darunavir binds primarily to plasma

1-acid glycoprotein.

Following intravenous administration, the volume of distribution of darunavir alone was 88.1 ± 59.0 l (Mean ± SD) and

increased to 131 ± 49.9 l (Mean ± SD) in the presence of 100 mg twice-daily ritonavir.

Biotransformation

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative

metabolism. Darunavir is extensively metabolised by the hepatic CYP system and almost exclusively by isozyme

CYP3A4. A

C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a

single 400/100 mg darunavir with ritonavir dose was due to the parent active substance. At least 3 oxidative metabolites

of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of

darunavir against wild type HIV.

HIV-1 RNA < 50 copies/ml

83.3% (10)

CD4+ percent change from baseline

CD4+ cell count mean change from baseline

1.0 log

decrease from baseline in plasma viral

load

100%

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2

0

1

7

C

R

N

2

1

9

4

4

2

8

p

a

g

e

n

u

m

b

e

r

:

3

2

Elimination

After a 400/100 mg

C-darunavir with ritonavir dose, approximately 79.5% and 13.9% of the administered dose of

C-darunavir could be retrieved in faeces and urine, respectively. Unchanged darunavir accounted for approximately

41.2% and 7.7% of the administered dose in faeces and urine, respectively. The terminal elimination half-life of

darunavir was approximately 15 hours when combined with ritonavir.

The intravenous clearance of darunavir alone (150 mg) and in the presence of low dose ritonavir was 32.8 l/h and 5.9

l/h, respectively.

Special populations

Paediatric population

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 74 treatment-experienced

paediatric patients, aged 6 to 17 years and weighing at least 20 kg, showed that the administered weight-based doses of

darunavir/ritonavir resulted in darunavir exposure comparable to that in adults receiving darunavir/ritonavir 600/100

mg twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken twice daily in 14 treatment-experienced

paediatric patients, aged 3 to < 6 years and weighing at least 15 kg to < 20 kg, showed that weight-based dosages

resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 600/100 mg

twice daily (see section 4.2).

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 12 ART-naïve paediatric patients,

aged 12 to < 18 years and weighing at least 40 kg, showed that darunavir/ritonavir 800/100 mg once daily results in

darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg once daily.

Therefore the same once daily dosage may be used in treatment-experienced adolescents aged 12 to < 18 years and

weighing at least 40 kg without darunavir resistance associated mutations (DRV-RAMs)* and who have plasma HIV-1

RNA < 100,000 copies/ml and CD4+ cell count

100 cells x 10

/l (see section 4.2).

DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

The pharmacokinetics of darunavir in combination with ritonavir taken once daily in 10 treatment-experienced

paediatric patients, aged 3 to < 6 years and weighing at least 14 kg to < 20 kg, showed that weight-based dosages

resulted in darunavir exposure that was comparable to that achieved in adults receiving darunavir/ritonavir 800/100 mg

once daily (see section 4.2). In addition, pharmacokinetic modeling and simulation of darunavir exposures in paediatric

patients across the ages of 3 to < 18 years confirmed the darunavir exposures as observed in the clinical studies and

allowed the identification of weight-based darunavir/ritonavir once daily dosing regimens for paediatric patients

weighing at least 15 kg that are either ART-naïve or treatment-experienced paediatric patients without DRV-RAMs*

and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count

100 cells x 10

/l (see section 4.2).

DRV-RAMs: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V

Elderly

Population pharmacokinetic analysis in HIV infected patients showed that darunavir pharmacokinetics are not

considerably different in the age range (18 to 75 years) evaluated in HIV infected patients (n=12, age >65) (see section

4.4). However, only limited data were available in patients above the age of 65 year.

Gender

Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV infected females

compared to males. This difference is not clinically relevant.

Renal impairment

Results from a mass balance study with

C-darunavir with ritonavir showed that approximately 7.7% of the

administered dose of darunavir is excreted in the urine unchanged.

Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

7

/

0

7

/

2