PREZISTA 150 MG

Israel - English - Ministry of Health

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Active ingredient:
DARUNAVIR AS ETHANOLATE
Available from:
J-C HEALTH CARE LTD
ATC code:
J05AE10
Pharmaceutical form:
FILM COATED TABLETS
Composition:
DARUNAVIR AS ETHANOLATE 150 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
JANSSEN CILAG S.P.A., ITALY
Therapeutic group:
DARUNAVIR
Therapeutic area:
DARUNAVIR
Therapeutic indications:
Adult Patients:Prezista, co-administered with ritonavir (Prezista/rtv), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV -1) infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 controlled phase 3 trials of 48 weeks duration in antiretroviral treatment - naive and treatment-experienced patients and 2 controlled phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients .Pediatric patients:Prezista, co-administered with ritonavir (Prezista/rtv), and with other antiretroviral agents, is indicated for the treatment of HIV-1 infection in treatment-experienced pediatric patients 6 years of age and older .This indication is based on 24 Week analyses of plasma HIV-1 RNA levels and CD4+ cell counts from an open-label phase 2 trial in antiretroviral treatment-experienced pediatric patients 6 to < 18 years of age. In treatment-experienced adult and pediatric patients, the fol
Authorization number:
144 32 32992 00
Authorization date:
2015-08-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

25-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

03-11-2016

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

_

4.8.15

_

םש

רישכת

תילגנאב

רפסמו

םושירה

75mg Prezista

םושיר רפסמ

144-22-32957-00

Prezista 150mg

םושיר רפסמ

144-32-32992-00

Prezista 400mg

םושיר רפסמ

142-12-31999-00

Prezista 600mg

םושיר רפסמ

142-13-32000-00

Prezista 800mg

םושיר רפסמ

151-64-34005-00

םש

לעב

םושירה

_

J-C HEALTH CARE LTD

.

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Interactions

7.3

Established and Other

Potentially Significant Drug

Interactions

Darunavir and ritonavir are

both inhibitors of the CYP3A

isoform. Co-administration of

darunavir and ritonavir and

medicinal products primarily

metabolised by CYP3A may

result in increased systemic

exposure to such medicinal

products, which could increase

or prolong their therapeutic

effect and adverse reactions

PREZISTA 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). These medicinal

products include

amiodarone, bepridil,

quinidine, systemic

lidocaine, astemizole,

alfuzosin, terfenadine,

sildenafil (when used for the

treatment of pulmonary

arterial hypertension),

7.3

Established and Other Potentially

Significant Drug Interactions

Darunavir and ritonavir are both inhibitors of

the CYP3A isoform. Co-administration of

darunavir and ritonavir and medicinal

products primarily metabolised by CYP3A

may result in increased systemic exposure to

such medicinal products, which could

increase or prolong their therapeutic effect

and adverse reactions

PREZISTA 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). These medicinal products

include

amiodarone,

bepridil,

quinidine,

systemic lidocaine, astemizole, alfuzosin,

terfenadine, sildenafil (when used for the

treatment of pulmonary arterial hypertension),

avanafil ,quetiapine, midazolam administered

orally,

triazolam,

cisapride,

pimozide,

sertindole, simvastatin, lovastatin and the

ergot

alkaloids

(e.g.

ergotamine,

dihydroergotamine,

ergonovine

methylergonovine), Rifampin, St. John’s Wort

(Hypericum perforatum), Co-administration

with

combination

product

lopinavir/ritonavir

Lovastatin

Simvastatin

Not studied. Lovastatin and simvastatin are

,quetiapine, midazolam

administered orally,

triazolam, cisapride,

pimozide, sertindole,

simvastatin, lovastatin and

the ergot alkaloids (e.g.

ergotamine,

dihydroergotamine,

ergonovine and

methylergonovine),

Rifampin, St. John’s Wort

(Hypericum perforatum), Co-

administration with the

combination product

lopinavir/ritonavir

expected to have markedly increased

plasma concentrations when

co-administered with boosted PREZISTA

CYP3A inhibition

Increased plasma concentrations of

lovastatin or simvastatin may cause

myopathy, including

rhabdomyolysis. Concomitant use

of boosted PREZISTA with

lovastatin and simvastatin is

therefore contraindicated

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

שקובמה תו

לע

עקר

.בוהצ םייוניש

םניאש

רדגב

תורמחה

ונמוס

)ןולעב( עבצב

שי .הנוש

ןמסל

קר

ןכות

יתוהמ

אלו

םייוניש םוקימב

.טסקטה רבעוה

ראודב

ינורטקלא

.........ךיראתב

4.8.15

.......

____________________

Page 1 of 48

Prezista_SPC_Aug_15_sub

רשוא

8.15

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

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Prezista 400mg, Prezista 600mg, Prezista 800mg:

Adult patients:

Prezista, co-administered with ritonavir (Prezista/rtv), and with other antiretroviral agents, is indicated for the

treatment of human immunodeficiency virus (HIV -1) infection for patients over 18 years of age.

Prezista 75mg, Prezista 150mg:

Adult patients:

Prezista, co-administered with ritonavir (Prezista/rtv), and with other antiretroviral agents, is indicated for the

treatment of human immunodeficiency virus (HIV -1) infection.

This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from 2 controlled phase

3 trials of 48 weeks duration in antiretroviral treatment - naive and treatment-experienced patients and 2

controlled phase 2 trials of 96 weeks duration in clinically advanced, treatment-experienced adult patients .

Pediatric patients:

Prezista, co-administered with ritonavir (Prezista/rtv), and with other antiretroviral agents, is indicated for the

treatment of HIV-1 infection in treatment-experienced pediatric patients 6 years of age and older .

This indication is based on 24 Week analyses of plasma HIV-1 RNA levels and CD4+ cell counts from an open-

label phase 2 trial in antiretroviral treatment-experienced pediatric patients 6 to < 18 years of age.

In treatment-experienced adult and pediatric, the following points should be considered when initiating therapy

with Prezista/rtv:

- Treatment history and, when available, genotypic or phenotypic testing, should guide the use of Prezista/rtv.

- The use of other active agents with Prezista/rtv is associated with a greater likelihood of treatment response.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Patients

PREZISTA must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer

PREZISTA with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired

antiviral effect and will alter some drug interactions.

Treatment-Naïve Adult Patients

The recommended oral dose of PREZISTA tablets is 800 mg taken with ritonavir 100 mg once daily and with

food.

Treatment-Experienced Adult Patients

Treatment-Experienced Adult Patients

With no darunavir resistance associated substitutions*

With at least one darunavir resistance associated

substitution*

800 mg PREZISTA once daily with ritonavir 100 mg once

daily and with food

600 mg PREZISTA twice daily taken with ritonavir 100 mg

twice daily and with food

* V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V

For antiretroviral treatment-experienced patients genotypic testing is recommended. However, when genotypic

testing is not feasible, PREZISTA/ritonavir 600/100 mg twice daily dosing is recommended.

2.2 Pediatric Patients (age 6 to < 18 years)

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Prezista_SPC_Aug_15_sub

Do not use once daily dosing in pediatric patients.

Healthcare professionals should pay special attention to accurate dose selection of PREZISTA, transcription of

the medication order, dispensing information and dosing instruction to minimize risk for medication errors,

overdose, and underdose.

Prescribers should select the appropriate dose of PREZISTA/ritonavir for each individual child based on body

weight (kg) and should not exceed the recommended dose for treatment-experienced adults.

Before prescribing PREZISTA, children weighing greater than or equal to 20 kg

should be assessed for the

ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of PREZISTA tablets may not be

appropriate.

The recommended dose of PREZISTA/ritonavir for pediatric patients (6 to < 18 years of age and weighing at

least (20 kg)) is based on body weight (see Table 1) and should not exceed the recommended treatment-

experienced adult dose (PREZISTA/ritonavir 600/100 mg b.i.d.). PREZISTA tablets should be taken with ritonavir

twice daily and with food.

Table 1: Recommended Dose for Pediatric Patients (6 to < 18 years of age) for PREZISTA Tablets with ritonavir

Body Weight

Dose

(kg)

≥ 20 kg – < 30 kg

375 mg PREZISTA/50 mg ritonavir twice daily

≥ 30 kg – < 40 kg

450 mg PREZISTA/60 mg ritonavir twice daily

≥ 40 kg

600 mg PREZISTA/100 mg ritonavir twice daily

Do not use PREZISTA /ritonavir in pediatric patients below 3 years of age [see Warnings and Precautions (5.11)

and Nonclinical Toxicology (12.2)].

Prezista Tabs are intended only for pediatric patients ≥6years old weighing ≥20 Kg.

2.3 Missed dose(s)

If using the once daily regimen: in case a dose of PREZISTA and/or ritonavir was missed within 12 hours of the

time it is usually taken, patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with

food as soon as possible. If this was 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.

If using the twice daily regimen: in case a dose of PREZISTA and/or ritonavir was missed within 6 hours of the

time it is usually taken, patients should be instructed to take the prescribed dose of PREZISTA and ritonavir with

food as soon as possible. If this was noticed later than 6 hours after the time it is usually taken, the missed dose

should not be taken and the patient should resume the usual dosing schedule.

2.4 Patients with 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, PREZISTA 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, PREZISTA must not be used in patients with severe hepatic impairment (Child-Pugh

Class C).

3 DOSAGE FORMS AND STRENGTHS

3.1 PREZISTA 75 mg Tablets

PREZISTA (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with “75” on one side

and “TMC” on the other side.

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Prezista_SPC_Aug_15_sub

3.2 PREZISTA 150 mg Tablets

PREZISTA (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with “150” on one

side and “TMC,” on the other side.

3.4 PREZISTA 400 mg Tablets

PREZISTA (darunavir) 400 mg tablets are supplied as light orange, oval-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 400 mg of darunavir per tablet. Each tablet is debossed with “400” on one

side and “TMC” on the other side.

3.5 PREZISTA 600 mg Tablets

PREZISTA (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 600 mg of darunavir per tablet. Each tablet is debossed with “600” on one

side and “TMC” on the other side.

3.6 PREZISTA 800 mg Tablets

PREZISTA (darunavir) 800 mg tablets are supplied as dark red, oval-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 800 mg of darunavir per tablet. Each tablet is debossed with “800” on one

side and “T” on the other side.

4 CONTRAINDICATIONS

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

Patients with severe (Child-Pugh Class C) hepatic impairment..

Co-administration of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent on cytochrome

P450 3A (CYP3A) isoform for clearance and for which elevated plasma concentrations are associated with

serious and/or life-threatening events (narrow therapeutic index). These drugs and other contraindicated drugs

(which may lead to reduced efficacy of darunavir) are listed in Table 2 [also see Drug Interactions (7.3), Table

Table 2: Drugs That Are Contraindicated With PREZISTA/ritonavir

Drug Class

Drugs within Class that

are contraindicated with

PREZISTA/ritonavir

Clinical comment

Alpha 1adrenoreceptor

antagonist

Alfuzosin

Potential for serious and/or life-threatening reactions

such as hypotension.

Ergot Derivatives

Dihydroergotamine,

Ergonovine, Ergotamine,

Methylergonovine

Potential for serious and/or life-threatening events such

as acute ergot toxicity characterized by peripheral

vasospasm and ischemia of the extremities and other

tissues.

GI Motility Agent

Cisapride

Potential for serious and/or life-threatening reactions

such as cardiac arrhythmias.

Neuroleptic

Pimozide , sertindole

Potential for serious and/or life-threatening reactions

such as cardiac arrhythmias.

Sedative/hypnotics

Orally administered

Midazolam, Triazolam

Triazolam and orally administered midazolam are

extensively metabolized by CYP3A. Co-administration of

triazolam or orally administered midazolam with

PREZISTA/ritonavir may cause large increases in the

concentrations of these benzodiazepines. Potential for

serious and/or life-threatening events such as prolonged

or increased sedation or respiratory depression.

Herbal Products

St. John’s Wort

(Hypericum perforatum)

Patients taking PREZISTA/ritonavir should not use

products containing St. John’s wort because co-

Page 4 of 48

Prezista_SPC_Aug_15_sub

administration may result in reduced plasma

concentrations of darunavir. This may result in loss of

therapeutic effect and development of resistance.

HMG CoA Reductase

Inhibitors

Lovastatin, Simvastatin

Potential for serious reactions such as myopathy

including rhabdomyolysis. For dosing recommendation

regarding atorvastatin and pravastatin, see Table

Established and Other Potentially Significant Drug

Interactions: Alterations in Dose or Regimen May Be

Recommended Based on Drug Interaction Studies or

Predicted Interaction.

Antimycobacterial

Rifampin

Rifampin is a potent inducer of CYP450 metabolism.

PREZISTA/ritonavir should not be used in combination

with rifampin, as this may cause significant decreases in

darunavir plasma concentrations. This may result in loss

of therapeutic effect to PREZISTA.

PDE-5 inhibitor

Sildenafil for treatment of

pulmonary arterial

hypertension ,

avanafil (PDE-5

inhibitors)

A safe and effective dose for the treatment of pulmonary

arterial hypertension has not been established with

PREZISTA/ritonavir.There is an increased potential for

sildenafil-associated adverse events (which include visual

disturbances, hypotension, prolonged erection, and

syncope).

Anti Allergic

Astemizole, Terfenadine

Anti HIV

Co-administration with the

combination product

lopinavir/ritonavir

antiarrhythmics

amiodarone, bepridil,

dronedarone

quinidine,

ranolazine, systemic

lidocaine

ticagrelor (antiplatelets)

colchicine when used in

patients with renal and/or

hepatic impairment

(antigout)

Quetiapine

Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information

for a description of ritonavir contraindications.

5 WARNINGS AND PRECAUTIONS

5.1 General

PREZISTA must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to

administer PREZISTA with ritonavir and food may result in a loss of efficacy of darunavir.

Please refer to ritonavir prescribing information for additional information on precautionary measures.

5.2 Hepatotoxicity

Drug-induced hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/rtv.

During the clinical development program (N=3,063), hepatitis was reported in 0.5% of patients receiving

combination antiretroviral therapy with PREZISTA/rtv. 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 events. In case of concomitant antiviral therapy for hepatitis B or C, please refer

to the relevant product information for these medicinal products.

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Prezista_SPC_Aug_15_sub

Appropriate laboratory testing should be conducted prior to initiating therapy with PREZISTA/rtv 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 PREZISTA/rtv 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 PREZISTA/rtv, interruption or discontinuation of treatment should be considered

promptly.

5.3 Severe Skin Reactions

During

clinical

development

program

(n=3063),

severe

skin

reactions,

accompanied

fever and/or

elevations of transaminases in some cases,

have been

reported

in 0.4% of subjects.

Stevens-Johnson

Syndrome

rarely

(<0.1%)

reported

during

clinical

development

program.

During

post-marketing

experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute

generalized exanthematous pustulosis have been reported. Discontinue PREZISTA/rtv immediately if signs or

symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash

accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,

hepatitis and/or eosinophilia.

Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with PREZISTA/rtv [also see

Adverse Reactions (6)]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of

treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using

PREZISTA/rtv was 0.5%.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing PREZISTA/rtv

+ raltegravir compared to subjects receiving PREZISTA/rtv without raltegravir or raltegravir without

PREZISTA/rtv. However, rash that was considered drug related occurred at similar rates for all three groups.

These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to

rash.

5.4 Sulfa Allergy

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

sulfonamide allergy. In clinical studies with PREZISTA/ritonavir, the incidence and severity of rash was similar in

subjects with or without a history of sulfonamide allergy.

5.5 Drug Interactions

Initiation of PREZISTA/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or

initiation of medications metabolized by CYP3A in patients already receiving PREZISTA/ritonavir, may increase

plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce

CYP3A may increase or decrease concentrations of PREZISTA/ritonavir, respectively. These interactions may

lead to:

Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from

greater exposures of concomitant medications.

Clinically significant adverse reactions from greater exposures of PREZISTA/ritonavir.

Loss of therapeutic effect of PREZISTA/ritonavir and possible development of resistance.

See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including

dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and

during PREZISTA/ritonavir therapy; review concomitant medications during PREZISTA/ritonavir therapy; and

monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4) and Drug

Interactions (7)].

5.6 Diabetes Mellitus / Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been

reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy.

Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment

Page 6 of 48

Prezista_SPC_Aug_15_sub

of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI

therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during

clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these

events have not been established.

5.7 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump),

peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in

patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are

currently unknown. A causal relationship has not been established.

5.8 Immune reconstitution syndrome

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

including PREZISTA. During the initial phase of combination antiretroviral treatment, patients whose immune

systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as

Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis),

which may necessitate further evaluation and treatment.

In addition,reactivation of herpes simplex and herpes zoster has been observed in clinical studies with

PREZISTA co-administered with low dose ritonavir.

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

reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can

occur many months after initiation of antiretroviral treatment.

5.9 Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in

patients with hemophilia 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.

5.10 Resistance/Cross-Resistance

Because the potential for HIV cross-resistance among PIs has not been fully explored in PREZISTA/ritonavir

treated patients, the effect therapy with PREZISTA will have on the activity of subsequently administered PIs is

unknown [see Microbiology (11.4)].

5.11 Pediatric Patients

Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age in view of toxicity and mortality

observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see

Use in Specific Populations (8.1 and 8.3), Clinical Pharmacology (11.3), and Nonclinical Toxicology (12.2)].

Prezista Tabs are intended only for pediatric patients ≥6years old weighing ≥20 Kg.

5.12 Osteonecrosis

Although the etiology 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.

5.13 Elderly

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

exercised in the administration of PREZISTA in elderly patients, reflecting the greater frequency of decreased

hepatic function and of concomitant disease or other therapy.

5.14 Renal impairment

No special precautions or dose adjustments 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

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

patients

6 ADVERSE REACTIONS

Summary of the safety profile

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

therapy with PREZISTA/rtv 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 syndrome, thrombocytopenia, osteonecrosis, diarrhoea, hepatitis and

pyrexia.

In the 96 week analysis, the safety profile of PREZISTA/rtv 800/100 mg once daily in treatment-naïve

subjects was similar to that seen with PREZISTA/rtv 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-naive subjects in which the mean treatment duration of PREZISTA/rtv 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).

System Organ Class

Frequency category

Adverse reaction

Infections and infestations

uncommon

herpes simplex

Blood and lymphatic system disorders

uncommon

thrombocytopenia, neutropenia, anaemia,

leukopenia

rare

increased eosinophil count

Immune system disorders

uncommon

immune reconstitution syndrome, (drug)

hypersensitivity

Endocrine disorders

uncommon

hypothyroidism, increased blood thyroid

stimulating hormone

Metabolism and nutrition disorders

common

lipodystrophy (including lipohypertrophy,

lipodystrophy, lipoatrophy), diabetes

mellitus, hypertriglyceridaemia,

hypercholesterolaemia, hyperlipidaemia

uncommon

gout, anorexia, decreased appetite,

decreased weight, increased weight,

Page 8 of 48

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hyperglycaemia, insulin resistance,

decreased high density lipoprotein,

increased appetite, polydipsia,

increased blood lactate dehydrogenase

Psychiatric disorders

common

insomnia

uncommon

depression, disorientation, anxiety, sleep

disorder, abnormal dreams, nightmare,

decreased libido

rare

confusional state, altered mood,

restlessness

Nervous system disorders

common

headache, peripheral neuropathy,

dizziness

uncommon

lethargy, paraesthesia, hypoaesthesia,

dysgeusia,disturbance in attention,

memory impairment,somnolence

rare

syncope, convulsion, ageusia, sleep phase

rhythm disturbance

Eye disorders

uncommon

conjunctival hyperaemia, dry eye

rare

visual disturbance

Ear and labyrinth disorders

uncommon

vertigo

Cardiac disorders

uncommon

myocardial infarction, angina pectoris,

prolonged electrocardiogram QT,

tachycardia

rare

acute myocardial infarction, sinus

bradycardia,palpitations

Vascular disorders

uncommon

hypertension, flushing

Respiratory, thoracic and mediastinal disorders

uncommon

dyspnoea, cough, epistaxis, throat

irritation

rare

rhinorrhoea

Gastrointestinal disorders

Very common

diarrhoea

common

vomiting, nausea, abdominal pain,

increased blood amylase, dyspepsia,

abdominal distension, flatulence

uncommon

pancreatitis, gastritis, gastrooesophageal

reflux disease, aphthous stomatitis,

retching, dry mouth, abdominal discomfort,

constipation, increased lipase, eructation,

oral dysaesthesia

rare

stomatitis, haematemesis, cheilitis, dry lip,

coated tongue

Hepatobiliary disorders

common

increased alanine aminotransferase

uncommon

hepatitis, cytolytic hepatitis, hepatic

Page 9 of 48

Prezista_SPC_Aug_15_sub

steatosis,hepatomegaly, increased

transaminase, increased aspartate

aminotransferase, increased blood

bilirubin, increased blood alkaline

phosphatase,increased gamma-

glutamyltransferase, hepatotoxicity

Skin and subcutaneous tissue disorders

common

rash (including macular, maculopapular,

papular,erythematous and pruritic rash),

pruritus

uncommon

angioedema, generalised rash, allergic

dermatitis,urticaria, eczema, erythema,

hyperhidrosis, night sweats, alopecia,

acne, dry skin, nail pigmentation

rare

DRESS, Stevens-Johnson syndrome,

erythema multiforme, dermatitis,

seborrhoeic dermatitis, skin lesion,

xeroderma

Not known

toxic epidermal necrolysis, acute

generalized exanthematous pustulosis

Musculoskeletal and connective tissue disorders

uncommon

myalgia, osteonecrosis, muscle spasms,

muscular weakness, arthralgia, pain in

extremity, osteoporosis, increased blood

creatine phosphokinase

rare

musculoskeletal stiffness, arthritis, joint

stiffness

Renal and urinary disorders

uncommon

acute renal failure, renal failure,

nephrolithiasis, increased blood creatinine,

proteinuria, bilirubinuria, dysuria, nocturia,

pollakiuria

rare

decreased creatinine renal clearance

Reproductive system and breast disorders

uncommon

erectile dysfunction, gynaecomastia

General disorders and administration site conditions

common

asthenia, fatigue

uncommon

pyrexia, chest pain, peripheral oedema,

malaise,

feeling hot, irritability, pain

rare

chills, abnormal feeling, xerosis

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 5.3.

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

irrespective of causality, was more commonly observed with regimens containing PREZISTA/ritonavir

+raltegravir compared to those containing PREZISTA/ritonavir without raltegravir or raltegravir

Page 10 of 48

Prezista_SPC_Aug_15_sub

without PREZISTA/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, 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 .

Lipodystrophy

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)

in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal

and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) .

Metabolic abnormalities

Combination antiretroviral therapy has also been associated with metabolic abnormalities such as

hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and

hyperlactataemia .

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 .

Immune reconstitution 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 .

Bleeding in haemophiliac patients

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

antiretroviral protease inhibitors .

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:

* 80 ART-experienced HIV-1 infected paediatric patients aged from 6 to 17 years and weighing at

least 20 kg who received PREZISTA 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 PREZISTA 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 PREZISTA tablets with low dose ritonavir once daily in combination with

other antiretroviral agents.

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

Page 11 of 48

Prezista_SPC_Aug_15_sub

population.

Other special populations

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

Among 1,968 treatment-experienced patients receiving PREZISTA 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 .

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

National Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@mo

h.health.gov.il ) or by email (adr@MOH.HEALTH.GOV.IL ).

7 DRUG INTERACTIONS

See also Contraindications (4) and Clinical Pharmacology (11.3).

7.1 Potential for PREZISTA/ritonavir to Affect Other Drugs

PREZISTA co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of PREZISTA

and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 may result in increased plasma

concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see

Table

3

7.2 Potential for Other Drugs to Affect Darunavir

Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to

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

ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A may decrease the

clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir

(see Table

3

7.3 Established and Other Potentially Significant Drug Interactions

Darunavir and ritonavir are both inhibitors of the CYP3A isoform. Co-administration of darunavir and ritonavir and

medicinal products primarily metabolised by CYP3A may result in increased systemic exposure to such

medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.

PREZISTA 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). These medicinal products include amiodarone, bepridil,

quinidine, systemic lidocaine, astemizole, alfuzosin, terfenadine, sildenafil (when used for the treatment of

pulmonary arterial hypertension), avanafil ,quetiapine, midazolam administered orally, triazolam, cisapride,

pimozide,

sertindole,

simvastatin,

lovastatin

ergot

alkaloids

(e.g.

ergotamine,

dihydroergotamine,

ergonovine and methylergonovine), Rifampin, St. John’s Wort (Hypericum perforatum), Co-administration with

the combination product lopinavir/ritonavir.

Table

3

provides dosing recommendations as a result of drug interactions with PREZISTA/ritonavir. These

recommendations are based on either drug interaction studies or predicted interactions due to the expected

magnitude of interaction and potential for serious adverse events or loss of efficacy.

Table 3: Established and Other Potentially Significant Drug Interactions:

Alterations in Dose or Regimen May Be Recommended

Based on Drug Interaction Studies or Predicted Interaction

See Clinical Pharmacology (11.3)

for Magnitude of Interaction, Tables 8 and 9]

Page 12 of 48

Prezista_SPC_Aug_15_sub

Concomitant Drug

Class:

Drug Name

Effect on

Concentration of

Darunavir

or

Concomitant Drug

Clinical Comment

Integrase strand tranfer inhibitors

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.

PREZISTA co-administered with low dose

ritonavir and raltegravir can be used without

dose adjustments.

Elvitegravir

elvitegravir AUC ↔

elvitegravir Cmin ↔

elvitegravir Cmax ↔

darunavir AUC ↔

darunavir Cmin 17%

darunavir Cmax ↔

When PREZISTA 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 or with

elvitegravir/cobicistat have not been

established. Therefore,

co-administration of PREZISTA

with low dose ritonavir in doses

other than 600/100 mg twice daily

and elvitegravir is not

recommended. Co-administration of

PREZISTA with low dose ritonavir

and elvitegravir in the presence of

cobicistat is not recommended

HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

didanosine

↔ darunavir

↔ didanosine

Didanosine should be administered one hour

before or two hours after

PREZISTA/ritonavir (which are

administered with food).

HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)

indinavir

(The reference regimen for indinavir

was indinavir/ritonavir 800/100 mg

twice daily.)

↑ darunavir

↑ indinavir

The appropriate dose of indinavir in

combination with PREZISTA/ritonavir has

not been established.

lopinavir/ritonavir

↓ darunavir

↔ lopinavir

Appropriate doses of the combination have

not been established. Hence, it is not

recommended to co-administer

lopinavir/ritonavir and PREZISTA, with or

without ritonavir.

saquinavir

↓ darunavir

↔ saquinavir

Appropriate doses of the combination have

not been established. Hence, it is not

recommended to co-administer saquinavir

and PREZISTA, with or without ritonavir.

HIV-1-Antiviral Agents: CCR5 co-receptor antagonists

maraviroc

↑ maraviroc

Maraviroc concentrations are increased

when co-administered with

PREZISTA/ritonavir. When used in

combination with PREZISTA/ritonavir, the

Page 13 of 48

Prezista_SPC_Aug_15_sub

dose of maraviroc should be 150 mg twice

daily.

ANAESTHETIC

Alfentanil

Not studied. The metabolism

of alfentanil

is mediated via CYP3A, and

may as such

be inhibited by boosted

PREZISTA.

The concomitant use with boosted

PREZISTA may require to lower

the dose of alfentanil and requires

monitoring for risks of prolonged or

delayed respiratory depression.

Other Agents

Antiarrhythmics:

flecainide,

propafenone

Disopyramide

Mexiletine

digoxin

↑ antiarrhythmics

↑ digoxin

Concentrations of these drugs may be

increased when co-administered with

PREZISTA/ritonavir. Caution is warranted

and therapeutic concentration monitoring, if

available, is recommended for

antiarrhythmics when co-administered with

PREZISTA/ritonavir.

The lowest dose of digoxin should initially

be prescribed. The serum digoxin

concentrations should be monitored and used

for titration of digoxin dose to obtain the

desired clinical effect.

Anticoagulant:

Apixaban

Dabigatran etexilate

Rivaroxaban

Not studied. Co-administration

PREZISTA with these

anticoagulants may

increase concentrations of the

anticoagulant.

(CYP3A and/or P-gp

inhibition).

The use of PREZISTA

co-administered with low dose

ritonavir and these anticoagulants is

not recommended.

Anticoagulant:

warfarin

↓ warfarin

↔ darunavir

Warfarin concentrations are decreased when

co-administered with PREZISTA/ritonavir.

It is recommended that the international

normalized ratio (INR) be monitored when

warfarin is combined with

PREZISTA/ritonavir.

Anticonvulsant:

carbamazepine

↔ darunavir

↑ carbamazepine

The dose of either darunavir/ritonavir or

carbamazepine does not need to be adjusted

when initiating co-administration with

darunavir/ritonavir and carbamazepine.

Clinical monitoring of carbamazepine

concentrations and its dose titration is

recommended to achieve the desired clinical

response.

Anticonvulsant:

phenobarbital,

phenytoin

Not studied. Phenobarbital and

phenytoin are expected to

decrease plasma

concentrations of darunavir.

(induction of CYP450

enzymes)

PREZISTA co-administered with

low dose ritonavir should not be

used in combination with these medicines.

Antidepressant:

↑ trazodone

Concomitant use of trazodone or

Page 14 of 48

Prezista_SPC_Aug_15_sub

trazodone,

desipramine

↑ desipramine

desipramine and PREZISTA/ritonavir may

increase plasma concentrations of trazodone

or desipramine which may lead to adverse

events such as nausea, dizziness,

hypotension and syncope. If trazodone or

desipramine is used with

PREZISTA/ritonavir, the combination

should be used with caution, and a lower

dose of trazodone or desipramine should

be considered.

Antidepressant:

Amitriptyline

Desipramine

Imipramine

Nortriptyline

Trazodone

Concomitant use of

PREZISTA

co-administered wirth low

dose ritonavir

and these antidepressants may

increase concentrations of the

antidepressant.

(CYP2D6 and/or CYP3A

inhibition).

Clinical monitoring is

recommended when

co-administering PREZISTA with

low dose ritonavir with these

antidepressants and a dose

adjustment of the antidepressant may be

needed.

Anti-infective

clarithromycin

↔darunavir

↑clarithromycin

No dose adjustment of the combination is

required for patients with normal renal

function. For patients with renal impairment,

the following dose adjustments should be

considered:

For subjects with CLcr of 30-60

mL/min, the dose of clarithromycin

should be reduced by 50%.

For subjects with CLcr of < 30

mL/min, the dose of clarithromycin

should be reduced by 75%.

Antifungals:

ketoconazole,

itraconazole,

voriconazole

↑ketoconazole

↑darunavir

↑itraconazole

(not studied)

↓voriconazole

(not studied)

Ketoconazole and itraconazole are potent

inhibitors as well as substrates of CYP3A.

Concomitant systemic use of ketoconazole,

itraconazole, and darunavir/ritonavir may

increase plasma concentration of darunavir.

Plasma concentrations of ketoconazole or

itraconazole may be increased in the

presence of darunavir/ritonavir. When co-

administration is required, the daily dose of

ketoconazole or itraconazole should not

exceed 200 mg.

Plasma concentrations of voriconazole may

be decreased in the presence of

darunavir/ritonavir. Voriconazole should not

be administered to patients receiving

darunavir/ritonavir unless an assessment of

the benefit/risk ratio justifies the use of

voriconazole.

Antifungals:

Clotrimazole

Not studied. Concomitant

systemic use of

clotrimazole andboosted

Caution is warranted and clinical

monitoring is recommended, when

co-administration of clotrimazole is

Page 15 of 48

Prezista_SPC_Aug_15_sub

PREZISTAmay

increase plasma concentrations

of darunavir and/or

clotrimazole. darunavir

AUC24h

33% (based on

population pharmacokinetic

model)

required.

Antifungals:

Fluconazole

Posaconazole

Not studied. PREZISTA may

increase

antifungal plasma

concentrations (P-gp

inhibition) and posaconazole

may increase

darunavir concentrations.

(CYP3A inhibition)

Caution is warranted and clinical

monitoring is recommended.

Anti-gout

colchicine

↑colchicine

Treatment of gout-flares – co-administration

of colchicine in patients on

PREZISTA/ritonavir:

0.6 mg (1 tablet) x 1 dose, followed by 0.3

mg (half tablet) 1 hour later. Treatment

course to be repeated no earlier than 3 days.

Prophylaxis of gout-flares – co-

administration of colchicine in patients on

PREZISTA/ritonavir:

If the original regimen was 0.6 mg twice a

day, the regimen should be adjusted to 0.3

mg once a day.

If the original regimen was 0.6 mg once a

day, the regimen should be adjusted to 0.3

mg once every other day.

Treatment of familial Mediterranean fever

– co-administration of colchicine in

patients on PREZISTA/ritonavir:

maximum daily dose of 0.6 mg (may be

given as 0.3 mg twice a day).

Co-administration of PREZISTA/rtv with

colchicine in patients with renal or hepatic

impairment is contraindicated.

ANTIMYCOBACTERIAL:

Rifapentine

Not studied. Rifapentine is

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

The combination of rifapentine and

boosted PREZISTA is not recommended.

Page 16 of 48

Prezista_SPC_Aug_15_sub

was seen with rifampicin.

Antimycobacterial:

rifabutin

The reference regimen for rifabutin

was 300 mg once daily

↑darunavir

↑rifabutin

↑25-O-desacetylrifabutin

Dose reduction of rifabutin by at least 75%

of the usual dose (300 mg once daily) is

recommended (i.e., a maximum dose of

150 mg every other day). Increased

monitoring for adverse events is warranted in

patients receiving this combination and

further dose reduction of rifabutin may be

necessary.

ANTINEOPLASTICS:

Dasatinib

Nilotinib

Vinblastine

Vincristine

Everolimus

Not studied. PREZISTA is

expected to

increase these antineoplastic

plasma concentrations.

(CYP3A inhibition)

Concentrations of these medicinal

products may be increased when

co-administered with PREZISTA

with low dose ritonavir 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

PREZISTA with low dose ritonavir.

Concominant use of everolimus and

PREZISTA co-administered with low dose

ritonavir is not recommended.

β-Blockers:

metoprolol,

timolol

Carvedilol

↑beta-blockers

Caution is warranted and clinical monitoring

of patients is recommended. A dose decrease

may be needed for these drugs when co-

administered with PREZISTA/ritonavir.

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Midazolam (parenteral)

Zoldipem

Not studied.

Sedative/hypnotics are

extensively metabolised by

CYP3A.Co-administration

with boosted PREZISTA may

cause a large increase in the

concentration of these

medicines.

If parenteral midazolam is co-

administered with boosted

PREZISTA 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 fold increase in

midazolam plasma levels.

Clinical monitoring is

recommended when

co-administering boosted

PREZISTA with these

sedatives/hypnotics and a lower

dose of the sedatives/hypnotics should be

considered.

If parenteral midazolam is

co-administered with boosted

PREZISTA, it should be done in an

intensive care unit (ICU) or similar

setting, which ensures close 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.

Calcium Channel

Blockers:

felodipine,

nifedipine,

nicardipine

Amlodipine

Diltiazem

Verapamil

↑calcium channel blockers

Plasma concentrations of calcium channel

blockers may increase when

PREZISTA/ritonavir are co-administered.

Caution is warranted and clinical monitoring

of patients is recommended.

Page 17 of 48

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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

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

PREZISTA co-administered with

low dose ritonavir 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.

Prednisone

Not studied. Darunavir may

increase

plasma concentrations of

prednisone.

(CYP3A inhibition)

Concomitant use of PREZISTA

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

PREZISTA with low dose ritonavir with

corticosteroids.

Corticosteroid:

Systemic:

dexamethasone

↓darunavir

Systemic dexamethasone induces CYP3A

and can thereby decrease darunavir plasma

concentrations. This may result in loss of

therapeutic effect to PREZISTA.

Endothelin receptor antagonists:

bosentan

↑bosentan

Co-administration of bosentan in patients on

PREZISTA/ritonavir:

Page 18 of 48

Prezista_SPC_Aug_15_sub

In patients who have been receiving

PREZISTA/ritonavir for at least 10 days,

start bosentan at 62.5 mg once daily or

every other day based upon individual

tolerability.

Co-administration of PREZISTA/ritonavir

in patients on bosentan:

Discontinue use of bosentan at least 36

hours prior to initiation of

PREZISTA/ritonavir. After at least 10

days following the initiation of

PREZISTA/ritonavir, resume bosentan at

62.5 mg once daily or every other day

based upon individual tolerability.

Hepatitis C Virus (HCV) Direct-

Acting Agents:

NS3-4A protease inhibitors:

boceprevir

telaprevir

↓darunavir

↓boceprevir

↓telaprevir

Concomitant administration of

PREZISTA/ritonavir and boceprevir or

telaprevir resulted in reduced steady-state

exposures to darunavir and boceprevir or

telaprevir. It is not recommended to co-

administer boceprevir or telaprevir and

PREZISTA/ritonavir.

Simeprevir

simeprevir AUC

159%

simeprevir Cmin

358%

simeprevir Cmax

darunavir AUC

darunavir Cmin

darunavir Cmax

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 PREZISTA

and simeprevir.

HMG-CoA

Reductase Inhibitors:

pravastatin,

atorvastatin,

rosuvastatin

↑pravastatin

↑atorvastatin

↑rosuvastatin

Titrate atorvastatin, pravastatin or

rosuvastatin dose carefully and use the

lowest necessary dose while monitoring for

safety. Do not exceed atorvastatin 20

mg/day.

Lovastatin

Simvastatin

Not studied. Lovastatin and

simvastatin are

expected to have markedly

increased

plasma concentrations when

co-administered with boosted

PREZISTA.

(CYP3A inhibition)

Increased plasma concentrations of

lovastatin or simvastatin may cause

myopathy, including

rhabdomyolysis. Concomitant use

of boosted PREZISTA with

lovastatin and simvastatin is

therefore contraindicated

Immunosuppressants:

cyclosporine,

tacrolimus,

sirolimus

↑immunosuppressants

Plasma concentrations of cyclosporine,

tacrolimus or sirolimus may be increased

when co-administered with

PREZISTA/ritonavir. Therapeutic

concentration monitoring of the

immunosuppressive agent is recommended

Page 19 of 48

Prezista_SPC_Aug_15_sub

Everolimus

when co-administered with

PREZISTA/ritonavir.

Concomitant use of everolimus and

boosted PREZISTA is not recommended.

Inhaled beta agonist:

salmeterol

↑salmeterol

Concurrent administration of salmeterol and

PREZISTA/ritonavir is not recommended.

The combination may result in increased risk

of cardiovascular adverse events associated

with salmeterol, including QT prolongation,

palpitations and sinus tachycardia.

Narcotic Analgesic/Treatment of

Opioid Dependence

methadone,

buprenorphine,

buprenorphine/naloxone

↓methadone

↔buprenorphine, naloxone

↑norbuprenorphine

(metabolite)

No adjustment of methadone dosage is

required when initiating co-administration of

PREZISTA/ritonavir. However, clinical

monitoring is recommended as the dose of

methadone during maintenance therapy may

need to be adjusted in some patients.

No dose adjustment for buprenorphine or

buprenorphine/naloxone is required with

concurrent administration of

PREZISTA/ritonavir. Clinical monitoring is

recommended if PREZISTA/ritonavir and

buprenorphine or buprenorphine/naloxone

are coadministered.

Neuroleptics:

risperidone,

thioridazine

Perphenazine

↑neuroleptics

A dose decrease may be needed for these

drugs when co-administered with

PREZISTA/ritonavir.

Oral Contraceptives/estrogen:

ethinyl estradiol,

norethindrone

↓ethinyl estradiol

↓norethindrone

Plasma concentrations of ethinyl estradiol

are decreased due to induction of its

metabolism by ritonavir. Alternative

methods of nonhormonal contraception are

recommended.

PDE-5 inhibitors

sildenafil,

vardenafil,

tadalafil

↑PDE-5 inhibitors (only the

use of sildenafil at doses

used for treatment of

erectile dysfunction has

been studied with

PREZISTA/ritonavir)

Co-administration with PREZISTA/ritonavir

may result in an increase in PDE-5 inhibitor-

associated adverse events, including

hypotension, syncope, visual disturbances

and priapism.

Use of PDE-5 inhibitors for pulmonary

arterial hypertension (PAH):

-Use of sildenafil is contraindicated

when used for the treatment of

pulmonary arterial hypertension (PAH)

see Contraindications (4)

-The following dose adjustments are

recommended for use of tadalafil with

PREZISTA/ritonavir:

Co-administration of tadalafil in patients

on PREZISTA/ritonavir:

Page 20 of 48

Prezista_SPC_Aug_15_sub

In patients receiving

PREZISTA/ritonavir for at least one

week, start tadalafil at 20 mg once daily.

Increase to 40 mg once daily based upon

individual tolerability.

Co-administration of

PREZISTA/ritonavir in patients on

tadalafil:

Avoid use of tadalafil during the

initiation of PREZISTA/ritonavir. Stop

tadalafil at least 24 hours prior to starting

PREZISTA/ritonavir. After at least one

week following the initiation of

PREZISTA/ritonavir, resume tadalafil at

20 mg once daily. Increase to 40 mg

once daily based upon individual

tolerability.

Use of PDE-5 inhibitors for erectile

dysfunction:

Sildenafil at a single dose not exceeding

25 mg in 48 hours, vardenafil at a single

dose not exceeding 2.5 mg dose in 72 hours,

or tadalafil at a single dose not exceeding

10 mg dose in 72 hours can be used with

increased monitoring for PDE-5 inhibitor-

associated adverse events.

Selective Serotonin Reuptake

Inhibitors (SSRIs)

sertraline,

paroxetine

↔darunavir

↓sertraline

↓paroxetine

If sertraline or paroxetine is co-administered

with PREZISTA/ritonavir, the recommended

approach is a careful dose titration of the

SSRI based on a clinical assessment of

antidepressant response. In addition, patients

on a stable dose of sertraline or paroxetine

who start treatment with

PREZISTA/ritonavir should be monitored

for antidepressant response.

Antimalarials:

An interaction trial between PREZISTA/rtv (600/100 mg b.i.d.) and artemether/lumefantrine (80/480 mg, 6 doses

at 0, 8, 24, 36, 48, and 60 hours) showed an increase in exposure to lumefantrine by 2.75-fold, while exposure to

darunavir was not affected. The exposure to artemether and its active metabolite, dihydroartemisinin, decreased

by 16% and 18%, respectively. The combination of PREZISTA and artemether/lumefantrine can be used without

dose adjustments; however, due to the increase in lumefantrine exposure, the combination should be used with

caution.

In addition to the drugs included in Table

3

, the interaction between PREZISTA/ritonavir and the following drugs

were evaluated in clinical studies and no dose adjustments are needed for either drug [see Clinical

Pharmacology (11.3)]: atazanavir, efavirenz, etravirine, nevirapine, , ranitidine, rilpivirine, and tenofovir disoproxil

fumarate.

Using cross-trial comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the

pharmacokinetics of darunavir. Darunavir/ritonavir had no clinically significant effect on the pharmacokinetics of

dolutegravir.

Proton Pump Inhibitors

Omeprazole, pantoprazole, rabeprazole, Esomeprazole, Lansoprazole

Page 21 of 48

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Co-administration of omeprazole (20 mg q.d.) and PREZISTA/rtv (400/100 mg b.i.d.) did not affect the exposure

to darunavir. PREZISTA and proton pump inhibitors can be co-administered without dose adjustment

Other nucleoside reverse transcriptase inhibitors (NRTIs): Based on the different elimination pathways of the

other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally

excreted, no drug interactions are expected for these drugs and PREZISTA/ritonavir.

Other PIs: The co-administration of PREZISTA/ritonavir and PIs other than lopinavir/ritonavir, saquinavir,

atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine

Co-administration of PREZISTA/rtv and delavirdine may increase darunavir and delavirdine concentrations

(inhibition of CYP3A). The appropriate doses of PREZISTA/rtv and delavirdine have not been established. The

combination of PREZISTA/rtv and delavirdine is not recommended.

Antacids

e.g. Aluminium/magnesium hydroxide, calcium carbonate

No interaction is expected between antacids and PREZISTA/rtv. PREZISTA/rtv and antacids can be used

concomitantly without dose adjustments.

-Receptor antagonists

e.g. Cimetidine, famotidine, nizatidine, ranitidine

Co-administration of ranitidine (150 mg b.i.d.) and PREZISTA/rtv (400/100 mg b.i.d.) did not affect the exposure

to darunavir. PREZISTA/rtv can be co-administered with H2-receptor antagonists without dose adjustments.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: PREZISTA should be used during pregnancy only if the potential benefit justifies the

potential risk.

No adequate and well-controlled studies have been conducted in pregnant women. Reproduction studies

conducted with darunavir showed no embryotoxicity or teratogenicity in mice and rats in the presence or

absence of ritonavir as well as in rabbits with darunavir alone. In these studies, darunavir exposures (based on

AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold)

compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.

In the rat pre-and postnatal development study, a reduction in pup body weight gain was observed with darunavir

alone or in combination with ritonavir during lactation. This was due to exposure of pups to drug substances via

the milk. Sexual development, fertility and mating performance of offspring were not affected by maternal

treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats

were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.

In the juvenile toxicity study where rats were directly dosed with darunavir, deaths occurred from post-natal day 5

through 11 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat

toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age),

no deaths were observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma

exposure levels.

8.2 Nursing Mothers

Although it is not known whether darunavir is secreted in human milk, darunavir is secreted into the milk of

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

in nursing infants, mothers should be instructed not to breastfeed if they are receiving PREZISTA.

Page 22 of 48

Prezista_SPC_Aug_15_sub

8.3 Pediatric Use

Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age because of toxicity and mortality

observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see

Warnings

and

Precautions

(5.11),

Use

in

Specific

Populations

(8.1),

Clinical

Pharmacology

(11.3)

and

Nonclinical Toxicology (12.2)].

8.4 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

8.5 Effects on ability to drive and use machines

PREZISTA 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 PREZISTA

co-administered with low dose ritonavir and should be borne in mind when considering a patient

s ability to

drive or operate machinery.

Prezista Tabs are intended only for pediatric patients ≥6years old weighing ≥20 Kg.

The safety, pharmacokinetic profile, and virologic and immunologic responses of PREZISTA/ritonavir were

evaluated in treatment-experienced HIV-1-infected pediatric subjects 6 to < 18 years of age and weighing at

least 44 lbs (20 kg) [see Adverse Reactions (6.6), Clinical Pharmacology (11.3) and Clinical Studies ( 13.4)].

Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed

adults

[see

Adverse

Reactions

(6.6)].

Please

Dosage

and

Administration

(2.2)

dosing

recommendations for pediatric subjects 6 to < 18 years of age and weighing at least 44 lbs (20 kg).

8.4 Geriatric Use

Clinical studies of PREZISTA did not include sufficient numbers of patients aged 65 and over to determine

whether

they

respond

differently

from

younger

patients.

general,

caution

should be

exercised

administration and monitoring of PREZISTA in elderly patients reflecting the greater frequency of decreased

hepatic function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (11.3)].

8.5 Hepatic Impairment

No dose adjustment of PREZISTA/ritonavir is necessary for patients with either mild or moderate hepatic

impairment. No pharmacokinetic or safety data are available regarding the use of PREZISTA/ritonavir in subjects

with severe hepatic impairment, therefore, PREZISTA/ritonavir is not recommended for use in patients with

severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (11.3)].

8.6 Renal Impairment

Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly

affected in HIV-infected subjects with moderate renal impairment (CrCL between 30-60 mL/min, n=20). No

pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal

disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not

expected 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 hemodialysis or peritoneal dialysis [see Clinical Pharmacology

(11.3)].

9 OVERDOSAGE

Human experience of acute overdose with PREZISTA/ritonavir is limited. Single doses up to 3200 mg of the oral

solution of darunavir alone and up to 1600 mg of the tablet formulation of darunavir in combination with ritonavir

have been administered to healthy volunteers without untoward symptomatic effects.

No specific antidote is available for overdose with PREZISTA. Treatment of overdose with PREZISTA 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 or gastric lavage. In

general gastric lavage should not be performed more than 1 hour after

ingestion of an overdose

Page 23 of 48

Prezista_SPC_Aug_15_sub

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

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

substance.

10 DESCRIPTION

PREZISTA (darunavir) is an inhibitor of the human immunodeficiency virus (HIV-1) protease.

PREZISTA (darunavir), in the form of darunavir ethanolate, has the following chemical name: [(1S,2R)-3-[[(4-

aminophenyl) sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid

(3R,3aS,6aR)hexahydrofuro[2,3-b] furan-3-yl ester monoethanolate. Its molecular formula is C27H37N3O7S

C2H5OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:

Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at

20°C.

PREZISTA 75 mg tablets are available as white, caplet-shaped, film-coated tablets for oral administration.

PREZISTA 150 mg tablets are available as white, oval-shaped, film-coated tablets for oral administration.

PREZISTA 600 mg tablets are available as orange, oval-shaped, film-coated tablets for oral administration.

PREZISTA 400 mg is available as a light orange, oval-shaped, film-coated tablet for oral administration.

PREZISTA 800 mg tablets are available as dark red, oval-shaped, film-coated tablets for oral administration.

Each 75 mg tablet contains darunavir ethanolate equivalent to 75 mg of darunavir. Each 150 mg tablet contains

darunavir ethanolate equivalent to 150 mg of darunavir. Each 400 mg tablet contains darunavir ethanolate

equivalent to 400 mg of darunavir. Each 600 mg tablet contains darunavir ethanolate equivalent to 600 mg of

darunavir. Each 800 mg tablet contains darunavir ethanolate equivalent to 800 mg of darunavir.

During storage, partial conversion from ethanolate to hydrate may occur; however, this does not affect product

quality or performance.

Each 75mg 150mg 400mg 600mg tablet also contains the inactive ingredients colloidal anhydrous silica

crospovidone, magnesium stearate, and PROSOLV SMCC. The 75 and 150 mg tablet film coating, OPADRY®

White, contains polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. The

400 and 600 mg tablet film coating, OPADRY® Light Orange and OPADRY® Orange, respectively, contains

FD&C Yellow No. 6, polyethylene glycol, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.

Each 800mg tablet also contain inactive ingredients: hypromellose 2910 15 mPa.s, silicified

microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate and OPADRY

II DARK RED 85F150004 (contains

polyvinyl alcohol-partially hydrolyzed, macrogol 3350, macrogol 4000,

titanium dioxide, talc, iron oxide red.

All dosages for PREZISTA are expressed in terms of the free form of darunavir.

11 CLINICAL PHARMACOLOGY

11.1 Mechanism of Action

Darunavir is an HIV antiviral drug [see Clinical Pharmacology (11.4)].

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Prezista_SPC_Aug_15_sub

11.2 Pharmacodynamics

In an open-label, randomized, placebo- and active-controlled, four-way crossover trial, 40 healthy subjects were

administered supratheraputic doses of darunavir/ritonavir 1600/100 mg once daily and 800/100 mg twice daily

for seven days.

At the mean maximum darunavir concentration of 6599 ng/mL observed in this study, the mean increase in

QTcF was 2.2 ms with a 90% two-sided confidence interval (CI) of -2.0 to 6.3 ms. When evaluating the 2-sided

90% CI on the time-matched mean changes in QTcF versus placebo control, the upper bounds of both

darunavir/ritonavir groups never exceeded the 10 ms boundary. In the setting of this trial, darunavir/ritonavir did

not appear to prolong the QTc interval.

11.3 Pharmacokinetics

Pharmacokinetics in Adults

General

Darunavir

primarily

metabolized

CYP3A.

Ritonavir

inhibits

CYP3A,

thereby

increasing

plasma

concentrations of darunavir. When a single dose of PREZISTA 600 mg was given orally in combination with 100

mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir.

Therefore, PREZISTA should only be used in combination with 100 mg of ritonavir to achieve sufficient

exposures of darunavir.

The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in

healthy adult volunteers and in HIV-1-infected subjects. Table 4displays the population pharmacokinetic

estimates of darunavir after oral administration of PREZISTA/ritonavir 600/100 mg twice daily [based on sparse

sampling in 285 patients in study TMC114-C214, 278 patients in Study TMC114-C229 and 119 patients

(integrated data) from Studies TMC114-C202 and TMC114-C213] and PREZISTA/ritonavir 800/100 mg once

daily [based on sparse sampling in 335 patients in Study TMC114-C211 and 280 patients in Study TMC114-

C229] to HIV-1-infected patients.

Table 4: Population Pharmacokinetic Estimates of Darunavir at PREZISTA/ritonavir 800/100 mg once

daily(Study

TMC114-C211,

48

Week

Analysis

and

Study

TMC114-C229

48

week

analysis)

and

PREZISTA/ritonavir 600/100 mg twice daily(Study TMC114-C214, 48 Week Analysis ,Study TMC114-229,

48 Week Analysis and Integrated data from Studies TMC114-C213 and TMC114-C202, Primary 24-Week

Analysis)

Parameter

StudyTMC114-

C211

PREZISTA/ritonav

ir

800/100 mg once

daily

N = 335

Study

TMC114-C229

PREZISTA/

ritonavir

800/100 mg

once daily

N = 280

Study

TMC114-

C214

PREZISTA

/ritonavir

600/100

mg

twice

daily

N = 285

Study

TMC114-C229

PREZISTA/

ritonavir

600/100 mg

twice daily

N = 278

Studies

TMC114-

C213 and TMC114-

C202

(integrated

data)

PREZISTA/ritonavi

r

600/100

mg

twice

daily

N =119

(ng·h/mL)*

Mean ± Standard

Deviation

93026 ± 27050

93334±28626

116796

33594

114302±32681

124698 ± 32286

Median (Range)

87854

(45000-219240)

87788 (45456-

236920)

111632

(64874-

355360)

109401

(48934±32382

123336

(67714-

212980)

(ng/mL)

Mean ± Standard

Deviation

2282 ± 1168

2160±1201

3490

1401

3386±1372

3578 ± 1151

Page 25 of 48

Prezista_SPC_Aug_15_sub

Median (Range)

2041

(368-7242)

1896

(184-

7881)

3307

(1517-

13198)

3197

(250-

11865)

3539 (1255-7368)

N = number of subjects with data.

*AUC

is calculated as AUC

Absorption and Bioavailability

Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a

Tmax of approximately 2.5-4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone

and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data

suggests that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters.

Effects of Food on Oral Absorption

When administered with food, the C

and AUC of darunavir, co-administered with ritonavir, is approximately

40% higher relative to the fasting state. Therefore, PREZISTA tablets, co-administered with ritonavir, should

always be taken with food. Within the range of meals studied, darunavir exposure is similar. The total caloric

content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).

Distribution

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid

glycoprotein (AAG).

Metabolism

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

metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study

in healthy volunteers showed that after a single dose administration of 400 mg

C-darunavir, co-administered

with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative

metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the

activity of darunavir against wild-type HIV.

Elimination

A mass balance study in healthy volunteers showed that after single dose administration of 400 mg

darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of

C-darunavir

recovered

feces

urine,

respectively.

Unchanged

darunavir

accounted

approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal

elimination

half-life

darunavir

approximately

hours

when

co-administered

with

ritonavir.

After

intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg

twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.

Special Populations

Hepatic Impairment

Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were

similar after multiple dose co-administration of PREZISTA/ritonavir 600/100 mg twice daily to subjects with

normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic

impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of

darunavir has not been evaluated [see Dosage and Administration ( 2.2) and Use in Specific Populations (8.4)].

Hepatitis B or Hepatitis C Virus Co-infection

The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1-infected subjects

indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of

darunavir.

Renal Impairment

Results

from

mass

balance

study

with

C-darunavir/ritonavir

showed

that

approximately

7.7%

administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly

Page 26 of 48

Prezista_SPC_Aug_15_sub

bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal

dialysis.

Population

pharmacokinetic

analysis

showed

that

pharmacokinetics

darunavir

were

significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30-60 mL/min,

n=20). There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or

end stage renal disease [see Use in Specific Populations (8.5)].

Gender

Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-infected females compared

to males. This difference is not clinically relevant.

Race

Population pharmacokinetic analysis of darunavir in HIV-infected subjects indicated that race had no apparent

effect on the exposure to darunavir.

Geriatric Patients

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

considerably different in the age range (18 to 75 years) evaluated in HIV-infected subjects (n = 12, age ≥ 65)

[see Use in Specific Populations (8.3)].

Pediatric Patients

The pharmacokinetics of darunavir in combination with ritonavir in 92 antiretroviral treatment-experienced HIV-1-

infected pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg showed that the

administered weight-based dosages resulted in darunavir exposure that was comparable to the exposures

achieved in treatment-experienced adults receiving PREZISTA/ritonavir 600/100 mg twice daily [see Dosage and

Administration (2.2)].

Table 5: Population Pharmacokinetic Estimates of Darunavir Exposure (Study TMC114-C212 and

Study TMC114-C228) Following Administration of Doses in Tables 1 and 2

Parameter

Study TMC114-

C212

PREZISTA/

ritonavir twice daily

N = 74

Study TMC114-C228

PREZISTA/

ritonavir

twice daily*

10 to less than 15

kg‡

N = 10

15 to less than 20

kg§

N = 12

(ng·h/mL)

Mean ± Standard

Deviation

126377 ± 34356

137896±51420

157760±54080

Median (Range)

127340 (67054-

230720)

124044 (89688-

261090)

132698 (112310-

294840)

C0h (ng/mL)

Mean ± Standard

Deviation

3948 ± 1363

4510±2031

4848± 2143

Page 27 of 48

Prezista_SPC_Aug_15_sub

Median (Range)

3888 (1836-7821)

4126 (2456-9361)

3927(3046-10292)

N = number of subjects with data.

* Subjects may have contributed pharmacokinetic data to both the 10 kg to less than 15 kg weight group

and the 15 kg to less than 20 kg weight group.

is calculated as AUC

Calculated from individual pharmacokinetic parameters estimated for Week 2 and Week 4, based on the

Week 48 analysis that evaluated a darunavir dose of 20 mg/kg twice daily with ritonavir 3 mg/kg twice

daily.

The 15 kg to less than 20 kg weight group received 380 mg (3.8 mL) PREZISTA oral suspension twice

daily with 48 mg (0.6 mL) ritonavir oral solution twice daily in TMC114-C228..Calculated from

individual pharmacokinetic parameters estimated for Week 2 post-dose adjustment visit; Week 24 and

Week 48 based on the -Week 48 analysis that evaluated a darunavir dose of 380 mg twice daily.

Drug Interactions

[See also Contraindications (4), Warnings and Precautions (5.5), and Drug Interactions (7).]

Darunavir co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of darunavir

and ritonavir with drugs primarily metabolized by CYP3A and CYP2D6 may result in increased plasma

concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events.

Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to

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

ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A may decrease the

clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and

ritonavir.

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

drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir

on the AUC, C

, and C

values are summarized in Table

6

(effect of other drugs on darunavir) and Table

7

(effect of darunavir on other drugs). For information regarding clinical recommendations, see Drug Interactions

(7).

Several interaction studies have been performed with a dose other than the recommended dose of the co-

administered drug or darunavir; however, the results are applicable to the recommended dose of the co-

administered drug and/or darunavir.

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

Co-

Administered

Drug

Dose/Schedule

N

PK

LS Mean Ratio (90% CI) of

Darunavir

Pharmacokinetic Parameters

With/Without Co-administered Drug

No Effect =1.00

Co-

Administered

Drug

Darunavir/

ritonavir

C

max

AUC

C

min

Co-Administration With Other HIV Protease Inhibitors

Atazanavir

300 mg q.d.*

Page 28 of 48

Prezista_SPC_Aug_15_sub

400/100

mg b.i.d.

1.02

(0.96-1.09)

1.03

(0.94-

1.12)

1.01

(0.88-

1.16)

Indinavir

800 mg b.i.d.

400/100

mg b.i.d.

1.11

(0.98-1.26)

1.24

(1.09-

1.42)

1.44

(1.13-

1.82)

Lopinavir/

onavir

400/100 mg

b.i.d.

533/133.3 mg

b.i.d.

1200/100

mg b.i.d.

1200 mg

b.i.d.

0.79

(0.67-0.92)

0.79

(0.64-0.97)

0.62

(0.53-

0.73)

0.59

(0.50-

0.70)

0.49

(0.39-

0.63)

0.45

(0.38-

0.52)

Saquinavir

hard gel

capsule

1000

b.i.d.

400/100

mg b.i.d.

0.83

(0.75-0.92)

0.74

(0.63-

0.86)

0.58

(0.47-

0.72)

Co-Administration With Other HIV Antiretrovirals

Didanosine

400 mg q.d.

600/100

mg b.i.d.

0.93

(0.86-1.00)

1.01

(0.95-

1.07

1.07

(0.95-

1.21)

Efaviren

600 mg q.d.

300/100

mg b.i.d.

0.85

(0.72-1.00)

0.87

(0.75-

1.01)

0.69

(0.54-

0.87)

Etravirine

200 mg b.i.d.

600/100

mg b.i.d.

1.11

(1.01-1.22)

1.15

(1.05-

1.02

(0.90-

1.17)

Nevir

200 mg b.i.d.

400/100

mg b.i.d.

1.40 §

(1.14-1.73)

1.24 §

(0.97-

1.57)

1.02 §

(0.79-

1.32)

Rilpivirine

150 mg q.d.

800/100

mg q.d.

0.90

(0.81-1.00)

0.89

.81-

0.99)

0.89

(0.68-

1.16)

Tenofovir

Disoproxil

Fumarate

300 mg q.d.

300/100

mg b.i.d.

1.16

(0.94-

1.42)

1.21

(0.95-

1.54)

1.24

(0.90-

1.69)

Co-Administration With HCV NS3-4A Protease Inhibitors

Boceprevir

800 mg three

times daily

600/100

mg b.i.d.

0.64 (0.58-

0.71)

0.56

(0.51-

0.61)

0.41 (0.38-

0.45)

Telaprevir

750 mg every

8 hours

1125 mg

every 12

hours

600/100

mg b.i.d.

600/100

mg b.i.d.

11║

0.60

(0.56-0.64)

0.53

(0.47

0.60

(0.57-

0.63)

0.49

(0.43-

0.58

(0.52-

0.64)

0.42

(0.35-

Page 29 of 48

Prezista_SPC_Aug_15_sub

0.55)

0.51)

Co-Administration With Other Drugs

Artemether/Lume

fantrine

80/480mg (6

doses at 0,

8,24,36,48 and

60 hours)

600/100 mg

b.i.d.

1.00

(0.93-1.07)

0.96 (0.90-1.03)

0.87 (0.77-

0.98)

Carbamazepine

200 mg b.i.d.

600/100

mg b.i.d.

1.04

(0.93-1.16)

0.99

(0.90-

1.08)

0.85

(0.73-

1.00)

Clarithromycin

500 mg b.i.d.

400/100

mg b.i.d.

0.83

(0.72-0.96)

0.87

(0.75-

1.01)

1.01

(0.81-

1.26)

Ketoconazole

200 mg b.i.d.

400/100

mg b.i.d.

1.21

(1.04-1.40)

1.42

(1.23-

1.65)

1.73

(1.39-

2.14)

Omeprazole

20 mg q.d.

400/100

mg b.i.d.

1.02

(0.95-1.09)

1.04

(0.96-

1.13)

1.08

(0.93-

1.25)

Paroxetine

20 mg q.d.

400/100

mg b.i.d.

0.97

(0.92-1.02)

1.02

(0.95-

1.10)

1.07

(0.96-

1.19)

Ranitidine

150 mg b.i.d.

400/100

g b.i.d.

0.96

(0.89-

.05)

0.95

(0.90-

1.01)

0.94

(0.90-

0.99)

Rifabutin

150 mg q.o.d.

600/100

mg b.i.d.

1.42

(1.21-1.67)

1.57

(1.28-

1.93)

1.75

(1.28-

2.37)

Sertraline

50 mg q.d.

400/

mg b.i.d.

1.01

1.14)

0.98

(0.84-

1.14)

0.94

(0.76-

1.16)

N = number of subjects with data

q.d. = once daily

b.i.d. = twice daily

The pharmacokinetic parameters of darunavir in this study were compared with the pharmacokinetic parameters

following administration of darunavir/ritonavir 600/100 mg b.i.d.

Ratio based on between-study comparison.

q.o.d. = every other day

^ AUC is AUC

(0-last)

; N = 10 for C

in the reference arm

N = 14 for C

Page 30 of 48

Prezista_SPC_Aug_15_sub

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

Darunavir/Ritonavir

Co-Administered

Drug

Dose/Schedule

N

P

K

LS Mean Ratio (90% CI) of

Co-Administered Drug

Pharmacokinetic Parameters

With/Without Darunavir

No effect =1.00

Co-Administered

Drug

Darunavir

/

ritonavir

C

max

AUC

C

min

Co-Administration With Other HIV Protease Inhibitors

Atazanavir

300 mg q.d.* /100

mg ritonavir q.d.

when administered

alone

300 mg q.d. when

administered with

darunavir/

ritonavir

400/100

mg b.i.d.

0.89

(0.78-

1.01)

1.08

(0.94-

1.24)

1.52

(0.99-

2.34)

Indinavir

800 mg b.i.d. /100

mg ritonavir b.i.d.

when administered

alone

800 mg b.i.d. when

administered with

darunavir/

ritonavir

400/100

mg b.i.d.

1.08

(0.95-

1.22)

1.23

(1.06-

1.42)

2.25

(1.63-

3.10)

Lopinavir/

Ritonavir

400/100 mg

b.i.d.‡

533/133.3 mg b.i.d.

1200/100

mg b.i.d.

1200 mg

b.i.d.

0.98

(0.78-

1.22)

1.11

(0.96-

1.30)

1.09

(0.86-

1.37)

1.09

(0.96-

1.24)

1.23

(0.90-

1.69)

1.13

(0.90-

1.42)

Saquinavir hard

gel capsule

1000 mg b.i.d. /100

mg ritonavir b.i.d.

when administered

alone

1000 mg b.i.d.

when administered

with darunavir/

ritonavir

400/100

mg b.i.d.

0.94

(0.78-

1.13)

0.94

(0.76-

1.17)

0.82

(0.52-

1.30)

Page 31 of 48

Prezista_SPC_Aug_15_sub

Co-Administration With Other HIV Antiretrovirals

Didanosine

400 mg q.

600/100

mg b.i.d.

0.84

(0.59-

1.20)

0.91

(0.75-

1.10)

Efavirenz

600 mg q.d.

300/100

mg b.i.d.

1.15

(0.97-

1.35)

1.21

(1.08-

1.36)

1.17

(1.01-

1.36)

Etravirine

100 mg b.i.d.

600/100

b.i.d.

0.68

(0.57-

0.82)

0.63

(0.54-

0.73)

0.51

(0.44-

0.61)

Nevirapine

200 mg b.i.d.

400/100

b.i.d.

1.18

(1.02

1.37)

1.27

(1.12

1.44)

1.47

(1.20

1.82)

Rilpivirine

150 mg q

800/100

mg q.d.

1.79

(1.56-

2.06)

2.30

(1.98-

2.67)

2.78

(2.39-

3.24)

Tenofovir

Disoproxil

Fumarate

300 mg q.d.

300/100

mg b.i.d.

1.24

(1.08-

1.42)

1.22

(1.10-

1.35)

1.37

(1.19-

1.57)

Maraviroc

150 mg b.i.d.

600/100

mg b.i.d.

2.29

(1.46-

3.59)

4.05

(2.94-

5.59)

8.00

(6.35-

10.1)

Maraviroc

150 mg b.i.d.

600/100

mg b.i.d.

with 200

mg b.i.d.

etravirine

1.77

(1.20-

2.60)

3.10

(2.57-

5.27

(4.51-

6.15)

Co-Administration With HCV NS3-4A Protease Inhibitors

Boceprevir

800 mg three times

daily

600/100

mg b.i.d.

0.75

(0.67-

0.85)

0.68

(0.65-

0.72)

0.65

(0.56-

0.76)

Telaprevir

750 mg every 8

hours

600/100

mg b.i.d.

11║

0.64

(0.61-

0.67)

0.65

(0.61-

0.69)

0.68

(0.63-

0.74)

Co-Administration With Other Drugs

Atorvastatin

40 mg q.d. when

administered alone

10 mg q.d. when

administered with

darunavir/

onavir

300/100

mg b.i.d.

0.56

(0.48-

0.67)

0.85

(0.76-

0.97)

1.81

(1.37-

2.40)

Page 32 of 48

Prezista_SPC_Aug_15_sub

Artemether

Dihydroartemisinin

80 mg

single dose

600/100 mg

b.i.d.

0.85 (0.68-

1.05)

0.91 (0.78-

1.06)

1.06 (0.82-

1.39)

1.12 (0.96-

1.30)

Artemether

Dihydroartemisinin

Lumefantrine

Artemether/

lumefantrine

80/480 mg (

6 doses at 0, 8, 24, 36,

48, and 60 hours)

600/100 mg

b.i.d.

0.82 (0.61-

1.11)

0.84 (0.69-

1.02)

0.97 (0.90-

1.05)

0.82 (0.66-

1.01)

0.82 (0.74-

0.91)

1.00 (0.82-

1.22)

1.65 (1.49-

1.83)

2.75 (2.46-

3.08)

2.26 (1.92-

2.67)

Buprenorphine/

Naloxone

Norbuprenorphine

8/2 mg to 16/4 mg

q.d.

600/100

mg b.i.d.

0.92 §

(0.79-

1.08)

1.36

(1.06-

1.74)

0.89 §

(0.78-

1.02)

1.46

(1.15-

1.85)

0.98 §

(0.82-

1.16)

1.71

(1.29-

2.27)

Carbamazepine

Carbamazepine

epoxide

200 mg b.i.d.

600/100

mg b.i.d.

1.43

(1.34-

1.53)

0.46

(0.43-

0.49)

1.45

(1.35-

1.57)

0.46

0.49)

1.54

(1.41-

1.68)

0.48

(0.45-

0.51)

Clarithromycin

500 mg b.i.d.

400/100

mg b.i.d.

1.26

(1.03-

1.54)

1.57

(1.35-

1.84)

2.74

(2.30-

3.26)

Dextromethorpha

Dextrorphan

30 mg

600/100

mg b.i.d

2.27

(1.59-

3.26)

0.87

(0.77-

0.98)

2.70

(1.80-

4.05)

0.96

(0.90-

1.03)

Digoxin

0.4 mg

600/100

mg b.i.d.

1.15

(0.89-

1.48)

1.36

(0.81-

2.27)

Ethinyl estradiol

(EE)

Norethindrone

Ortho-Novum 1/35

(35 μg EE /

1 mg NE)

600/100

mg b.i.d.

0.68

(0.61-

0.74)

0.90

(0.83-

0.97)

0.56

(0.50-

0.63)

0.86

(0.75-

0.98)

0.38

(0.27-

0.54)

0.70

(0.51-

0.97)

Ketoconazole

200 mg b.i.d.

/100

mg b.i.d.

2.11

(1.81-

2.44)

3.12

(2.65-

3.68)

9.68

(6.44-

14.55)

Page 33 of 48

Prezista_SPC_Aug_15_sub

R-Methadone

55-150 mg q.d.

600/100

mg b.i.d.

0.76

(0.71-

0.81)

0.84

(0.78-

0.91)

0.85

(0.77-

0.94)

Omeprazole

5-hydroxy

meprazole

40 mg single dose

600/100

mg b.i.d.

0.66

(0.48-

0.90)

0.93

(0.71-

1.21)

0.58

(0.50-

0.66)

0.84

(0.77-

0.92)

Paroxetine

20 mg q.d.

400/100

mg b.i.d.

0.64

(0.59-

0.71)

0.61

(0.56-

0.66)

0.63

(0.55-

0.73)

Pravastatin

40 mg

single dose

600/100

mg b.i.d.

1.63

(0.95-

2.82)

1.81

(1.23-

2.66)

Rifabutin

O

-desacetyl-

rifabutin

150 mg q.o.d.

when administered

with

PREZISTA/ritonavi

300 mg q.d. when

administered alone

600/100

mg b.i.d.

0.72

(0.55-

0.93)

4.77

(4.04-

5.63)

0.93

(0.80-

1.09)

9.81

(8.09-

11.9)

1.64

(1.48-

1.81)

27.1

(22.2-

33.2)

Sertraline

50 mg q.d.

400/100

mg b.i.d.

0.56

(0.49-

0.63)

0.51

(0.46-

0.58)

0.51

(0.45-

0.57)

Sildenafil

100 mg (single

dose) administered

alone

25 mg (single dose)

when administered

with darunavir/

ritonavir

400/100

mg b.i.d.

0.62

(0.55-

0.70)

0.97

(0.86-

1.09)

S-warfarin

7-OH-S-warfarin

10 mg single dose

600/100

mg b.i.d.

0.92

(0.86-

0.97)

1.42

(1.24-

1.63)

0.79

(0.73-

0.85)

1.23

(0.97-

1.57)

Page 34 of 48

Prezista_SPC_Aug_15_sub

N = number of subjects with data;- = no information available

q.d. = once daily

b.i.d. = twice daily

The pharmacokinetic parameters of lopinavir in this study were compared with the pharmacokinetic parameters

following administration of lopinavir/ritonavir 400/100 mg b.i.d.

ratio is for buprenorphine; mean C

and AUC

for naloxone were comparable when buprenorphine/naloxone was

administered with or without PREZISTA/ritonavir

¶ q.o.d. = every other day

# In comparison to rifabutin 300 mg q.d.

║ N = 14 for Cmax

A cocktail study was conducted in 12 healthy volunteers to evaluate the effect of steady state pharmacokinetics of

darunavir/ritonavir on the activity of CYP2D6 (using dextromethorphan as probe substrate), CYP2C9 (using warfarin as

probe substrate), and CYP2C19 (using omeprazole as probe substrate). The pharmacokinetic results are shown in Table 7.

11.4 Microbiology

Mechanism of Action

Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol

polyproteins in infected cells, thereby preventing the formation of mature virus particles.

Antiviral Activity

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

values ranging from < 0.1 to 4.3 nM. The EC

value of darunavir increases by a median factor of 5.4 in the

presence of human serum. Darunavir did not show antagonism when studied in combination with the PIs

amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir,

didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine,

rilpivirine, efavirenz, etravirine, or nevirapine, and the fusion inhibitor enfuvirtide.

Resistance

Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and

obtained from subjects treated with darunavir/ritonavir. Darunavir-resistant virus derived in cell culture from wild-

type HIV had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino

acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell

culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated

mutations resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid

substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V,

G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V,

and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions

and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC

values ranging from 125 nM to

3461 nM.

Clinical studies of PREZISTA/ritonavir in treatment-experienced subjects: In a pooled analysis of the 600/100 mg

PREZISTA/ritonavir twice daily arms of Studies TMC114-C213, TMC114-C202, TMC114-C215, and the control

arms of etravirine studies TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or M

developed most frequently on PREZISTA/ritonavir in 41% and 25%, respectively, of the treatment-experienced

subjects who experienced virologic failure, either by rebound or by never being suppressed (< 50 copies/mL).

Other substitutions that developed frequently in PREZISTA/ritonavir virologic failure isolates occurred at amino

acid positions V11I, I15V, L33F, I47V, I50V, and L89V. These amino acid substitutions were associated with

decreased susceptibility to darunavir; 90% of the virologic failure isolates had a > 7-fold decrease in susceptibility

to darunavir at failure. The median darunavir phenotype (fold change from reference) of the virologic failure

isolates was 4.3-fold at baseline and 85-fold at failure. Amino acid substitutions were also observed in the

protease cleavage sites in the Gag polyprotein of some PREZISTA/ritonavir virologic failure isolates. In Study

Page 35 of 48

Prezista_SPC_Aug_15_sub

TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M

developed most frequently in virologic failures on PREZISTA/ritonavir.

In the 96-week as-treated analysis of the Phase 3 Study TMC114-C214, the percent of virologic failures (never

suppressed, rebounders and discontinued before achieving suppression) was 21% (62/298) in the group of

subjects receiving PREZISTA/ritonavir 600/100 mg twice daily compared to 32% (96/297) of subjects receiving

lopinavir/ritonavir 400/100 mg twice daily. Examination of subjects who failed on PREZISTA/ritonavir 600/100 mg

twice daily and had post-baseline genotypes and phenotypes showed that 7 subjects (7/43; 16%) developed PI

substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the 7 had

baseline PI resistance-associated substitutions and baseline darunavir phenotypes > 7. The most common

emerging PI substitutions in these virologic failures were V32I, L33F, M46I or L, I47V, I54L, T74P and L76V.

These amino acid substitutions were associated with 59- to 839-fold decreased susceptibility to darunavir at

failure. Examination of individual subjects who failed in the comparator arm on lopinavir/ritonavir and had post-

baseline genotypes and phenotypes showed that 31 subjects (31/75; 41%) developed substitutions on lopinavir

treatment resulting in decreased susceptibility to lopinavir (> 10-fold) and the most common substitutions

emerging on treatment were L10I or F, M46I or L, I47V or A, I54V and L76V. Of the 31 lopinavir/ritonavir virologic

failure subjects, 14 had reduced susceptibility (> 10-fold) to lopinavir at baseline.

In the 48-week analysis of the Phase 3 Study TMC114-C229, the number of virologic failures (including those

who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving

PREZISTA/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving PREZISTA/ritonavir

600/100 mg twice daily. Examination of isolates from subjects who failed on PREZISTA/ritonavir 800/100 mg

once daily and had post-baseline genotypes showed that 8 subjects (8/60; 13%) had isolates that developed

IAS-USA defined PI resistance-associated substitutions compared to 5 subjects (5/39; 13%) on

PREZISTA/ritonavir 600/100 mg twice daily. Isolates from 2 subjects developed PI resistance associated

substitutions associated with decreased susceptibility to darunavir; 1 subject isolate in the PREZISTA/ritonavir

800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with a 24-fold

decreased susceptibility to darunavir, and 1 subject isolate in the PREZISTA/ritonavir 600/100 mg twice daily

arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In

the PREZISTA/ritonavir 800/100 mg once daily and PREZISTA/ritonavir 600/100 mg twice daily groups, isolates

from 7 (7/60, 12%) and 4 (4/42, 10%) virologic failures, respectively, developed decreased susceptibility to an

NRTI included in the treatment regimen.

Clinical

studies

of

PREZISTA/ritonavir

in

treatment-naive

subjects:

192-week

as-treated

analysis

censoring those who discontinued before Week 4 of the Phase 3 Study TMC114-C211, the percentage of

virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 22%

(64/288) in the group of subjects receiving PREZISTA/ritonavir 800/100 mg once daily compared to 29%

(76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the PREZISTA/ritonavir arm, emergent

PI resistance-associated substitutions were identified in 11 of the virologic failures with post-baseline genotypic

data (n=43) .

However, none of the darunavir virologic failures had a decrease in darunavir susceptibility (> 7-fold change) at

failure. In the comparator lopinavir/ritonavir arm, emergent PI resistance-associated

substitutions were identified

in 17 of the virologic failures with post-baseline genotypic data (n=53), but none of the lopinavir/ritonavir virologic

failures had decreased susceptibility to lopinavir (> 10-fold change) at failure. The reverse transcriptase M184V

substitution and resistance to emtricitabine, which was included in the fixed background regimen, was identified

in 4 virologic failures from the PREZISTA/ritonavir arm and 7 virologic failures in the lopinavir/ritonavir arm.

Cross-resistance

Cross-resistance among PIs has been observed. Darunavir has a < 10-fold decreased susceptibility in cell

culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir,

ritonavir, saquinavir and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir.

Darunavir-resistant

viruses

were

susceptible

amprenavir,

atazanavir,

indinavir,

lopinavir,

nelfinavir,

ritonavir or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from

PI-resistant viruses showed a fold change in EC

values < 3 for tipranavir, indicative of limited cross-resistance

Page 36 of 48

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between darunavir and tipranavir. In Studies TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187)

of subjects in the darunavir/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir

(tipranavir fold change > 3) achieved < 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses

isolated from subjects experiencing virologic failure on PREZISTA/ritonavir 600/100 mg twice daily (> 7 fold

change), 41% were still susceptible to tipranavir and 10% were susceptible to saquinavir while less than 2%

were susceptible to the other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir or nelfinavir).

In Study TMC114-C214, the 7 darunavir/ritonavir virologic failures with reduced susceptibility to darunavir at

failure were also resistant to the approved PIs (fos) amprenavir, atazanavir, lopinavir, indinavir, and nelfinavir at

failure. Six of these 7 were resistant to saquinavir and 5 were resistant to tipranavir. Four of these virologic

failures were already PI-resistant at baseline. .

Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside

reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase inhibitors is unlikely

because the viral targets are different.

Baseline Genotype/Phenotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before

initiation of PREZISTA/ritonavir 600/100 mg twice daily therapy. The effect of baseline genotype and phenotype

on virologic response at 96 weeks was analyzed in as-treated analyses using pooled data from the Phase 2b

studies (Studies TMC114-C213, TMC114-C202, and TMC114-C215) (n=439). The findings were confirmed with

additional genotypic and phenotypic data from the control arms of etravirine Studies TMC125-C206 and

TMC125C-216 at Week 24 (n=591).

Diminished virologic responses were observed in subjects with 5 or more baseline IAS-defined primary protease

inhibitor resistance-associated substitutions (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V,

V82A/F/L/S/T, I84V, N88S, L90M) (see Table 8).

Table 8: Response to PREZISTA/ritonavir 600/100mg twice daily by Baseline Number of IAS-Defined

Primary PI Resistance-Associated Substitutions: As-treated Analysis of Studies TMC114-C213, TMC114-

C202, and TMC114-C215

Studies TMC114-C213, TMC114-C202, TMC114-C215

< 50 copies/mL at Week 96

N=439

# IAS-Defined Primary

PI Substitutions

Overall

De Novo ENF

Re-Used/No ENF

44% (192/439)

54% (61/112)

40% (131/327)

0 - 4

50% (162/322)

58% (49/85)

48% (113/237)

22% (16/74)

47% (9/19)

13% (7/55)

≥ 6

9% (3/32)

17% (1/6)

8% (2/26)

IAS Primary PI Substitutions (2008): D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V,

V82A/F/L/S/T, I84V, N88S, L90M

The presence at baseline of two or more of the substitutions V11I, V32I, L33F, I47V, I50V, I54L or M, T74P,

L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA/ritonavir. In subjects not

taking enfuvirtide de novo, the proportion of subjects achieving viral load < 50 plasma HIV RNA copies/mL at 96

weeks was 59%, 29%, and 12% when the baseline genotype had 0-1, 2 and ≥ 3 of these substitutions,

respectively.

Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of

virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 9. These

baseline phenotype groups are based on the select patient populations in the Studies TMC114-C213, TMC114-

C202, and TMC114-C215, and are not meant to represent definitive clinical susceptibility breakpoints for

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PREZISTA/ritonavir. The data are provided to give clinicians information on the likelihood of virologic success

based on pre-treatment susceptibility to darunavir.

Table 9: Response (HIV-1 RNA < 50 copies/mL at Week 96) to PREZISTA/ritonavir 600/100 mg twice daily

by Baseline Darunavir Phenotype and by Use of Enfuvirtide (ENF): As-treated Analysis of Studies

TMC114-C213, TMC114-C202, and TMC114-C215

Proportion of Subjects with < 50 copies/mL at Week 96

N=417

Baseline

DRV

Phenotype

All

De Novo ENF

Re-Used/ No ENF

Overall

175/417 (42%)

61/112 (54%)

131/327 (40%)

0 - 7

148/270 (55%)

44/65 (68%)

104/205 (51%)

> 7 - 20

16/53 (30%)

7/17 (41%)

9/36 (25%)

> 20

11/94 (12%)

6/23 (26%)

5/71 (7%)

12 NONCLINICAL TOXICOLOGY

12.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis and Mutagenesis

Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104

weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg

were administered to rats. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas

were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in

male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans.

Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid

hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses,

the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7-and 1-fold

(rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or

800/100 mg once daily).

Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reserve

mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.

Impairment of Fertility

No effects on fertility or early embryonic development were observed with darunavir in rats and darunavir has

shown no teratogenic potential in mice or rats (in the presence or absence of ritonavir) and rabbits.

12.2 Animal Toxicology and/or Pharmacology

In juvenile rats single doses of darunavir (20 mg/kg to 160 mg/kg at ages 5-11 days) or multiple doses of

darunavir (40 mg/kg to 1000 mg/kg at age 12 days) caused mortality. The mortalities were associated with

convulsions in some of the animals. Within this age range exposures in plasma, liver and brain were dose and

age dependent and were considerably greater than those observed in adult rats. These findings were attributed

to the ontogeny of the CYP450 liver enzymes involved in the metabolism of darunavir and the immaturity of the

blood-brain barrier. No treatment-related mortalities were noted in juvenile rats after a single dose of darunavir at

1000 mg/kg on day 26 of age or after repeat dosing at 500 mg/kg from day 23 to 50 of age. The exposures and

toxicity profile in the older animals (day 23 or day 26) were comparable to those observed in adult rats. Due to

uncertainties regarding the rate of development of the human blood-brain barrier and liver enzymes, do not

administer PREZISTA/ritonavir in pediatric patients below 3 years of age.

13 CLINICAL STUDIES

13.1 Description of Adult Clinical Studies

The evidence of efficacy of PREZISTA/ritonavir is based on the analyses of 192-week data from a randomized,

controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211) HIV-1-infected adult subjects and 96-

week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced

(TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data are included from 2 randomized,

controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-

infected adult subjects.

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13.2 Treatment-Naïve Adult Subjects

Study TMC114-C211

Study TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir

800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily

regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects. Both arms used a fixed background

regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily

(FTC).

HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA ≥ 5000 copies/mL. Randomization

was stratified by screening plasma viral load (HIV-1 RNA < 100,000 copies/mL or ≥ 100,000 copies/mL) and

screening CD4+ cell count (< 200 cells/mm

or ≥ 200 cells/mm

). Virologic response was defined as a confirmed

plasma HIV-1 RNA viral load < 50 copies/mL. Analyses included 689 subjects in Study TMC114-C211 who had

completed 192 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the

lopinavir/ritonavir arm (see Table 10). Table 10compares the demographic and baseline characteristics between

subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg

per day arm in Study TMC114-C211.

Table 10: Demographic and Baseline Characteristics of Subjects in Study TMC114-C211

Randomized Study TMC114-C211

PREZISTA/ritonavir

800/100 mg once daily

+ TDF/FTC

N = 343

lopinavir/ritonavir

800/200 mg per day

+ TDF/FTC

N = 346

Demographic Characteristics

Median Age (years)

(range, years)

(18-70)

(19-68)

Male

Female

Race

White

Black

Hispanic

Asian

Baseline Characteristics

Mean

Baseline

Plasma

HIV-1

(log

copies/mL)

4.86

4.84

Median

Baseline

CD4+

Cell

Count

(cells/mm

(range, cells/mm

(4-750)

(2-714)

Percentage

Patients

with

Baseline

Viral Load ≥ 100,000 copies/mL

Percentage of Patients with Baseline

CD4+ Cell Count < 200 cells/mm

Week 192 outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from Study TMC114-C211 are

shown in Table

11

Table 11: Virologic Outcome of Randomized Treatment of Study TMC114-C211 at 96 Weeks

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PREZISTA/

ritonavir

800/100 mg once daily

+ TDF/FTC

N = 343

lopinavir/ritonavir

800/200 mg per day

+ TDF/FTC

N = 346

Virologic success HIV-1 RNA < 50

copies/mL

70%*

Virologic failure†

No virologic data at Week 192

window

Reasons

Discontinued study due to adverse

event or death

Discontinued study

for other reasons¶

Missing data during window

on study

<1%

N = total number of subjects with data

* 95% CI: 1.9; 16.1

† Includes patients who discontinued prior to Week 96 for lack or loss of efficacy and patients who are ≥ 50 copies in the

96-week window and patients who had a change in their background regimen that was not permitted by the protocol

‡ Window 90-102 Weeks

§ Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time

window if this resulted in no virologic data on treatment during the specified window

¶ Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was < 50

copies/mL

In Study TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258

cells/mm

in the PREZISTA/ritonavir 800/100 mg once daily arm and 263 cells/mm

in the lopinavir/ritonavir 800/200 mg

per day arm. Of the PREZISTA/ritonavir subjects with a confirmed virologic response of < 50 copies/mL at Week 48, 81%

remained undetectable at Week 192 versus 68% with lopinavir/ritonavir. In the 192 week analysis, statistical superiority of

the PREZISTA/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.

13.3 Treatment-Experienced Adult Subjects

Study TMC114-C229

Study TMC114-C229 is a randomized, open-label trial comparing PREZISTA/ritonavir 800/100 mg once daily to

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

resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M,

T74P, L76V, I84V, L89V) and a screening viral load of greater than 1,000 HIV-1 RNA copies/mL. Both arms used an

optimized background regimen consisting of greater than or equal to 2 NRTIs selected by the investigator.

HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for

at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL.

Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.

Table

12

compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg

once daily arm and subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm in Study TMC114-C229. No

imbalances between the 2 arms were noted.

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Week 48 outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from Study TMC114-C229 are shown in

Table 13.

Table 12:

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The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm

and 112

cells/mm

in the PREZISTA/ritonavir 800/100 mg once daily arm and the PREZISTA/ritonavir 600/100 mg twice daily arm,

respectively).

Study TMC114-C214

Study TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir

600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced,

lopinavir/ritonavir-naïve HIV-1-infected adult subjects. Both arms used an optimized background regimen (OBR)

consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).

HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA > 1000 copies/mL and were on a

highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a

confirmed plasma HIV-1 RNA viral load < 400 copies/mL. Analyses included 595 subjects in Study TMC114-

C214 who had completed 96 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the

lopinavir/ritonavir arm (see Table 14). Table 14 compares the demographic and baseline characteristics between

subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg

twice daily arm in Study TMC114-C214.

Table 13:

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Table 14:

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Prezista_SPC_Aug_15_sub

Week 96 outcomes for subjects on PREZISTA/ritonavir 600/100 mg twice daily from Study TMC114-C214 are

shown in Table 15.

In Study TMC114-C214 at 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81

cells/mm

in the PREZISTA/ritonavir 600/100 mg twice daily arm and 93 cells/mm

in the lopinavir/ritonavir

400/100 mg twice daily arm.

Studies TMC114-C213 and TMC114-C202

Studies TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a

high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-

term part in which all subjects randomized to PREZISTA/ritonavir received the recommended dose of 600/100

mg twice daily.

HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA > 1000 copies/mL, had prior

treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V,

V82A/F/S/T, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8

Table

:

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Prezista_SPC_Aug_15_sub

weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of

enfuvirtide.

The virologic response rate was evaluated in subjects receiving PREZISTA/ritonavir plus an OBR versus a

control group receiving an investigator-selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and

OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR

consisted of at least 2 NRTIs with or without enfuvirtide. Selected PI(s) in the control arm included: lopinavir in

36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received a

ritonavir boosted PI regimen out of which 23% of control subjects used dual-boosted PIs. Approximately 47% of

all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naïve. Virologic response was

defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log

versus baseline.

In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were

balanced between the PREZISTA/ritonavir arm and the comparator PI arm (see Table 16). Table 16 compares

the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice

daily arm and subjects in the comparator PI arm in the pooled analysis of Studies TMC114-C213 and TMC114-

C202.

Table 16: Demographic and Baseline Characteristics of Subjects in the Studies TMC114-C213 and

TMC114C-202 (Pooled Analysis)

Randomized Studies TMC114-C213 and TMC114-C202

PREZISTA/ritonavir

600/100 mg twice daily

+ OBR

N = 131

Comparator PI(s)

+ OBR

N = 124

Demographic Characteristics

Median Age (years)

(range, years)

(27-73)

(25-65)

Male

Female

Race

White

Black

Hispanic

Baseline Characteristics

Mean Baseline Plasma HIV-1 RNA

(log

copies/mL)

4.61

4.49

Median Baseline CD4+ Cell Count

(cells/mm

(range, cells/mm

(3-776)

(3-1274)

Percentage

Patients

with

Baseline

Viral

Load

>

100,000

copies/mL

Percentage

Patients

with

Baseline CD4+ Cell Count < 200

cells/mm

Median Darunavir Fold Change

Median

Number

Resistance-

Associated*:

PI mutations

NNRTI mutations

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NRTI mutations

Percentage of Subjects with

Number of Baseline Primary

Protease Inhibitor Mutations*:

≤ 1

≥ 3

Median Number of ARVs

Previously Used†:

NRTIs

NNRTIs

PIs (excluding low-dose ritonavir)

Percentage of Subjects Resistant†

to All Available‡ PIs at Baseline,

excluding Tipranavir and Darunavir

Percentage of Subjects with Prior

Use of Enfuvirtide

* Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top

HIV Med 2006; 14(3): 125-130

† Based on phenotype (Antivirogram™)

‡ Commercially available PIs at the time of study enrollment

Week 96 outcomes for subjects on the recommended dose PREZISTA/ritonavir 600/100 mg twice daily from the

pooled Studies TMC114-C213 and TMC114-C202 are shown in Table 17.

Table 17: Outcomes of Randomized Treatment Throu

gh Week 96 of the Studies TMC114-C213 and

TMC114-C202 (Pooled Analysis)

Randomized Studies TMC114-C213 and TMC114-C202

PREZISTA/ritonavir

600/100 mg twice daily

+ OBR

N=131

Comparator PI

+ OBR

N=124

Virologic Responders confirmed at

least 1 log

HIV-1 RNA below

baseline through Week 96

(< 50 copies/mL at Week 96)

(39%)

(9%)

Virologic failures

Lack of initial response*

Rebounder†

Never Suppressed‡

Death or discontinuation due to

adverse events

Discontinuation due to other

reasons

* Subjects who did not achieve at least a confirmed 0.5 log

HIV-1 RNA drop from baseline at Week 12

† Subjects with an initial response (confirmed 1 log

drop in viral load), but without a confirmed 1 log

drop in

viralload at Week 96

‡ Subjects who never reached a confirmed 1 log

drop in viral load before Week 96

In the pooled Studies TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of

subjects with HIV-1 RNA < 400 copies/mL in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily

compared to the comparator PI arm was 55.0% and 14.5%, respectively. In addition, the mean changes in

plasma HIV-1 RNA from baseline were –1.69 log

copies/mL in the arm receiving PREZISTA/ritonavir 600/100

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Prezista_SPC_Aug_15_sub

mg twice daily and – 0.37 log

copies/mL for the comparator PI arm. The mean increase from baseline in CD4+

cell counts was higher in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily (103 cells/mm

) than in

the comparator PI arm (17 cells/mm

13.4 Pediatric Patients

The pharmacokinetic profile, safety and antiviral activity of PREZISTA/ritonavir were evaluated in 2 randomized,

open-label, multicenter studies.

Study TMC114-C212

Treatment-experienced pediatric subjects between the ages of 6 and less than 18 years and weighing at least 20

kg were stratified according to their weight (greater than or equal to 20 kg to less than 30 kg, greater than or

equal to 30kg to less than 40 kg, greater than or equal to 40 kg) and received PREZISTA tablets with either

ritonavir capsules or oral solution plus background therapy consisting of at least two non-protease inhibitor

antiretroviral drugs. Eighty patients were randomized and received at least one dose of PREZISTA/ritonavir.

Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g.,

taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir

oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir

dose without changes in observed safety.

The 80 randomized pediatric subjects had a median age of 14 (range 6 to less than 18 years), and were 71%

male, 54% Caucasian, 30% Black, 9% Hispanic and 8% other. The mean baseline plasma HIV-1 RNA was 4.64

copies/mL, and the median baseline CD4+ cell count was 330 cells/mm

(range: 6 to 1505 cells/mm

Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA 100,000 copies/mL. Most pediatric subjects

(79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI.

Seventy-seven pediatric subjects (96%) completed the 24-week period. Of the patients who discontinued, one

patient discontinued treatment due to an adverse event. An additional 2 patients discontinued for other reasons,

one patient due to compliance and another patient due to relocation.

The proportion of pediatric subjects with HIV-1 RNA less than 400 copies/mL and less than 50 copies/mL was

64% and 50%, respectively. The mean CD4+ cell count increase from baseline was 117 cells/mm

Study TMC114-C228

Treatment-experienced pediatric subjects between the ages of 3 and less than 6 years and weighing greater

than or equal to 10 kg to less than 20 kg received PREZISTA oral suspension with ritonavir oral solution plus

background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs. Twenty-one

subjects received at least one dose of PREZISTA/ritonavir.

The 21 subjects had a median age of 4.4 years (range 3 to less than 6 years), and were 48% male, 57% Black,

29%, Caucasian and 14% other. The mean baseline plasma HIV-1 was 4.34 log

copies/mL, the median

baseline CD4+ cell count was 927 x 10

cells/l (range: 209 to 2,429 x 10

cells/l) and the median baseline CD4+

percentage was 27.7% (range: 15.6% to 51.1%). Overall, 24% of subjects had a baseline plasma HIV-1 RNA

greater than or equal to 100,000 copies/mL. All subjects had used greater than or equal to 2 NRTIs, 62% of

subjects had used greater than or equal to 1 NNRTI and 76% had previously used at least one HIV PI.

Twenty subjects (95%) completed the 24 week period. One subject prematurely discontinued treatment due to

vomiting assessed as related to ritonavir.

The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was 57% and

81%, respectively. The mean change in CD4+ percentage from baseline was 4%. The mean change in CD4+

cell count from baseline was 109 x 10

cells/L.

14 HOW SUPPLIED/STORAGE AND HANDLING

PREZISTA (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with “75” on one side

and “TMC” on the other side.

PREZISTA (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with “150” on one

side and “TMC” on the other side.

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PREZISTA (darunavir) 400 mg tablets are supplied as light orange, oval-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 400 mg of darunavir per tablet. Each tablet is debossed with “400” on one

side and “TMC” on the other side.

PREZISTA (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 600 mg of darunavir per tablet. Each tablet is debossed with “600” on one

side and “TMC” on the other side.

PREZISTA (darunavir) 800 mg tablets are supplied as dark red, oval-shaped, film-coated tablets containing

darunavir ethanolate equivalent to 800 mg of darunavir per tablet. Each tablet is debossed with “800” on one

side and “T” on the other side.

PREZISTA tablets are packaged in bottles in the following configuration:

75 mg tablets—bottles of 480

150 mg tablets—bottles of 240

400 mg tablets—bottles of 60

600 mg tablets—bottles of 60

800 mg tablets - bottles of 30

Storage:

Store PREZISTA tablets at 15°-30°C (59°-86°F).

Shelf life after first opening: prezista 400mg, prezista 600 mg – 1 month

Prezista 800 mg – 3 months

15 PATIENT COUNSELING INFORMATION

A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out

about medicines that should NOT be taken with PREZISTA. A Patient Package Insert for PREZISTA is

available for patient information.

15.1 General

PREZISTA is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with

HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when

using PREZISTA.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

*Do not share needles or other injection equipment.

*Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor

blades.

*Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane

condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

*Do not breastfeed. We do not know if PREZISTA can be passed to the baby through breast milk and whether it

could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby

in the breast milk.

15.2 Instructions for Use

General

Patients should be advised to take PREZISTA and ritonavir with food every day as prescribed. Patients should

be instructed to swallow whole tablets with a drink such as water or milk. PREZISTA must always be used with

ritonavir ) in combination with other antiretroviral drugs. Patients should not alter the dose of either PREZISTA or

ritonavir discontinue ritonavir, or discontinue therapy with PREZISTA without consulting their physician.

Page 48 of 48

Prezista_SPC_Aug_15_sub

Patients Taking PREZISTA Once Daily

If a patient misses a dose of PREZISTA or ritonavir by more than 12 hours, the patient should be told to wait and

then take the next dose of PREZISTA and ritonavir at the regularly scheduled time. If the patient misses a dose

of PREZISTA or ritonavir by less than 12 hours, the patient should be told to take PREZISTA and ritonavir

immediately, and then take the next dose of PREZISTA and ritonavir at the regularly scheduled time. If a dose of

PREZISTA or ritonavir is skipped, the patient should not double the next dose. Inform the patient that he or she

should not take more or less than the prescribed dose of PREZISTA or ritonavir.

Patients Taking PREZISTA Twice Daily

If a patient misses a dose of PREZISTA or ritonavir by more than 6 hours, the patient should be told to wait and

then take the next dose of PREZISTA and ritonavir at the regularly scheduled time. If the patient misses a dose

of PREZISTA or ritonavir by less than 6 hours, the patient should be told to take PREZISTA and ritonavir

immediately, and then take the next dose of PREZISTA and ritonavir at the regularly scheduled time. If a dose of

PREZISTA or ritonavir is skipped, the patient should not double the next dose. Inform the patient that he or she

should not take more or less than the prescribed dose of PREZISTA or ritonavir.

15.3 Hepatotoxicity

Patients should be informed that Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been

reported with PREZISTA co-administered with 100 mg of ritonavir. Monitor liver function before and during

therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment

elevations of transaminases. Post-marketing cases of liver injury, including some fatalities, have been reported.

Patients should be advised about the signs and symptoms of liver problems. These may include jaundice of the

skin or eyes, dark (tea colored) urine, pale colored stools, nausea, vomiting, loss of appetite, or pain, aching or

sensitivity in the right upper quadrant of the abdomen.

15.4 Severe Skin Reactions

Patients should be informed that skin reactions ranging from mild to severe, including Stevens-Johnson

Syndrome and toxic epidermal necrolysis, have been reported with PREZISTA co-administered with 100 mg of

ritonavir. Patients should be advised to discontinue PREZISTA/ritonavir immediately if signs or symptoms of

severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with

fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or

eosinophilia

15.5 Drug Interactions

PREZISTA/ritonavir may interact with many drugs; therefore, patients should be advised to report to their

healthcare provider the use of any other prescription or nonprescription medication or herbal products, including

St. John's wort.

Patients receiving estrogen-based contraceptives should be instructed to use alternate contraceptive measures

during therapy with PREZISTA/ritonavir because hormonal levels may decrease.

15.6 Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving

antiretroviral therapy, including PREZISTA/ritonavir, and that the cause and long-term health effects of these

conditions are not known at this time.

Manufacturer: Janssen Cilag SpA, Latina, Italy

Registration holder: J-C Health Care Ltd. Kibbutz Shefayim, 60990, Israel

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ל

ל

אפור אפור

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

_

14.4.15

_

םש

רישכת

תילגנאב

רפסמו

םושירה

75mg Prezista

םושיר רפסמ

144-22-32957-00

Prezista 150mg

םושיר רפסמ

144-32-32992-00

Prezista 400mg

םושיר רפסמ

142-12-31999-00

Prezista 600mg

םושיר רפסמ

142-13-32000-00

Prezista 800mg

םושיר רפסמ

151-64-34005-00

םש

לעב

םושירה

_

J-C HEALTH CARE LTD

.

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

contraindications

Hypersensitivity to the active substance or to any of the excipients

Patients with severe (Child-Pugh Class C) hepatic impairment

Co-administration of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent

on cytochrome P450 3A (CYP3A) isoform for clearance and for which elevated plasma

concentrations are associated with serious and/or life-threatening events (narrow therapeutic

index). These drugs and other contraindicated drugs (which may lead to reduced efficacy of

darunavir) are listed in Table 2 [also see Drug Interactions (7.3), Table

Table 2: Drugs That Are Contraindicated With PREZISTA/ritonavir

Drug Class

Drugs within

Class that are

contraindicated

with

PREZISTA/ritonav

ir

Clinical comment

Alpha

1adrenorecepto

r antagonist

Alfuzosin

Potential for serious and/or life-threatening

reactions such as hypotension.

Ergot

Derivatives

Dihydroergotamine,

Ergonovine,

Ergotamine,

Methylergonovine

Potential for serious and/or life-threatening

events such as acute ergot toxicity

characterized by peripheral vasospasm and

ischemia of the extremities and other tissues.

GI Motility

Agent

Cisapride

Potential for serious and/or life-threatening

reactions such as cardiac arrhythmias.

Neuroleptic

Pimozide ,

sertindole

Potential for serious and/or life-threatening

reactions such as cardiac arrhythmias.

Sedative/

hypnotics

Orally administered

Midazolam,

Triazolam

Triazolam and orally administered midazolam

are extensively metabolized by CYP3A. Co-

administration of triazolam or orally

administered midazolam with

PREZISTA/ritonavir may cause large

increases in the concentrations of these

benzodiazepines. Potential for serious and/or

life-threatening events such as prolonged or

increased sedation or respiratory depression.

Herbal Products

St. John’s Wort

(Hypericum

perforatum)

Patients taking PREZISTA/ritonavir should not

use products containing St. John’s wort

because co-administration may result in

reduced plasma concentrations of darunavir.

This may result in loss of therapeutic effect

and development of resistance.

HMG CoA

Reductase

Inhibitors

Lovastatin,

Simvastatin

Potential for serious reactions such as

myopathy including rhabdomyolysis. For

dosing recommendation regarding

atorvastatin and pravastatin, see Table

Established and Other Potentially Significant

Drug Interactions: Alterations in Dose or

Regimen May Be Recommended Based on

Drug Interaction Studies or Predicted

Interaction.

Antimycobacteri

Rifampin

Rifampin is a potent inducer of CYP450

metabolism. PREZISTA/ritonavir should not

be used in combination with rifampin, as this

may cause significant decreases in darunavir

plasma concentrations. This may result in loss

of therapeutic effect to PREZISTA.

PDE-5 inhibitor

Sildenafil for

treatment of

pulmonary arterial

hypertension ,

avanafil (PDE-5

inhibitors)

A safe and effective dose for the treatment of

pulmonary arterial hypertension has not been

established with PREZISTA/ritonavir.There is

an increased potential for sildenafil-

associated adverse events (which include

visual disturbances, hypotension, prolonged

erection, and syncope).

Anti Allergic

Astemizole,

Terfenadine

Anti HIV

Co-administration

with the

combination

product

lopinavir/ritonavir

antiarrhythmics

amiodarone,

bepridil,

dronedarone

quinid

ine, ranolazine,

systemic lidocaine

ticagrelor

(antiplatelets)

colchicine when

used in patients

with renal and/or

hepatic impairment

(antigout)

Quetiapine

Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir

prescribing information for a description of ritonavir contraindications

8.4 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

8.5 Effects on ability to drive and use machines

PREZISTA 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

PREZISTA co-administered with low dose ritonavir and

should be borne in mind when considering a patient

ability to drive or operate machinery

Special Warnings and

Special Precautions

for Use

5.

3

Severe Skin Reactions

During

clinical

development

program

(n=3063),

severe

skin

reactions,

accompanied

fever

and/or elevations of transaminases in

some cases, have been reported in

0.4% of subjects. DRESS (Drug Rash

with

Eosinophilia

Systemic

Symptoms)

Stevens-Johnson

Syndrome was rarely (<0.1%) reported

during

clinical

development

program.

During

post-marketing

5.

3

Severe Skin Reactions

During the clinical

development program (n=3063),

severe skin reactions, accompanied by fever and/or

elevations of transaminases in some cases, have been

reported in 0.4% of subjects.

DRESS (Drug Rash with

Eosinophilia

Systemic

Symptoms)

Stevens-

Johnson Syndrome was rarely (<0.1%) reported during

the clinical development program. During post-marketing

experience toxic epidermal necrolysis, drug rash with

eosinophilia and systemic symptoms (DRESS), and

acute generalized exanthematous pustulosis have been

reported.

During

post-marketing

experience

toxic

experience toxic epidermal necrolysis,

and acute generalized exanthematous

pustulosis

been

reported.

Discontinue

PREZISTA/rtv

immediately if signs or symptoms of

severe skin reactions develop. These

can include but are not limited to

severe rash or rash accompanied with

fever, general malaise, fatigue, muscle

or joint aches, blisters, oral lesions,

conjunctivitis,

hepatitis

and/or

eosinophilia

Rash (all grades, regardless of

causality) occurred in 10.3% of

subjects treated with PREZISTA/rtv

[also see Adverse Reactions (6)].

Rash was mostly mild-to-moderate,

often occurring within the first four

weeks of treatment and resolving with

continued dosing. The discontinuation

rate due to rash in subjects using

PREZISTA/rtv was 0.5%.

Rash occurred more commonly in

treatment-experienced subjects

receiving regimens containing

PREZISTA/rtv + raltegravir compared

to subjects receiving PREZISTA/rtv

without raltegravir or raltegravir without

PREZISTA/rtv. However, rash that

was considered drug related occurred

at similar rates for all three groups.

These rashes were mild to moderate

in severity and did not limit therapy;

there were no discontinuations due to

rash.

5.5 Drug Interactions

See Table 2 for a listing of drugs that

are contraindicated for use with

PREZISTA/ritonavir due to potentially

life-threatening adverse events,

significant drug-drug interactions, or

loss of therapeutic effect to PREZISTA

[see Contraindications (4)]. Please

refer to Table

3

for established and

other potentially significant drug-drug

interactions [see Drug Interactions

(7.3)]

epidermal

necrolysis,

acute

generalized

exanthematous

pustulosis

been

reported.

Discontinue PREZISTA/rtv immediately if signs or

symptoms of severe skin reactions develop. These can

include but are not limited to severe rash or rash

accompanied with fever, general

malaise, fatigue,

muscle or joint aches, blisters, oral lesions, conjunctivitis,

hepatitis and/or eosinophilia

Rash (all grades, regardless of causality) occurred in

10.3% of subjects treated with PREZISTA/rtv [also see

Adverse Reactions (6)]. Rash was mostly mild-to-

moderate, often occurring within the first four weeks of

treatment and resolving with continued dosing. The

discontinuation rate due to rash in subjects using

PREZISTA/rtv was 0.5%.

Rash occurred more commonly in treatment-experienced

subjects receiving regimens containing PREZISTA/rtv +

raltegravir compared to subjects receiving PREZISTA/rtv

without raltegravir or raltegravir without PREZISTA/rtv.

However, rash that was considered drug related

occurred at similar rates for all three groups. These

rashes were mild to moderate in severity and did not limit

therapy; there were no discontinuations due to rash.

5.5 Drug Interactions

See Table 2 for a listing of drugs that are contraindicated

for use with PREZISTA/ritonavir due to potentially life-

threatening adverse events, significant drug-drug

interactions, or loss of therapeutic effect to PREZISTA

[see Contraindications (4)]. Please refer to Table

3

established and other potentially significant drug-drug

interactions [see Drug Interactions (7.3)]

Initiation of PREZISTA/ritonavir, a CYP3A inhibitor, in

patients receiving medications metabolized by CYP3A or

initiation of medications metabolized by CYP3A in

patients already receiving PREZISTA/ritonavir, may

increase

plasma concentrations of medications metabolized by

CYP3A. Initiation of medications that inhibit or induce

CYP3A may increase or decrease concentrations of

PREZISTA/ritonavir, respectively. These interactions

may lead to:

Clinically significant adverse reactions, potentially

leading to severe, life threatening, or fatal events from

greater exposures of concomitant medications

Clinically significant adverse reactions from greater

exposures of PREZISTA/ritonavir

Loss of therapeutic effect of PREZISTA/ritonavir and

possible development of resistance

See Table 3 for steps to prevent or manage these

possible

known

significant

drug

interactions,

including

dosing

recommendations

[see

Drug

Interactions

(7)]. Consider

potential

for drug

interactions prior to and during PREZISTA/ritonavir

therapy;

review

concomitant

medications

during

PREZISTA/ritonavir therapy; and monitor for the adverse

reactions associated with the concomitant drugs [see

Contraindications (4) and Drug Interactions (7)].

Adverse events

DRUG

INTERACTIONS

Table

3

provides dosing recommendations as a result of drug interactions with

PREZISTA/ritonavir. These recommendations are based on either drug interaction studies or

predicted interactions due to the expected magnitude of interaction and potential for serious

adverse events or loss of efficacy

Table 3: Established and Other Potentially Significant Drug

Interactions:

Alterations in Dose or Regimen May Be Recommended

Based on Drug Interaction Studies or Predicted Interaction

[See Clinical Pharmacology (11.3) for Magnitude of Interaction, Tables 8 and 9]

Concomitant Drug

Class:

Drug Name

Effect on

Concentration of

Darunavir

or

Concomitant Drug

Clinical Comment

Integrase strand tranfer inhibitors

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. PREZISTA

co-administered with low dose

ritonavir and raltegravir can be used

without dose adjustments.

Elvitegravir

When PREZISTA 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 or with

elvitegravir/cobicistat have not been

established. Therefore

co-administration of PREZISTA

with low dose ritonavir in doses

other than 600/100 mg twice daily

and elvitegravir is not

recommended. Co-administration of

PREZISTA with low dose ritonavir

and elvitegravir in the presence of

cobicistat is not recommended

HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors

(NRTIs)

didanosine

↔ darunavir

↔ didanosine

Didanosine should be

administered one hour before or

two hours after

PREZISTA/ritonavir (which are

administered with food).

HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)

indinavir

(The reference regimen for

indinavir was

indinavir/ritonavir 800/100 mg

twice daily.)

↑ darunavir

↑ indinavir

The appropriate dose of indinavir

in combination with

PREZISTA/ritonavir has not been

established.

lopinavir/ritonavir

↓ darunavir

↔ lopinavir

Appropriate doses of the

combination have not been

established. Hence, it is not

recommended to co-administer

lopinavir/ritonavir and

PREZISTA, with or without

ritonavir.

saquinavir

↓ darunavir

↔ saquinavir

Appropriate doses of the

combination have not been

established. Hence, it is not

recommended to co-administer

saquinavir and PREZISTA, with

or without ritonavir.

HIV-1-Antiviral Agents: CCR5 co-receptor

antagonists

maraviroc

↑ maraviroc

Maraviroc concentrations are

increased

when co-administered with

PREZISTA/ritonavir. When used

in combination with

PREZISTA/ritonavir, the dose of

maraviroc should be 150 mg

twice daily.

ANAESTHETIC

Alfentanil

Not studied. The

metabolism of alfentanil

is mediated via CYP3A,

and may as such

be inhibited by boosted

PREZISTA.

The concomitant use with boosted

PREZISTA may require to lower

the dose of alfentanil and requires

monitoring for risks of prolonged or

delayed respiratory depression.

Other Agents

Antiarrhythmics:

bepridil,

lidocaine (systemic),

quinidine,

amiodarone,

flecainide,

propafenone

Disopyramide

Mexiletine

digoxin

↑ antiarrhythmics

↑ digoxin

Concentrations of these drugs

may be increased when co-

administered with

PREZISTA/ritonavir. Caution is

warranted and therapeutic

concentration monitoring, if

available, is recommended for

antiarrhythmics when co-

administered with

PREZISTA/ritonavir.

The lowest dose of digoxin

should initially be prescribed.

The serum digoxin concentrations

should be monitored and used for

titration of digoxin dose to obtain

the desired clinical effect.

Anticoagulant:

Apixaban

Dabigatran etexilate

Rivaroxaban

Not studied. Co-

administration of

PREZISTA with these

anticoagulants may

increase concentrations of

anticoagulant.

(CYP3A and/or P-gp

inhibition).

The use of PREZISTA

co-administered with low dose

ritonavir and these anticoagulants is

not recommended.

Anticoagulant:

warfarin

↓ warfarin

↔ darunavir

Warfarin concentrations are

decreased when co-administered

with PREZISTA/ritonavir. It is

recommended that the

international normalized ratio

(INR) be monitored when

warfarin is combined with

PREZISTA/ritonavir.

Anticonvulsant:

carbamazepine

↔ darunavir

↑ carbamazepine

The dose of either

darunavir/ritonavir or

carbamazepine does not need to

be adjusted when initiating co-

administration with

darunavir/ritonavir and

carbamazepine. Clinical

monitoring of carbamazepine

concentrations and its dose

titration is recommended to

achieve the desired clinical

response.

Anticonvulsant:

phenobarbital,

phenytoin

↔ darunavir

↓ phenytoin

↓ phenobarbital

Not studied. Phenobarbital

and phenytoin

are expected to

decrease plasma

concentrations of

darunavir. (induction of

CYP450 enzymes)

Co-administration of PREZISTA/

ritonavir may cause a decrease in

the steady-state concentrations of

phenytoin and phenobarbital.

Phenytoin and phenobarbital

levels should be monitored when

co-administering with

PREZISTA/ritonavir.

PREZISTA co-administered with

low dose ritonavir should not be

used in combination with these

medicines.

Antidepressant:

trazodone,

desipramine

↑ trazodone

↑ desipramine

Concomitant use of trazodone or

desipramine and

PREZISTA/ritonavir may

increase plasma concentrations of

trazodone or desipramine which

may lead to adverse events such

as nausea, dizziness, hypotension

and syncope. If trazodone or

desipramine is used with

PREZISTA/ritonavir, the

combination should be used with

caution, and a lower

dose of trazodone or

desipramine should be

considered.

Antidepressant:

Amitriptyline

Desipramine

Imipramine

Nortriptyline

Trazodone

Concomitant use of

PREZISTA

co-administered wirth low

dose ritonavir

and these antidepressants

may increase

concentrations of the

antidepressant.

(CYP2D6 and/or CYP3A

inhibition).

Clinical monitoring is

recommended when

co-administering PREZISTA with

low dose ritonavir with these

antidepressants and a dose

adjustment of the antidepressant

may be needed.

Anti-

infective:

clarithromycin

↔darunavir

↑clarithromycin

No dose adjustment of the

combination is required for

patients with normal renal

function. For patients with renal

impairment, the following dose

adjustments should be

considered:

For subjects with CLcr

of 30-60 mL/min, the

dose of clarithromycin

should be reduced by

50%.

For subjects with CLcr

of < 30 mL/min, the

dose of clarithromycin

should be reduced by

75%.

Antifungals:

ketoconazole

itraconazole,

voriconazole

↑ketoconazol

↑darunavir

↑itraconazole

(not studied)

↓voriconazole

(not studied)

Ketoconazole and itraconazole

are potent inhibitors as well as

substrates of CYP3A.

Concomitant systemic use of

ketoconazole, itraconazole, and

darunavir/ritonavir may increase

plasma concentration of

darunavir.

Plasma concentrations of

ketoconazole or itraconazole may

be increased in the presence of

darunavir/ritonavir. When co-

administration is required, the

daily dose of ketoconazole or

itraconazole should not exceed

200 mg.

Plasma concentrations of

voriconazole may be decreased in

the presence of

darunavir/ritonavir. Voriconazole

should not be administered to

patients receiving

darunavir/ritonavir unless an

assessment of the benefit/risk

ratio justifies the use of

voriconazole.

Antifungals:

Clotrimazole

Not studied. Concomitant

systemic use of

clotrimazole andboosted

PREZISTAmay

increase plasma

concentrations of darunavir

and/or clotrimazole.

darunavir AUC24h ↑ 33%

(based on

population

pharmacokinetic model

Caution is warranted and clinical

monitoring is recommended, when

co-administration of clotrimazole is

required

Antifungals:

Fluconazole

Posaconazole

Not studied. PREZISTA

may increase

antifungal plasma

concentrations (P-gp

inhibition) and

posaconazole may increase

darunavir concentrations

(CYP3A inhibition)

Caution is warranted and clinical

monitoring is recommended.

Anti-gout:

colchicine

↑colchicine

Treatment of gout-flares – co-

administration of colchicine in

patients on PREZISTA/ritonavir:

0.6 mg (1 tablet) x 1 dose,

followed by 0.3 mg (half tablet) 1

hour later. Treatment course to be

repeated no earlier than 3 days.

Prophylaxis of gout-flares – co-

administration of colchicine in

patients on PREZISTA/ritonavir:

If the original regimen was 0.6

mg twice a day, the regimen

should be adjusted to 0.3 mg once

a day.

If the original regimen was 0.6

mg once a day, the regimen

should be adjusted to 0.3 mg once

every other day.

Treatment of familial

Mediterranean fever – co-

administration of colchicine in

patients on

PREZISTA/ritonavir:

maximum daily dose of 0.6 mg

(may be given as 0.3 mg twice

a day).

Patients with renal or hepatic

impairment should not be

given colchicine with

PREZISTA/ritonavir.

Co-administration of

PREZISTA/rtv with colchicine

in patients with renal or

hepatic impairment is

contraindicated.

ANTIMYCOBACTERIAL:

Rifapentine

Not studied. Rifapentine is

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

dose ritonavir, a high

frequency of liver reactions

was seen with rifampicin.

The combination of rifapentine and

boosted PREZISTA is not

recommended.

Antimycobacterial:

rifabutin

The reference regimen for

rifabutin was 300 mg once

daily

↑darunavir

↑rifabutin

↑25-O-

desacetylrifabutin

Dose reduction of rifabutin by at

least 75% of the usual dose (300

mg once daily) is recommended

(i.e., a maximum dose of

150 mg every other day).

Increased monitoring for adverse

events is warranted in patients

receiving this combination and

further dose reduction of rifabutin

may be necessary.

ANTINEOPLASTICS:

Dasatinib

Nilotinib

Vinblastine

Vincristine

Not studied. PREZISTA is

expected to

increase these

antineoplastic plasma

concentrations.

(CYP3A inhibition)

Concentrations of these medicinal

products may be increased when

co-administered with PREZISTA

with low dose ritonavir 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

PREZISTA with low dose ritonavir.

Everolimus

Concominant use of everolimus and

PREZISTA co-administered with

low dose ritonavir is not

recommended.

β-Blockers:

metoprolol,

timolol

Carvedilol

↑beta-blockers

Caution is warranted and clinical

monitoring of patients is

recommended. A dose decrease

may be needed for these drugs

when co-administered with

PREZISTA/ritonavir.

Benzodiazepines:

parenterally administered

midazolam

↑midazolam

Concomitant use of parenteral

midazolam with

PREZISTA/ritonavir may

increase plasma concentrations of

midazolam. Co-administration

should be done in a setting which

ensures close clinical monitoring

and appropriate medical

management in case of

respiratory depression and/or

prolonged sedation. Dosage

reduction for midazolam should

be considered, especially if more

than a single dose of midazolam

is administered. Co-

administration of oral midazolam

with PREZISTA/ritonavir is

CONTRAINDICATED.

Buspirone

Clorazepate

Diazepam

Estazolam

Flurazepam

Midazolam (parenteral)

Zoldipem

Not studied.

Sedative/hypnotics are

extensively metabolised by

CYP3A.Co-administration

with boosted PREZISTA

may cause a large increase

the concentration of these

medicines.

If parenteral midazolam is

co-administered with

boosted PREZISTA 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 fold increase

in midazolam plasma

levels.

Clinical monitoring is

recommended when

co-administering boosted

PREZISTA with these

sedatives/hypnotics and a lower

dose of the sedatives/hypnotics

should be considered.

If parenteral midazolam is

co-administered with boosted

PREZISTA, it should be done in an

intensive care unit (ICU) or similar

setting, which ensures close 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.

Calcium Channel

Blockers:

felodipine,

nifedipine,

nicardipine

Amlodipine

Diltiazem

Verapamil

↑calcium channel

blockers

Plasma concentrations of calcium

channel blockers (e.g., felodipine,

nifedipine, nicardipine) may

increase when

PREZISTA/ritonavir are co-

administered. Caution is

warranted and clinical monitoring

of patients is recommended.

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

PREZISTA co-administered with

low dose ritonavir 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.

Prednisone

Not studied. Darunavir

may increase

plasma concentrations of

prednisone.

(CYP3A inhibition)

Concomitant use of PREZISTA

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 PREZISTA with

low dose ritonavir with

corticosteroids.

Corticosteroid:

Systemic:

dexamethasone

↓darunavir

Systemic dexamethasone induces

CYP3A and can thereby decrease

darunavir plasma concentrations.

This may result in loss of

therapeutic effect to PREZISTA.

Corticosteroid:

↑fluticasone

Concomitant use of inhaled

Inhaled/Nasal:

fluticasone

fluticasone and

PREZISTA/ritonavir may

increase plasma concentrations of

fluticasone. Alternatives should

be considered, particularly for

long-term use.

Endothelin receptor

antagonists:

bosentan

↑bosentan

Co-administration of bosentan in

patients on PREZISTA/ritonavir:

In patients who have been

receiving PREZISTA/ritonavir

for at least 10 days, start

bosentan at 62.5 mg once daily

or every other day based upon

individual tolerability.

Co-administration of

PREZISTA/ritonavir in

patients on bosentan:

Discontinue use of bosentan at

least 36 hours prior to

initiation of

PREZISTA/ritonavir. After at

least 10 days following the

initiation of

PREZISTA/ritonavir, resume

bosentan at 62.5 mg once daily

or every other day based upon

individual tolerability.

Hepatitis C Virus (HCV)

Direct-Acting Agents:

NS3-4A protease inhibitors:

boceprevir

telaprevir

↓darunavir

↓boceprevir

↓telaprevir

Concomitant administration of

PREZISTA/ritonavir and

boceprevir or telaprevir resulted

in reduced steady-state exposures

to darunavir and boceprevir or

telaprevir. It is not recommended

to co-administer boceprevir or

telaprevir and

PREZISTA/ritonavir.

Simeprevir

simeprevir AUC ↑ 159%

simeprevir Cmin ↑ 358%

simeprevir Cmax ↑ 79%

darunavir AUC ↑ 18%

darunavir Cmin ↑ 31%

darunavir Cmax

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 PREZISTA

and simeprevir.

HMG-CoA

Reductase Inhibitors:

pravastatin,

atorvastatin,

rosuvastatin

↑pravastatin

↑atorvastatin

↑rosuvastatin

Titrate atorvastatin, pravastatin or

rosuvastatin dose carefully and

use the lowest necessary dose

while monitoring for safety. Do

not exceed atorvastatin 20

mg/day.

Immunosuppressants:

cyclosporine,

tacrolimus,

sirolimus

↑immunosuppressants

Plasma concentrations of

cyclosporine, tacrolimus or

sirolimus may be increased when

co-administered with PREZISTA/

ritonavir. Therapeutic

concentration monitoring of the

Everolimus

immunosuppressive agent is

recommended when co-

administered with

PREZISTA/ritonavir.

Concomitant use of everolimus and

boosted PREZISTA is not

recommended

Inhaled beta agonist:

salmeterol

↑salmeterol

Concurrent administration of

salmeterol and

PREZISTA/ritonavir is not

recommended. The combination

may result in increased risk of

cardiovascular adverse events

associated with salmeterol,

including QT prolongation,

palpitations and sinus

tachycardia.

Narcotic

Analgesic/Treatment of

Opioid Dependence:

methadone,

buprenorphine,

buprenorphine/naloxone

↓methadone

↔buprenorphine,

naloxone

↑norbuprenorphine

(metabolite)

No adjustment of methadone

dosage is required when initiating

co-administration of

PREZISTA/ritonavir. However,

clinical monitoring is

recommended as the dose of

methadone during maintenance

therapy may need to be adjusted

in some patients.

No dose adjustment for

buprenorphine or buprenorphine/

naloxone is required with

concurrent administration of

PREZISTA/ritonavir. Clinical

monitoring is recommended if

PREZISTA/ritonavir and

buprenorphine or buprenorphine/

naloxone are coadministered.

Neuroleptics:

risperidone,

thioridazine

Perphenazine

↑neuroleptics

A dose decrease may be needed

for these drugs when co-

administered with

PREZISTA/ritonavir.

Oral

Contraceptives/estrogen:

ethinyl estradiol,

norethindrone

↓ethinyl estradiol

↓norethindrone

Plasma concentrations of ethinyl

estradiol are decreased due to

induction of its metabolism by

ritonavir. Alternative methods of

nonhormonal contraception are

recommended.

PDE-5 inhibitors:

sildenafil,

vardenafil,

tadalafil

↑PDE-5 inhibitors (only

the use of sildenafil at

doses used for treatment

of erectile dysfunction

has been studied with

PREZISTA/ritonavir)

Co-administration with

PREZISTA/ritonavir may result

in an increase in PDE-5 inhibitor-

associated adverse events,

including hypotension, syncope,

visual disturbances and priapism.

Use of PDE-5 inhibitors for

pulmonary arterial hypertension

(PAH):

-Use of sildenafil is

contraindicated when used

for the treatment of

pulmonary arterial

hypertension (PAH) [see

Contraindications (4)].

-The following dose

adjustments are

recommended for use of

tadalafil with

PREZISTA/ritonavir:

Co-administration of tadalafil

in patients on

PREZISTA/ritonavir:

In patients receiving

PREZISTA/ritonavir for at

least one week, start tadalafil

at 20 mg once daily. Increase

to 40 mg once daily based

upon individual tolerability.

Co-administration of

PREZISTA/ritonavir in

patients on tadalafil:

Avoid use of tadalafil during

the initiation of

PREZISTA/ritonavir. Stop

tadalafil at least 24 hours

prior to starting

PREZISTA/ritonavir. After at

least one week following the

initiation of

PREZISTA/ritonavir, resume

tadalafil at 20 mg once daily.

Increase to 40 mg once daily

based upon individual

tolerability.

Use of PDE-5 inhibitors for

erectile dysfunction:

Sildenafil at a single dose not

exceeding 25 mg in 48 hours,

vardenafil at a single dose not

exceeding 2.5 mg dose in 72

hours, or tadalafil at a single dose

not exceeding 10 mg dose in 72

hours can be used with increased

monitoring for PDE-5 inhibitor-

associated adverse events.

Selective Serotonin

Reuptake Inhibitors (SSRIs):

sertraline,

paroxetine

↔darunavir

↓sertraline

↓paroxetine

If sertraline or paroxetine is co-

administered with

PREZISTA/ritonavir, the

recommended approach is a

careful dose titration of the SSRI

based on a clinical assessment of

antidepressant response. In

addition, patients on a stable dose

of sertraline or paroxetine who

start treatment with

PREZISTA/ritonavir should be

monitored for antidepressant

response.

Antimalarials

An interaction trial between PREZISTA/rtv (600/100 mg b.i.d.) and artemether/lumefantrine

(80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours) showed an increase in exposure to

lumefantrine by 2.75-fold, while exposure to darunavir was not affected. The exposure to

artemether and its active metabolite, dihydroartemisinin, decreased by 16% and 18%,

respectively. The combination of PREZISTA and artemether/lumefantrine can be used

without dose adjustments; however, due to the increase in lumefantrine exposure, the

combination should be used with caution

In addition to the drugs included in Table

3

, the interaction between PREZISTA/ritonavir and

the following drugs were evaluated in clinical studies and no dose adjustments are needed for

either drug [see Clinical Pharmacology (11.3)]: atazanavir, efavirenz, etravirine, nevirapine, ,

ranitidine, rilpivirine, and tenofovir disoproxil fumarate

Using cross-trial comparisons to historical pharmacokinetic data, dolutegravir did not appear

to affect the pharmacokinetics of darunavir. Darunavir/ritonavir had no clinically significant

effect on the pharmacokinetics of dolutegravir

Proton Pump Inhibitors

Omeprazole, pantoprazole, rabeprazole, Esomeprazole, Lansoprazole

Co-administration of omeprazole (20 mg q.d.) and PREZISTA/rtv (400/100 mg b.i.d.) did not

affect the exposure to darunavir. PREZISTA and proton pump inhibitors can be

co-administered without dose adjustment

Other nucleoside reverse transcriptase inhibitors (NRTIs): Based on the different elimination

pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine

and abacavir) that are primarily renally excreted, no drug interactions are expected for these

drugs and PREZISTA/ritonavir

Other PIs: The co-administration of PREZISTA/ritonavir and PIs other than lopinavir/ritonavir,

saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration

is not recommended

- nucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine

Co-administration of PREZISTA/rtv and delavirdine may increase darunavir and delavirdine

concentrations (inhibition of CYP3A). The appropriate doses of PREZISTA/rtv and delavirdine

have not been established. The combination of PREZISTA/rtv and delavirdine is not

recommended

Antacids

e.g. Aluminium/magnesium hydroxide, calcium carbonate

No interaction is expected between antacids and PREZISTA/rtv. PREZISTA/rtv and antacids

can be used concomitantly without dose adjustments

- Receptor antagonists

e.g. Cimetidine, famotidine, nizatidine, ranitidine

Co-administration of ranitidine (150 mg b.i.d.) and PREZISTA/rtv (400/100 mg b.i.d.) did not

affect the exposure to darunavir. PREZISTA/rtv can be co-administered with H2-receptor

antagonists without dose adjustments

ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

שקובמה תו

לע

עקר

.בוהצ םייוניש

םניאש

רדגב

תורמחה

ונמוס

)ןולעב( עבצב

שי .הנוש

ןמסל

קר

ןכות

יתוהמ

אלו

םייוניש םוקימב

.טסקטה רבעוה

ראודב

ינורטקלא

.........ךיראתב

14.4.15

.......

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ןכרצל ןכרצל

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

_

14.4.15

םש

רישכת

תילגנאב

רפסמו

םושירה

75mg Prezista

םושיר רפסמ

144-22-32957-00

Prezista 150mg

םושיר רפסמ

144-32-32992-00

םש

לעב

םושירה

_

J-C HEALTH CARE LTD

.

ספוט

הז

דעוימ

טורפל

תורמחהה

דבלב

תורמחהה

תושקובמה

קרפ

ןולעב טסקט

יחכונ טסקט

שדח

שמתשהל ןיא יתמ

?

רישכתב

םע דחיב הטסיזרפ לוטיל ןיא ( :תואבה תופורתה םלוזאדימ (הפה ךרד חקלנש) תיירשהל) םלוזאירטו תויעבל) דירפאזיס ,(העגרהל וא/ו הניש דיזומיפ ,(לוכיע לודניטרסו לופיטל) ןיטאטסבמיס ,(תויטוכיספ תוערפהב לש תוהובג תומרב לופיטל) ןיטאטסבולו (םדב לורטסלוכ

לופיטל) ןיפמאפיר לופיטל) ןידנפרטו לוזימטסא ;(תפחשב (היגרלא לש םימוטפמיסב

ןיסוזופלא (תלדגומ הטטסורפב לופיטל)

ליפנדליס (יקרוע יתאיר םד ץחל רתיב לופיטל)

ןיאקודילו ,ןידיניק ,לידירפב ,ןורדוימא תוערפהב לופיטל) ימטסיס ןתמב בלושמה רצומה ,(תומיוסמ תויבבל -ל) ריוונוטיר/ריווניפול

ןיפאיטווק , ( הערפה ,הינרפוזיכסב לופיטל) (ירו'גמ ןואכידו תיראלופיב

טב שמתשהל ןיא

עובשב ליפאל ןושארה .הטסיזרפב שומישל קיספהל שי תוחפל ליפאלאדאט תליטנ

תועש .הטסיזרפ תליטנ ינפל

ףסותה תא םיליכמה םירישכת ( יחמצה

St. John's Wort

םוקירפיה) (םוטרופרפ

תופורת

טוגראה תחפשממ ,ןימטוגרא ומכ םידיאולקלא גראורדיהיד

,ןימט ןירטמוגרא ןיוונוגראליתמו

יבאכו הנרגימב לופיטל) (שאר

:תואבה תופורתה םע דחיב הטסיזרפ לוטיל ןיא ( םלוזאדימ (הפה ךרד חקלנש) הניש תיירשהל) םלוזאירטו דיזומיפ ,(לוכיע תויעבל) דירפאזיס ,(העגרהל וא/ו לודניטרסו ןיטאטסבולו ןיטאטסבמיס ,(תויטוכיספ תוערפהב לופיטל) (םדב לורטסלוכ לש תוהובג תומרב לופיטל)

ןיפמאפיר םימוטפמיסב לופיטל) ןידנפרטו לוזימטסא ;(תפחשב לופיטל) (היגרלא לש

(תלדגומ הטטסורפב לופיטל) ןיסוזופלא

(יקרוע יתאיר םד ץחל רתיב לופיטל) ליפנדליס ,ןורדוימא , ,לידירפב ןורדנורד ,ןידיניק , ןיזלונר ימטסיס ןתמב ןיאקודילו בלושמה רצומה ,(תומיוסמ תויבבל תוערפהב לופיטל) -ל) ריוונוטיר/ריווניפול

,הינרפוזיכסב לופיטל) ןיפאיטווק , ( ,(ירו'גמ ןואכידו תיראלופיב הערפה תויעבב לופיטל) ליפנווא לופיטל (דבכ וא/ו היילכ תויעב ךל שיו הדימב) ןיציכלוכ ,(הפקיז ןודגישב

םד ילכו בל יעוריאל ןוכיס תתחפהל) רולרגקיט יתלב הזח תקועת רחאל וא בלה רירש םטוא רחאל םילוחב .(הביצי טב שמתשהל ןיא

ןושארה עובשב ליפאל שומישל .הטסיזרפב תוחפל ליפאלאדאט תליטנ קיספהל שי

תועש .הטסיזרפ תליטנ ינפל

יחמצה ףסותה תא םיליכמה םירישכת (

St. John's Wort

(םוטרופרפ םוקירפיה)

תופורת

םידיאולקלא טוגראה תחפשממ גראורדיהיד ,ןימטוגרא ומכ

,ןימט ןירטמוגרא ןיוונוגראליתמו (שאר יבאכו הנרגימב לופיטל)

ןיב תובוגת

:

תויתופורת תחקל םא וא ,חקול התא םא ללוכ תורחא תופורת ,הנורחאל ,הנוזת יפסותו םשרמ אלל תופורת תורחא תופורת ,הנורחאל תחקל םא וא ,חקול התא םא אפורל ךכ לע רפס ,הנוזת יפסותו םשרמ אלל תופורת ללוכ חקורל וא

חקורל וא אפורל ךכ לע רפס

םע דחיב לוטיל רוסא רשא תופורת ןנשי ןיא " ףיעסב תוטרופמ ןה .הטסיזרפ שמתשהל

הפורתב

םא

."

תופורתב שומיש יבגל אפורב ץעוויהל שי תליטנ .הטסיזרפ םע דחי תואבה הלולע ולא תופורת םע דחי הטסיזרפ ךרוצ היהיו ןכתייו ןתעפשה תא תונשל .ןנונימ תא תונשל

לופיטל) ןיזאדירוית ,ןודירפסיר ( .(הינרפוזיכסב

(ןואכידב לופיטל) ןימרפיזד ,ןודוזאר

ץחלב לופיטל) לולומית , לולורפוטמ ( (בל תויעבו םד

תודגונ תופורתה לכ אל (

.הטסיזרפ םע דחיב בולישל תומיאתמ םע אדוול שי

תא בלשל ןתינש אפורה תודגונ תופורתה

התאש תופסונה .הטסיזרפ םע לבקמ תוליעיה תא דירוהל תולולעה תופורת :הטסיזרפ לש

.(דיאורטס) ןוזאתמסקד (

לופיטל) ,ןיאותינפ ,לטיברבונפ ( ;(היספליפאב -ה םוהיזב לופיטל) זנריוופא

םוהיזב לופיטל) ריוורפסוב ,ריוורפלט גוסמ תיפיגנ תבהצ

-ה םוהיזב לופיטל) ריווניווקס

הלולע תואבה תופורת לש העפשהה :הטסיזרפ לטונ התא םא תונתשהל

,ןיפידרקינ ,ןיפידפינ ,ןיפידולפ יאקלפ דינ ןונפאפורפ ,

תויעבב לופיטל) ;(בל

;(השירק תויעבב לופיטל) ןירפאוו

ןגורטסא םיליכמה םירישכת לופיטכו ןוירה תעינמל םישמשמה .יפולח ילנומרוה הטסיזרפש ןוויכמ תוטרופמ ןה .הטסיזרפ םע דחיב לוטיל רוסא רשא תופורת ןנשי ןיא " ףיעסב

שמתשהל

הפורתב

םא

."

םע דחי תואבה תופורתב שומיש יבגל אפורב ץעוויהל שי תונשל הלולע ולא תופורת םע דחי הטסיזרפ תליטנ .הטסיזרפ .ןנונימ תא תונשל ךרוצ היהיו ןכתייו ןתעפשה תא

.(הינרפוזיכסב לופיטל) ןיזאדירוית ,ןודירפסיר (

(ןואכידב לופיטל) ןימרפיזד ,ןודוזאר

(בל תויעבו םד ץחלב לופיטל) לולומית , לולורפוטמ (

תודגונ תופורתה לכ אל (

םע דחיב בולישל תומיאתמ םע אדוול שי .הטסיזרפ

תופורתה תא בלשל ןתינש אפורה תודגונ

.הטסיזרפ םע לבקמ התאש תופסונה :הטסיזרפ לש תוליעיה תא דירוהל תולולעה תופורת

.(דיאורטס) ןוזאתמסקד (

;(היספליפאב לופיטל) ,ןיאותינפ ,לטיברבונפ ( -ה םוהיזב לופיטל) זנריוופא

גוסמ תיפיגנ תבהצ םוהיזב לופיטל) ריוורפסוב ,ריוורפלט

-ה םוהיזב לופיטל) ריווניווקס

(תפחש ןוגכ םימייוסמ םימוהיזב לופיטל) ןיטובפיר ,ןיטנפאפיר לטונ התא םא תונתשהל הלולע תואבה תופורת לש העפשהה :הטסיזרפ

יאקלפ ,ןיפידרקינ ,ןיפידפינ ,ןיפידולפ דינ ןונפאפורפ ,

,לולורפוטמ ,לולידוורק ,דימאריפוזיד ,םזאיטליד ,ןיפידולמא לימפרו ,לולומיט ,ןיטליסקמ

;(בל תויעבב לופיטל)

רחאמ .תולעל םילולע ולא תופורת לש יאוולה תועפות וא העפשההו

ןאבסקורביר ,טאליסקטא ןארטאגיבד ,ןאבסקיפא

ןירפאוו ;(השירק תויעבב לופיטל) העפשהה וא םהלש יאוולה תועפות .םד תקידב עצבל ךרטצי אפורה .תונתשהל הלולע םהלש

ןוירה תעינמל םישמשמה ןגורטסא םיליכמה םירישכת .יפולח ילנומרוה לופיטכו

ש ןוויכמ עוגפל הלולע הטסיזרפ םתוליעיב

אל תוטיש ,ןוירה תעינמל םישמשמ םירישכתה רשאכ תוצלמומ ןוירה תעינמל (םימודנוק ןוגכ) תוילנומרוה

שי עוויהל

העינמ יעצמאב שומיש יבגל אפורב ףסונ

אל ילנומרוה

;(םימודנוק ןוגכ)

סומילורווא

לופיטל) סומילוריס ,סומילורקט ,ןירופסולקיצ תינוסיחה תכרעמב תויעבב

תועפות וא העפשההו רחאמ תולעל םילולע הלא תופורת לש יאוולה

ךרטצי אפורהו ןכתי םתוליעיב עוגפל הלולע

שי עוויהל

ףסונ העינמ יעצמאב שומיש יבגל אפורב םיילנומרוה אל ;(םימודנוק ןוגכ)

סומילוריס ,סומילורקט ,ןירופסולקיצ ( תינוסיחה תכרעמב תויעבב לופיטל)

תוקידב עצבל ךרטצי אפורהו ןכתי תופסונ

לורטמלס ,ןוזאקיטולפ ( דינוסדוב, .(המטסאב לופיטל)

ןיפרונרפוב ןוסקולאנ/

תופורת) (םיטאיפואל תורכמתהב לופיטל

הירלמב לופיטל תבלושמ הפורת (

ןירטנפמול/רטמטרא

ןיטטסווזור ,ןיטטסוורפ ,ןיטטסוורטא ( (לורטסלוכ תדרוהל)

תויעבל הנכסה אפורה .תולעל הלולע רירשה תמקרב לורטסלוכ תדרוה רטשמ הזיא קודבי .ךרובע רתויב םיאתמ

;(הקיטויביטנא) ןיצימורטיראלק (

,ביניטולינ ,סומילורוא ,ביניטאסד ( (ןטרסב לופיטל) ןיטסירקניו ,ןיטסלבניו

(דיאורטסוקיטרוק) ןוזינדרפ (

ליפנדרו ,ליפלאדט ,ליפנדליס ( לופיטל וא הפקיזב תויעבב לופיטל) (יתאיר םד ץחל רתייב לש ןונימה תא תונשל ךרוצ היהיו ןכתי העפשההש ןוויכ תואבה תופורתה הטסיזרפ לש וא ןהלש תילופיטה

וא יאוולה תועפות

הלוכי

םילוכי

תונתשהל :ליבקמב תוחקלנ ןה רשאכ

ןתינה באכ ךכשמ) לינטנפלא ( (תויחותינ תורודצורפב שומישבו הקירזב

וא (טואג) ןודגישב לופיטל ) ןיציכלוכ ( ( תיתחפשמ תינוכית םי תחדקב

תומייוסמ תויעבב לופיטל) ןיסקוגיד ( (בלב

,לוזאנוקוטק (

לוזאנוקזופ

,לוזאנוקרטיא ,לוזאמירטולק לוזאנוקירוו ;(םייתיירטפ םימוהיזב לופיטל)

םימוהיזב לופיטל) ןיטובאפיר ( תופסונ תוקידב עצבל

,ןוזאקיטולפ ( לורטמלס

דינוסדוב .(המטסאב לופיטל)

שי דומצ רוטינ תחתו תיאופר הכרעה רחאל קר םהב שמתשהל .םידיאורטסוקיטרוק לש יאוול תועפותל אפורה לש

סיטיטפהב לופיטל) ריוורפמיס (

(המתסאב לופיטל) לורטמלס (

ןיפרונרפוב ןוסקולאנ/

תורכמתהב לופיטל תופורת) (םיטאיפואל

הירלמב לופיטל תבלושמ הפורת (

ןירטנפמול/רטמטרא

(לורטסלוכ תדרוהל) ןיטטסווזור ,ןיטטסוורפ ,ןיטטסוורטא (

קודבי אפורה .תולעל הלולע רירשה תמקרב תויעבל הנכסה .ךרובע רתויב םיאתמ לורטסלוכ תדרוה רטשמ הזיא

;(הקיטויביטנא) ןיצימורטיראלק (

ןיטסירקניו ,ןיטסלבניו ,ביניטולינ ,סומילורוא ,ביניטאסד ( (ןטרסב לופיטל)

(דיאורטסוקיטרוק) ןוזינדרפ (

וא הפקיזב תויעבב לופיטל) ליפנדרו ,ליפלאדט ,ליפנדליס ( (יתאיר םד ץחל רתייב לופיטל ןוויכ תואבה תופורתה לש ןונימה תא תונשל ךרוצ היהיו ןכתי הטסיזרפ לש וא ןהלש תילופיטה העפשההש

תועפות וא יאוולה

הלוכי

םילוכי

:ליבקמב תוחקלנ ןה רשאכ תונתשהל

שומישבו הקירזב ןתינה באכ ךכשמ) לינטנפלא ( (תויחותינ תורודצורפב

תינוכית םי תחדקב וא (טואג) ןודגישב לופיטל ) ןיציכלוכ ( ( תיתחפשמ

(בלב תומייוסמ תויעבב לופיטל) ןיסקוגיד (

,לוזאנוקוטק (

לוזאנוקזופ

,לוזאנוקרטיא ,לוזאמירטולק ;(םייתיירטפ םימוהיזב לופיטל) לוזאנוקירוו

;(םייקדייח םימוהיזב לופיטל) ןיטובאפיר (

-ה םוהיזב לופיטל) קוריוורמ

הפקז תויעבב לופיטל) ליפאלאדאט ,ליפאנדרו ,ליפאנדליס ( יתאיר םד ץחל רתיב לופיטל וא

ןילארטרס ,ןיטסקוראפ (

,ןימרפיזד ,ןיליטפירתימא ןודוזרט ,ןיליטפירטרונ ,ןימארפימיא ;(הדרחו ןואכדב לופיטל)

ןיפזמברק (

םיבאכב לופיטו םייטפליפא םיפקתה תעינמל יבצע רוקממ םינפב

trigeminal neuralgia

ןודאתמ (

(יתאיר םד ץחל רתיב לופיט) ןטנסוב (

,םאפזרולפ ,םאלוזטסא ,םפזאיד ,טאפזרולק ,ןוריפסוב ,הקירזב ןתינה םלוזדימ םפידלוז

;(םייקדייח

-ה םוהיזב לופיטל) קוריוורמ

ליפאלאדאט ,ליפאנדרו ,ליפאנדליס ( הפקז תויעבב לופיטל) רתיב לופיטל וא יתאיר םד ץחל

ןילארטרס ,ןיטסקוראפ (

,ןימארפימיא ,ןימרפיזד ,ןיליטפירתימא ןודוזרט ,ןיליטפירטרונ ןואכדב לופיטל) ;(הדרחו

ןיפזמברק (

םיפקתה תעינמל םינפב םיבאכב לופיטו םייטפליפא יבצע רוקממ

trigeminal neuralgia

ןודאתמ (

(יתאיר םד ץחל רתיב לופיט) ןטנסוב (

,םפזאיד ,טאפזרולק ,ןוריפסוב ,םאפזרולפ ,םאלוזטסא ןתינה םלוזדימ ,הקירזב םפידלוז

לופיטל) ןיזאדירוית ,ןודירפסיר ( (םירטאיכיספ םיבצמב עדיי .תופורת לש האלמ המישר הניא וז ךניהש תופורתה לכל עגונב אפורה תא . לטונ

(םירטאיכיספ םיבצמב לופיטל) ןיזאדירוית ,ןודירפסיר ( לכל עגונב אפורה תא עדיי .תופורת לש האלמ המישר הניא וז . לטונ ךניהש תופורתה ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

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ןמסל

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ןכות

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םייוניש םוקימב

.טסקטה רבעוה

ראודב

ינורטקלא

ךיראתב

...........

14.4.15

.....

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םייונישה

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םייק

ןולע

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השקבל

CPPI MAR 14,

NOV 2014 (EU)

אתכמסאה

.ב"צמ

יונישה

ל"נה

רשוא

לע

ידי

תויושר

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חקורה ,ינא

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J-C Health care Ltd

ריהצמ

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ןיא

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.ןולעב ,היוותה תפסותל השקב תרגסמב ןולע ןוכדע :ןוגכ) תרחא תרגסמב ליבקמב לפוטמ אל הז ןולע .תאז ןייצל שי -תרחא תרגסמב ליבקמ לופיט םייקו הדימב . ('וכו הרמחה תמיתח

חקורה

הנוממה

םש(

הנאיליל___: )המיתחו

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העדוה העדוה

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הרמחה הרמחה

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עדימ עדימ

ןולעב )תוחיטב ןולעב )תוחיטב

ןכרצל ןכרצל

ןכדועמ( ןכדועמ(

05.2013

05.2013

ךיראת

_

14.4.15

_

םש

רישכת

תילגנאב

רפסמו

םושירה

400mg Prezista

םושיר רפסמ

142-12-31999-00

-

Prezista 600mg

םושיר רפסמ

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םושיר רפסמ

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םש

לעב

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J-C HEALTH CARE LTD

.

ספוט

הז

דעוימ

טורפל

תורמחהה

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יחכונ טסקט

שדח

שמתשהל ןיא יתמ

?

רישכתב

םע דחיב הטסיזרפ לוטיל ןיא ( :תואבה תופורתה םלוזאדימ (הפה ךרד חקלנש) תיירשהל) םלוזאירטו תויעבל) דירפאזיס ,(העגרהל וא/ו הניש דיזומיפ ,(לוכיע לודניטרסו לופיטל) ןיטאטסבמיס ,(תויטוכיספ תוערפהב לש תוהובג תומרב לופיטל) ןיטאטסבולו (םדב לורטסלוכ

לופיטל) ןיפמאפיר לופיטל) ןידנפרטו לוזימטסא ;(תפחשב (היגרלא לש םימוטפמיסב

ןיסוזופלא (תלדגומ הטטסורפב לופיטל)

ליפנדליס (יקרוע יתאיר םד ץחל רתיב לופיטל)

ןיאקודילו ,ןידיניק ,לידירפב ,ןורדוימא תוערפהב לופיטל) ימטסיס ןתמב בלושמה רצומה ,(תומיוסמ תויבבל -ל) ריוונוטיר/ריווניפול

ןיפאיטווק , ( הערפה ,הינרפוזיכסב לופיטל) (ירו'גמ ןואכידו תיראלופיב

טב שמתשהל ןיא

עובשב ליפאל ןושארה .הטסיזרפב שומישל קיספהל שי תוחפל ליפאלאדאט תליטנ

תועש .הטסיזרפ תליטנ ינפל

:תואבה תופורתה םע דחיב הטסיזרפ לוטיל ןיא ( םלוזאדימ (הפה ךרד חקלנש) הניש תיירשהל) םלוזאירטו דיזומיפ ,(לוכיע תויעבל) דירפאזיס ,(העגרהל וא/ו לודניטרסו ןיטאטסבולו ןיטאטסבמיס ,(תויטוכיספ תוערפהב לופיטל) (םדב לורטסלוכ לש תוהובג תומרב לופיטל)

ןיפמאפיר םימוטפמיסב לופיטל) ןידנפרטו לוזימטסא ;(תפחשב לופיטל) (היגרלא לש

(תלדגומ הטטסורפב לופיטל) ןיסוזופלא

(יקרוע יתאיר םד ץחל רתיב לופיטל) ליפנדליס ,ןורדוימא , ,לידירפב ןורדנורד ,ןידיניק , ןיזלונר ימטסיס ןתמב ןיאקודילו בלושמה רצומה ,(תומיוסמ תויבבל תוערפהב לופיטל) -ל) ריוונוטיר/ריווניפול

,הינרפוזיכסב לופיטל) ןיפאיטווק , ( ,(ירו'גמ ןואכידו תיראלופיב הערפה תויעבב לופיטל) ליפנווא לופיטל (דבכ וא/ו היילכ תויעב ךל שיו הדימב) ןיציכלוכ ,(הפקיז ןודגישב

םד ילכו בל יעוריאל ןוכיס תתחפהל) רולרגקיט יתלב הזח תקועת רחאל וא בלה רירש םטוא רחאל םילוחב .(הביצי טב שמתשהל ןיא

ןושארה עובשב ליפאל שומישל .הטסיזרפב תוחפל ליפאלאדאט תליטנ קיספהל שי

תועש .הטסיזרפ תליטנ ינפל

יחמצה ףסותה תא םיליכמה םירישכת (

St. John's Wort

(םוטרופרפ םוקירפיה)

תופורת

םידיאולקלא טוגראה תחפשממ גראורדיהיד ,ןימטוגרא ומכ

,ןימט ןירטמוגרא ןיוונוגראליתמו

ףסותה תא םיליכמה םירישכת ( יחמצה

St. John's Wort

םוקירפיה) (םוטרופרפ

תופורת

טוגראה תחפשממ ,ןימטוגרא ומכ םידיאולקלא גראורדיהיד

,ןימט ןירטמוגרא ןיוונוגראליתמו

יבאכו הנרגימב לופיטל) (שאר

(שאר יבאכו הנרגימב לופיטל)

ןיב תובוגת

:

תויתופורת תחקל םא וא ,חקול התא םא ללוכ תורחא תופורת ,הנורחאל ,הנוזת יפסותו םשרמ אלל תופורת חקורל וא אפורל ךכ לע רפס

םע דחיב לוטיל רוסא רשא תופורת ןנשי ןיא " ףיעסב תוטרופמ ןה .הטסיזרפ שמתשהל

הפורתב

םא

."

תופורתב שומיש יבגל אפורב ץעוויהל שי תליטנ .הטסיזרפ םע דחי תואבה הלולע ולא תופורת םע דחי הטסיזרפ ךרוצ היהיו ןכתייו ןתעפשה תא תונשל .ןנונימ תא תונשל

לופיטל) ןיזאדירוית ,ןודירפסיר ( .(הינרפוזיכסב

(ןואכידב לופיטל) ןימרפיזד ,ןודוזאר

ץחלב לופיטל) לולומית , לולורפוטמ ( (בל תויעבו םד

תודגונ תופורתה לכ אל (

.הטסיזרפ םע דחיב בולישל תומיאתמ םע אדוול שי

תא בלשל ןתינש אפורה תודגונ תופורתה

התאש תופסונה .הטסיזרפ םע לבקמ תוליעיה תא דירוהל תולולעה תופורת :הטסיזרפ לש

.(דיאורטס) ןוזאתמסקד (

לופיטל) ,ןיאותינפ ,לטיברבונפ ( ;(היספליפאב -ה םוהיזב לופיטל) זנריוופא

םוהיזב לופיטל) ריוורפסוב ,ריוורפלט גוסמ תיפיגנ תבהצ

-ה םוהיזב לופיטל) ריווניווקס

תורחא תופורת ,הנורחאל תחקל םא וא ,חקול התא םא אפורל ךכ לע רפס ,הנוזת יפסותו םשרמ אלל תופורת ללוכ חקורל וא

תוטרופמ ןה .הטסיזרפ םע דחיב לוטיל רוסא רשא תופורת ןנשי ןיא " ףיעסב

שמתשהל

הפורתב

םא

."

םע דחי תואבה תופורתב שומיש יבגל אפורב ץעוויהל שי תונשל הלולע ולא תופורת םע דחי הטסיזרפ תליטנ .הטסיזרפ .ןנונימ תא תונשל ךרוצ היהיו ןכתייו ןתעפשה תא

.(הינרפוזיכסב לופיטל) ןיזאדירוית ,ןודירפסיר (

(ןואכידב לופיטל) ןימרפיזד ,ןודוזאר

(בל תויעבו םד ץחלב לופיטל) לולומית , לולורפוטמ (

תודגונ תופורתה לכ אל (

םע דחיב בולישל תומיאתמ םע אדוול שי .הטסיזרפ

תופורתה תא בלשל ןתינש אפורה תודגונ

.הטסיזרפ םע לבקמ התאש תופסונה :הטסיזרפ לש תוליעיה תא דירוהל תולולעה תופורת

.(דיאורטס) ןוזאתמסקד (

;(היספליפאב לופיטל) ,ןיאותינפ ,לטיברבונפ ( -ה םוהיזב לופיטל) זנריוופא

גוסמ תיפיגנ תבהצ םוהיזב לופיטל) ריוורפסוב ,ריוורפלט

-ה םוהיזב לופיטל) ריווניווקס

(תפחש ןוגכ םימייוסמ םימוהיזב לופיטל) ןיטובפיר ,ןיטנפאפיר לטונ התא םא תונתשהל הלולע תואבה תופורת לש העפשהה :הטסיזרפ

יאקלפ ,ןיפידרקינ ,ןיפידפינ ,ןיפידולפ דינ ןונפאפורפ ,

,לולורפוטמ ,לולידוורק ,דימאריפוזיד ,םזאיטליד ,ןיפידולמא לימפרו ,לולומיט ,ןיטליסקמ

;(בל תויעבב לופיטל)

רחאמ .תולעל םילולע ולא תופורת לש יאוולה תועפות וא העפשההו

ןאבסקורביר ,טאליסקטא ןארטאגיבד ,ןאבסקיפא

ןירפאוו ;(השירק תויעבב לופיטל) העפשהה וא םהלש יאוולה תועפות הלולע תואבה תופורת לש העפשהה :הטסיזרפ לטונ התא םא תונתשהל

,ןיפידרקינ ,ןיפידפינ ,ןיפידולפ יאקלפ דינ ןונפאפורפ ,

תויעבב לופיטל) ;(בל

;(השירק תויעבב לופיטל) ןירפאוו

ןגורטסא םיליכמה םירישכת לופיטכו ןוירה תעינמל םישמשמה .יפולח ילנומרוה הטסיזרפש ןוויכמ םתוליעיב עוגפל הלולע

שי עוויהל

ףסונ העינמ יעצמאב שומיש יבגל אפורב םיילנומרוה אל ;(םימודנוק ןוגכ)

סומילוריס ,סומילורקט ,ןירופסולקיצ ( תינוסיחה תכרעמב תויעבב לופיטל)

תוקידב עצבל ךרטצי אפורהו ןכתי תופסונ

לורטמלס ,ןוזאקיטולפ ( דינוסדוב, .(המטסאב לופיטל)

ןיפרונרפוב ןוסקולאנ/

תופורת) (םיטאיפואל תורכמתהב לופיטל

הירלמב לופיטל תבלושמ הפורת (

ןירטנפמול/רטמטרא

ןיטטסווזור ,ןיטטסוורפ ,ןיטטסוורטא ( (לורטסלוכ תדרוהל)

תויעבל הנכסה אפורה .תולעל הלולע רירשה תמקרב לורטסלוכ תדרוה רטשמ הזיא קודבי .ךרובע רתויב םיאתמ

;(הקיטויביטנא) ןיצימורטיראלק (

,ביניטולינ ,סומילורוא ,ביניטאסד ( (ןטרסב לופיטל) ןיטסירקניו ,ןיטסלבניו

(דיאורטסוקיטרוק) ןוזינדרפ (

ליפנדרו ,ליפלאדט ,ליפנדליס ( לופיטל וא הפקיזב תויעבב לופיטל) (יתאיר םד ץחל רתייב לש ןונימה תא תונשל ךרוצ היהיו ןכתי העפשההש ןוויכ תואבה תופורתה הטסיזרפ לש וא ןהלש תילופיטה

וא יאוולה תועפות

הלוכי

םילוכי

תונתשהל .םד תקידב עצבל ךרטצי אפורה .תונתשהל הלולע םהלש

ןוירה תעינמל םישמשמה ןגורטסא םיליכמה םירישכת .יפולח ילנומרוה לופיטכו

ש ןוויכמ עוגפל הלולע הטסיזרפ םתוליעיב

אל תוטיש ,ןוירה תעינמל םישמשמ םירישכתה רשאכ תוצלמומ ןוירה תעינמל (םימודנוק ןוגכ) תוילנומרוה

שי עוויהל

העינמ יעצמאב שומיש יבגל אפורב ףסונ

אל ילנומרוה

;(םימודנוק ןוגכ)

סומילורווא

לופיטל) סומילוריס ,סומילורקט ,ןירופסולקיצ תינוסיחה תכרעמב תויעבב

תועפות וא העפשההו רחאמ תולעל םילולע הלא תופורת לש יאוולה

ךרטצי אפורהו ןכתי תופסונ תוקידב עצבל

,ןוזאקיטולפ ( לורטמלס

דינוסדוב .(המטסאב לופיטל)

שי דומצ רוטינ תחתו תיאופר הכרעה רחאל קר םהב שמתשהל .םידיאורטסוקיטרוק לש יאוול תועפותל אפורה לש

סיטיטפהב לופיטל) ריוורפמיס (

(המתסאב לופיטל) לורטמלס (

ןיפרונרפוב ןוסקולאנ/

תורכמתהב לופיטל תופורת) (םיטאיפואל

הירלמב לופיטל תבלושמ הפורת (

ןירטנפמול/רטמטרא

(לורטסלוכ תדרוהל) ןיטטסווזור ,ןיטטסוורפ ,ןיטטסוורטא (

קודבי אפורה .תולעל הלולע רירשה תמקרב תויעבל הנכסה .ךרובע רתויב םיאתמ לורטסלוכ תדרוה רטשמ הזיא

;(הקיטויביטנא) ןיצימורטיראלק (

ןיטסירקניו ,ןיטסלבניו ,ביניטולינ ,סומילורוא ,ביניטאסד ( (ןטרסב לופיטל)

(דיאורטסוקיטרוק) ןוזינדרפ (

וא הפקיזב תויעבב לופיטל) ליפנדרו ,ליפלאדט ,ליפנדליס ( (יתאיר םד ץחל רתייב לופיטל ןוויכ תואבה תופורתה לש ןונימה תא תונשל ךרוצ היהיו ןכתי הטסיזרפ לש וא ןהלש תילופיטה העפשההש

תועפות וא יאוולה

הלוכי

םילוכי

:ליבקמב תוחקלנ ןה רשאכ תונתשהל

שומישבו הקירזב ןתינה באכ ךכשמ) לינטנפלא ( (תויחותינ תורודצורפב

תינוכית םי תחדקב וא (טואג) ןודגישב לופיטל ) ןיציכלוכ ( ( תיתחפשמ

(בלב תומייוסמ תויעבב לופיטל) ןיסקוגיד (

,לוזאנוקוטק (

לוזאנוקזופ

,לוזאנוקרטיא ,לוזאמירטולק ;(םייתיירטפ םימוהיזב לופיטל) לוזאנוקירוו

;(םייקדייח םימוהיזב לופיטל) ןיטובאפיר ( :ליבקמב תוחקלנ ןה רשאכ

ןתינה באכ ךכשמ) לינטנפלא ( (תויחותינ תורודצורפב שומישבו הקירזב

וא (טואג) ןודגישב לופיטל ) ןיציכלוכ ( ( תיתחפשמ תינוכית םי תחדקב

תומייוסמ תויעבב לופיטל) ןיסקוגיד ( (בלב

,לוזאנוקוטק (

לוזאנוקזופ

,לוזאנוקרטיא ,לוזאמירטולק לוזאנוקירוו ;(םייתיירטפ םימוהיזב לופיטל)

םימוהיזב לופיטל) ןיטובאפיר ( ;(םייקדייח

-ה םוהיזב לופיטל) קוריוורמ

ליפאלאדאט ,ליפאנדרו ,ליפאנדליס ( הפקז תויעבב לופיטל) רתיב לופיטל וא יתאיר םד ץחל

ןילארטרס ,ןיטסקוראפ (

,ןימארפימיא ,ןימרפיזד ,ןיליטפירתימא ןודוזרט ,ןיליטפירטרונ ןואכדב לופיטל) ;(הדרחו

ןיפזמברק (

םיפקתה תעינמל םינפב םיבאכב לופיטו םייטפליפא יבצע רוקממ

trigeminal neuralgia

ןודאתמ (

(יתאיר םד ץחל רתיב לופיט) ןטנסוב (

,םפזאיד ,טאפזרולק ,ןוריפסוב ,םאפזרולפ ,םאלוזטסא ןתינה םלוזדימ ,הקירזב םפידלוז

לופיטל) ןיזאדירוית ,ןודירפסיר ( (םירטאיכיספ םיבצמב עדיי .תופורת לש האלמ המישר הניא וז ךניהש תופורתה לכל עגונב אפורה תא . לטונ

-ה םוהיזב לופיטל) קוריוורמ

הפקז תויעבב לופיטל) ליפאלאדאט ,ליפאנדרו ,ליפאנדליס ( יתאיר םד ץחל רתיב לופיטל וא

ןילארטרס ,ןיטסקוראפ (

,ןימרפיזד ,ןיליטפירתימא ןודוזרט ,ןיליטפירטרונ ,ןימארפימיא ;(הדרחו ןואכדב לופיטל)

ןיפזמברק (

םיבאכב לופיטו םייטפליפא םיפקתה תעינמל יבצע רוקממ םינפב

trigeminal neuralgia

ןודאתמ (

(יתאיר םד ץחל רתיב לופיט) ןטנסוב (

,םאפזרולפ ,םאלוזטסא ,םפזאיד ,טאפזרולק ,ןוריפסוב ,הקירזב ןתינה םלוזדימ םפידלוז

(םירטאיכיספ םיבצמב לופיטל) ןיזאדירוית ,ןודירפסיר ( לכל עגונב אפורה תא עדיי .תופורת לש האלמ המישר הניא וז . לטונ ךניהש תופורתה ב"צמ

ובש ,ןולעה

נמוסמ תו

תורמחהה

תושקובמה

לע

עקר

בוהצ

םייוניש

םניאש

רדגב

תורמחה

ונמוס

ןולעב עבצב )

שי .הנוש

ןמסל

קר

ןכות

יתוהמ

אלו

םייוניש םוקימב

.טסקטה רבעוה

ראודב

ינורטקלא

ךיראתב

...........

14.4.15

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