ACTEMRA 20MGML I.V.

Israel - English - Ministry of Health

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Active ingredient:
TOCILIZUMAB
Available from:
ROCHE PHARMACEUTICALS (ISRAEL) LTD
ATC code:
L04AC07
Pharmaceutical form:
CONCENTRATE FOR SOLUTION FOR INFUSION
Composition:
TOCILIZUMAB 20 MG/ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
HOFFMANN LA ROCHE LTD, SWITZERLAND
Therapeutic group:
TOCILIZUMAB
Therapeutic area:
TOCILIZUMAB
Therapeutic indications:
Actemra (tocilizumab), is indicated for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis who had an inadequate response to one or more DMARDs(Disease Modifying Anti-Rheumatic Drugs) or TNF antagonists or in whom DMARDs cannot be used. Actemra can be used alone or in combination with methotrexate or other DMARDs. Actemra has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate. Actemra is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older. Actemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic polyarthritis (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. Actemra can be given as monotherapy in case of intolerance to MTX or where
Authorization number:
142 21 31931 00
Authorization date:
2014-12-31

Roche Pharmaceuticals (Israel) Ltd

Drugs regulatory affairs

Hacharash St.

P.O.B. 6391

Hod Hasharon 4524079

Tel. + 972-9-9737777

Fax + 972-9-9737850

רבמצד

2019

,ה/רקי ה/אפור

,ה/רקי ת/חקו

לע םכעידוהל תשקבמ מ"עב )לארשי( הקיטבצמרפ שור תרבח אפורל ןולעב ועצובש םינוכדע רפסמ רישכתה לש

צמ וז העדוהב .הרמחה םיווהמ רשא םינוכדעו םייתוהמ םינוכדע קר םיניו

יוותהה תו

מושרה תו

ל

רישכת :לארשיב

Actemra (tocilizumab) is indicated for reducing signs and symptoms in adult patients with

moderately to severely active rheumatoid arthritis who had an inadequate response to

one or more DMARDs (Disease Modifying Anti-Rheumatic Drugs) or TNF antagonists or

in whom DMARDs cannot be used. Actemra can be used alone or in combination with

methotrexate or other DMARDs.

Actemra has been shown to reduce the rate of progression of joint damage as measured

by X-ray and to improve physical function when given in combination with methotrexate.

Actemra is indicated for the treatment of active systemic juvenile idiopathic arthritis in

patients 2 years of age and older.

Actemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile

idiopathic polyarthritis (rheumatoid factor positive or negative and extended oligoarthritis)

in patients 2 years of age and older, who have responded inadequately to previous

therapy with MTX.

Actemra can be given as monotherapy in case of intolerance to MTX or where continued

treatment with MTX is inappropriate.

Actemra in combination with methotrexate (MTX) in indicated for the treatment of severe,

active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX.

:רבסה

יתחת וק םע טסקט

.ןולעל ףסוהש טסקט ןייצמ

הצוח וק םע טסקט

.ןולעה ןמ רסוהש טסקט ןייצמ

ל ןולעב ןייעל שי ףסונ עדימל אפור

יפכ חלשנש

תואירבה דרשמ

ולעה

כדועמה

חלשנ

דרשמ רתאבש תופורתה רגאמב םוסרפל לבקל ןתינו ,תואירבה

ספדומ םי

י"ע

ד.ת ,מ"עב )לארשי( הקיטבצמרפ שור :םושירה לעבל היינפ

6391

ןורשה דוה ,

4524079

ןופלט

09-9737777

:טנרטניאב ונתבותכ .

www.roche.co.il

טורבסיו לטיבא

ימע איבל

דע

םושיר תקלחמ

הנוממ חקור

.

20 mg/ml I.V

®

Actemra

הרמטקא

20

ל"מ/ג"מ

I.V.

tocilizumab

Concentrate for solution for infusion

Actemra 20 mg/ml I.V.

Page 1 of 1

ןולעב םייתוהמ םינוכדע

ל

אפור

ףיעסב

4.4 Special warnings and precautions for use

ןכדוע אבה עדימה

:

Hepatic transaminase elevations

Hepatotoxicity

Transient In clinical trials, transient or intermittent mild and moderate elevations of hepatic

transaminases have been reported commonly with Actemra treatment, without progression to

hepatic injury (see section 4.8). An increased frequency of these elevations was observed when

potentially hepatotoxic drugs (e.g. MTX) were used in combination with Actemra. When

clinically indicated, other liver function tests including bilirubin should be considered.

Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have

been observed with Actemra (see section 4.8). Serious hepatic injury occurred between 2 weeks

to more than 5 years after initiation of Actemra. Cases of liver failure resulting in liver

transplantation have been reported. Patients should be advised to immediately seek medical

help if they experience signs and symptoms of hepatic injury.

Caution should be exercised when considering initiation of Actemra treatment in patients with

elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x ULN,

treatment is not recommended.

In RA, pJIA and sJIA patients, ALT and /AST levels should be monitored every 4 to 8 weeks

for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended

modifications, including Actemra discontinuation, based on transaminases levels see section

4.2. For ALT or AST elevations > 3–5 x ULN, confirmed by repeat testing, Actemra treatment

should be interrupted .

In sJIA and pJIA patients, ALT and AST levels should be monitored at the time of the second

infusion and thereafter according to good clinical practice, see section 4.2.

ףיעסב

4.8 Undesirable Effects

ןכדוע אבה עדימה

:

Table 1. List of ADRs occurring in patients with RA receiving tocilizumab as monotherapy or

in combination with MTX or other DMARDs in the double-blind controlled period or

during postmarketing experience

MedDRA

System Organ

Class

Frequency categories with preferred terms

Very Common

Common

Uncommon

Rare

Skin and

subcutaneous

tissue disorders

Rash, Pruritus,

Urticaria

Stevens-Johnson-Syndrome

Immune system

disorders

Anaphylaxis (fatal)

1, 2 ,3

Hepatobiliary

disorders

Drug-induced liver injury,

Hepatitis, Jaundice,

Very rare: Hepatic failure

* Includes elevations collected as part of routine laboratory monitoring (see text below)

See section 4.3

See section 4.4

This adverse reaction was identified through post marketing surveillance but not observed in controlled clinical trials.

The frequency category was estimated as the upper limit of the 95% confidence interval calculated on the basis of the

total number of patients exposed to TCZ in clinical trials.

Actemra 20 mg/ml I.V.

Page 2 of 1

[…]

Hepatic

transaminase elevations

During the 6-month controlled trials transient elevations in ALT/AST > 3 x ULN were

observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX

and in 6.5% of patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5% of

patients on placebo plus DMARDs.

The addition of potentially hepatotoxic drugs (e.g. MTX) to tocilizumab monotherapy resulted

in increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed

in 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab plus DMARD patients,

the majority of whom were discontinued permanently from tocilizumab treatment. These

elevations were not associated with clinically relevant increase in direct bilirubin, nor were they

associated with clinical evidence of hepatitis or hepatic impairment. During the double-blind

controlled period, the incidence of indirect bilirubin greater than the upper limit of normal,

collected as a routine laboratory parameter, is 6.2% in patients treated with 8 mg/kg

tocilizumab + DMARD. A total of 5.8% of patients experienced an elevation of indirect

bilirubin of > 1 to 2 x ULN and 0.4% had an elevation of > 2 x ULN

[…]

Skin Reactions

Very rare Rare reports of Stevens-Johnson Syndrome have occurred in the post marketing

setting.

[…]

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product.

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

National Regulation by using an online form : /https://sideeffects.health.gov.il

ic@moh.gov.il

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

EMEA/H/C/000955/II/II/97 (08.2020)

Actemra IV_PI_Ver 9.0

Actemra IV_PI_Ver 9.0

Actemra 20mg/ml I.V.

®

TOCILIZUMAB

Concentrate for solution for infusion

1.

NAME OF THE MEDICINAL PRODUCT

Actemra 20 mg/ mL concentrate for solution for infusion.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL concentrate contains 20 mg tocilizumab*.

Each vial contains 80 mg of tocilizumab* in 4 mL (20 mg/ mL).

Each vial contains 200 mg of tocilizumab* in 10 mL (20 mg/mL).

Each vial contains 400 mg of tocilizumab* in 20 mL (20 mg/mL).

*humanised IgG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor produced in

Chinese hamster ovary (CHO) cells by recombinant DNA technology.

Excipients with known effects

Each 80 mg vial contains 0.10 mmol (2.21 mg) sodium.

Each 200 mg vial contains 0.20 mmol (4.43 mg) sodium.

Each 400 mg vial contains 0.39 mmol (8.85 mg) sodium.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

Clear to opalescent, colourless to pale yellow solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Actemra (tocilizumab) is indicated for reducing signs and symptoms in adult patients with moderately

to severely active rheumatoid arthritis who had an inadequate response to one or more DMARDs

(Disease Modifying Anti-Rheumatic Drugs) or TNF antagonists or in whom DMARDs cannot be

used. Actemra can be used alone or in combination with methotrexate or other DMARDs.

Actemra has been shown to reduce the rate of progression of joint damage as measured by X-ray and

to improve physical function when given in combination with methotrexate.

Actemra is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2

years of age and older.

Actemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic

polyarthritis (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of

age and older, who have responded inadequately to previous therapy with MTX.

Actemra can be given as monotherapy in case of intolerance to MTX or where continued treatment

with MTX is inappropriate.

Actemra in combination with methotrexate (MTX) in indicated for the treatment of severe, active and

progressive rheumatoid arthritis (RA) in adults not previously treated with MTX.

ctemra is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or

life-threatening cytokine release syndrome (CRS) in adults and paediatric patients 3 years of age and

older.

4.2

Posology and method of administration

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment

of RA, sJIA, pJIA or CRS.

Posology

RA Patients

The recommended posology is 8 mg/kg body weight, given once every four weeks.

For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not

recommended (see section 5.2).

Doses above 1.2 g have not been evaluated in clinical studies (see section 5.1).

Dose adjustments due to laboratory abnormalities (see section 4.4).

Liver enzyme abnormalities

Laboratory Value

Action

> 1 to 3 x Upper

Limit

Normal

(ULN)

Modify the dose of the concomitant MTX if appropriate

For persistent increases in this range, reduce Actemra dose to 4 mg/kg or

interrupt

Actemra

until

alanine

aminotransferase

(ALT)

aspartate

aminotransferase (AST)

have normalised

Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate

> 3 to 5 x ULN

(confirmed by

repeat testing, see

section 4.4).

Interrupt Actemra dosing until < 3 x ULN and follow recommendations above

for > 1 to 3 x ULN

For persistent increases > 3 x ULN, discontinue Actemra

> 5 x ULN

Discontinue Actemra

Low absolute neutrophil count (ANC)

In patients not previously treated with

Actemra, initiation is not recommended in patients with an absolute

neutrophil count (ANC) below 2 x 10

Laboratory Value

(cells x 10

/ l )

Action

ANC > 1

Maintain dose

ANC 0.5 to 1

Interrupt Actemra dosing

When ANC increases > 1 x 10

/ l resume Actemra at 4 mg/kg and increase to

8 mg/kg as clinically appropriate

ANC < 0.5

Discontinue Actemra

Low platelet count

Laboratory Value

(cells x 10

/ μL)

Action

50 to 100

Interrupt Actemra dosing

When platelet count > 100 x 10

/μl resume Actemra at 4 mg/kg and increase to

8 mg/kg as clinically appropriate

< 50

Discontinue Actemra

Cytokine Release Syndrome (CRS) (adults and paediatrics)

The recommended posology for treatment of CRS given as a 60-minute intravenous infusion is

8 mg/kg in patients weighing greater than or equal to 30 kg or 12 mg/kg in patients weighing less than

30 kg. Actemra can be given alone or in combination with corticosteroids.

If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3

additional doses of Actemra may be administered. The interval between consecutive doses should be

at least 8 hours. Doses exceeding 800 mg per infusion are not recommended in CRS patients.

Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due

to the underlying malignancy, preceding lymphodepleting chemotherapy or the CRS.

Special populations

Paediatric patients

sJIA Patients

The recommended posology in patients above 2 years of age is 8 mg/kg once every 2 weeks in

patients weighing greater than or equal to 30 kg or 12 mg/kg once every 2 weeks in patients weighing

less than 30 kg. The dose should be calculated based on the patient’s body weight at each

administration. A change in dose should only be based on a consistent change in the patient’s body

weight over time.

The safety and efficacy of

intravenous Actemra in children below 2 years of age has not been

established.

Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in sJIA

patients in the tables below. If appropriate, the dose of concomitant MTX and/or other medications

should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation

has been evaluated. As there are many co-morbid conditions that may affect laboratory values in sJIA,

the decision to discontinue tocilizumab for a laboratory abnormality shou

ld be based upon the medical

assessment of the individual patient.

Liver enzyme abnormalities

Laboratory Value

Action

> 1 to 3 x ULN

Modify the dose of the concomitant MTX if appropriate

For persistent increases in this range, interrupt Actemra until ALT/AST have

normalized.

> 3 x ULN to 5x ULN

Modify the dose of the concomitant MTX if appropriate

Interrupt Actemra dosing until < 3x ULN and follow recommendations

above for >1 to 3x ULN

> 5x ULN

Discontinue Actemra.

The decision to discontinue Actemra in sJIA for a laboratory abnormality

should be based on the medical assessment of the individual patient.

Low absolute neutrophil count (ANC)

Laboratory Value

(cells x 10

9

/ l )

Action

ANC > 1

Maintain dose

ANC 0.5 to 1

Interrupt Actemra dosing

When ANC increases to > 1 x 10

/ l resume Actemra

ANC < 0.5

Discontinue Actemra

The decision to discontinue Actemra in sJIA for a laboratory abnormality

should be based on the medical assessment of the individual patient.

Low platelet count

Laboratory Value

(cells x 10

3

/

l)

Action

50 to 100

Modify the dose of the concomitant MTX if appropriate

Interrupt Actemra dosing

When platelet count is > 100 x 10

l resume Actemra

< 50

Discontinue Actemra.

The decision to discontinue Actemra in sJIA for a laboratory abnormality

should be based on the medical assessment of the individual patient.

There are insufficient clinical data to assess the impact of a tocilizumab dose reduction in sJIA

patients who have experienced laboratory abnormalities.

Available data suggest that clinical improvement is observed within 6 weeks of initiation of treatment

with Actemra. Continued therapy should be carefully reconsidered in a patient exhibiting

no improvement within this timeframe.

pJIA Patients

The recommended posology in patients above 2 years of age is 8 mg/kg once every 4 weeks in

patients weighing greater than or equal to 30 kg or 10 mg/kg once every 4 weeks in patients weighing

less than 30 kg. The dose should be calculated based on the patient’s body weight at each

administration. A change in dose should only be based on a consistent change in the patient’s body

weight over time.

The safety and efficacy of intravenous Actemra in children below 2 years of age has not been established.

Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in pJIA

patients in the tables below. If appropriate, the dose of concomitant MTX and/or other medications

should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation

has been evaluated. As there are many co-morbid conditions that may effect laboratory values in pJIA,

the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical

assessment of the individual patient.

Liver enzyme abnormalities

Laboratory Value

Action

> 1 to 3 x ULN

Modify the dose of the concomitant MTX if appropriate

persistent

increases

this

range,

interrupt

Actemra

until

ALT/AST have normalized.

> 3 x ULN to 5x ULN

Modify the dose of the concomitant MTX if appropriate

Interrupt Actemra dosing until < 3x ULN and follow recommendations

above for >1 to 3x ULN

> 5x ULN

Discontinue Actemra.

decision

discontinue

Actemra

pJIA

laboratory

abnormality

should

based

medical

assessment

individual patient.

Low absolute neutrophil count (ANC)

Laboratory Value

(cells x 10

9

/ l )

Action

ANC > 1

Maintain dose

ANC 0.5 to 1

Interrupt Actemra dosing

When ANC increases to > 1 x 10

/ l resume Actemra

ANC < 0.5

Discontinue Actemra

The decision to discontinue Actemra in pJIA for a laboratory

abnormality should be based on the medical assessment of the

individual patient.

Low platelet count

Laboratory Value

(cells x 10

3

/

l)

Action

50 to 100

Modify the dose of the concomitant MTX if appropriate

Interrupt Actemra dosing

When platelet count is > 100 x 10

l resume Actemra

< 50

Discontinue Actemra.

decision

discontinue

Actemra

pJIA

laboratory

abnormality

should

based

medical

assessment

individual patient.

Reduction of tocilizumab dose due to laboratory abnormalities has not been studied in pJIA patients.

Available data suggest that clinical improvement is observed within 12 weeks of initiation of treatment

with Actemra. Continued therapy should be carefully reconsidered in a patient exhibiting no

improvement within this timeframe.

Elderly

No dose adjustment is required in elderly patients >65 years of age.

Renal impairment

No dose adjustment is required in patients with mild renal impairment. Actemra has not been studied

in patients with moderate to severe renal impairment (see section 5.2). Renal function should be

monitored closely in these patients.

Hepatic impairment

Actemra has not been studied in patients with hepatic impairment. Therefore, no dose

recommendations can be made.

Method of administration

After dilution, Actemra for RA, sJIA, pJIA, and CRS patients should be administered as an

intravenous infusion over 1 hour.

RA, sJIA, pJIA and CRS Patients ≥ 30 kg

Actemra should be diluted to a final volume of 100 mL with sterile, non-pyrogenic sodium chloride

9 mg/ mL (0.9%) solution for injection using aseptic technique.

For instructions on dilution of the medicinal product before administration, see section 6.6.

sJIA,pJIA and CRS Patients < 30 kg

Actemra should be diluted to a final volume of 50 mL with sterile, non-pyrogenic sodium chloride

9 mg/ mL (0.9%) solution for injection using aseptic technique.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3

Contraindications

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

Active, severe infections (see section 4.4).

4.4

Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name of the administered

product should be clearly recorded.

Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive

agents including Actemra (see section 4.8, undesirable effects). Actemra treatment must not be

initiated in patients with active infections (see section 4.3). Administration of Actemra should be

interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8).

Healthcare professionals should exercise caution when considering the use of Actemra in patients with

a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes

and interstitial lung disease which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receiving

biological treatments for moderate to severe RA, sJIA or pJIA as signs and symptoms of acute

inflammation may be lessened, associated with suppression of the acute phase reaction. The effects of

tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be

considered when evaluating a patient for a potential infection. Patients (which includes younger

children with sJIA or pJIA who may be less able to communicate their symptoms) and

parents/guardians of sJIA or pJIA patients, should be instructed to contact their healthcare professional

immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and

appropriate treatment.

Tuberculosis

As recommended for other biological treatments, RA, sJIA and pJIA patients should be screened for

latent tuberculosis (TB) infection prior to starting Actemra therapy. Patients with latent TB should be

treated with standard anti-mycobacterial therapy before initiating Actemra. Prescribers are reminded

of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in

patients who are severely ill or immunocompromised.

Patients should be instructed to seek medical advice if signs/symptoms (e.g., persistent cough,

wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after

therapy with Actemra.

Viral reactivation

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical

studies with tocilizumab, patients who screened positive for hepatitis were excluded.

Complications of diverticulitis

Events of diverticular perforations as complications of diverticulitis have been reported uncommonly

with Actemra in RA patients (see section 4.8). Actemra should be used with caution in patients with

previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially

indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained

change in bowel habits with fever should be evaluated promptly for early identification of

diverticulitis which can be associated with gastrointestinal perforation.

Hypersensitivity reactions

Serious hypersensitivity reactions have been reported in association with infusion of Actemra (see

section 4.8). Such reactions may be more severe, and potentially fatal in patients who have

experienced hypersensitivity reactions during previous infusions even if they have received

premedication with steroids and antihistamines. Appropriate treatment should be available for

immediate use in the event of an anaphylactic reaction during treatment with Actemra. If an

anaphylactic reaction or other serious hypersensitivity / serious infusion related reaction occurs,

administration of Actemra should be stopped immediately and Actemra should be permanently

discontinued.

Active hepatic disease and hepatic impairment

Treatment with Actemra, particularly when administered concomitantly with MTX, may be associated

with elevations in hepatic transaminases, therefore, caution should be exercised when considering

treatment of patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).

Hepatotoxicity

Transient or intermittent mild and moderate elevations of hepatic transaminases have been reported

commonly with Actemra treatment (see section 4.8). An increased frequency of these elevations was

observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with Actemra.

When clinically indicated, other liver function tests including bilirubin should be considered.

Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been

observed with Actemra (see section 4.8). Serious hepatic injury occurred between 2 weeks to more

than 5 years after initiation of Actemra. Cases of liver failure resulting in liver transplantation have

been reported. Patients should be advised to immediately seek medical help if they experience signs

and symptoms of hepatic injury.

Caution should be exercised when considering initiation of Actemra treatment in patients with

elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x ULN, treatment is not

recommended.

In RA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the first 6

months of treatment followed by every 12 weeks thereafter. For recommended modifications,

including Actemra discontinuation, based on transaminases levels see section 4.2. For ALT or AST

elevations > 3–5 x ULN, confirmed by repeat testing, Actemra treatment should be interrupted.

Haematological abnormalities

Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab

8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in

patients who have previously been treated with a TNF antagonist.

In patients not previously treated with Actemra, initiation is not recommended in patients with an

absolute neutrophil count (ANC) below 2 x 10

/l. Caution should be exercised when considering

initiation of Actemra treatment in patients with a low platelet count (i.e. platelet count below

100 x 10

/ μL). In patients who develop an ANC < 0.5 x 10

/ l or a platelet count < 50 x 10

/ μL,

continued treatment is not recommended.

Severe neutropenia may be associated with an increased risk of serious infections, although there has

been no clear association between decreases in neutrophils and the occurrence of serious infections in

clinical trials with Actemra to date.

In RA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and

thereafter according to standard clinical practice. For recommended dose modifications based on ANC

and platelet counts, see section 4.2.

In sJIA and pJIA patients, neutrophils and platelets should be monitored at the time of second infusion

and thereafter according to good clinical practice, see section 4.2.

Lipid parameters

Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density

lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (see

section 4.8). In the majority of patients, there was no increase in atherogenic indices, and elevations in

total cholesterol responded to treatment with lipid lowering agents.

In sJIA, pJIA and RA patients, assessment of lipid parameters should be performed 4 to 8 weeks

following initiation of Actemra therapy. Patients should be managed according to local clinical

guidelines for management of hyperlipidaemia.

Neurological disorders

Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating

disorders. The potential for central demyelination with Actemra is currently unknown.

Malignancy

The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may

increase the risk of malignancy.

Vaccinations

Live and live attenuated vaccines should not be given concurrently with Actemra as clinical safety has

not been established. In a randomized open-label study, adult RA patients treated with Actemra and

MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide

and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is

recommended that all patients, particularly sJIA and pJIA patients, be brought up to date with all

immunisations in agreement with current immunisation guidelines prior to initiating Actemra therapy.

The interval between live vaccinations and initiation of Actemra therapy should be in accordance with

current vaccination guidelines regarding immunosuppressive agents.

Cardiovascular risk

RA patients have an increased risk for cardiovascular disorders and should have risk factors

(e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.

Combination with TNF antagonists

There is no experience with the use of Actemra with TNF antagonists or other biological treatments

for RA, sJIA or pJIA patients. Actemra is not recommended for use with other biological agents.

Sodium

This medicinal product contains 1.17 mmol (or 26.55 mg) sodium per maximum dose of 1200 mg. To

be taken into consideration by patients on a controlled sodium diet. Doses below 1025 mg of this

medicinal product contain less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium free’.

Paediatric population

sJIA Patients

Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA

patients. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.

4.5

Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once

weekly had no clinically significant effect on MTX exposure.

Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-

inflammatory drugs (NSAIDs) or corticosteroids on tocilizumab clearance.

The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate

chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory

therapy, such as tocilizumab, is introduced.

In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in

CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Tocilizumab normalises expression

of these enzymes.

In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following

a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy

subjects.

When starting or stopping therapy with tocilizumab, patients taking medicinal products which are

individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. . methylprednisolone,

dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin,

calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or

benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic

effect. Given its long elimination half-life (t

), the effect of tocilizumab on CYP450 enzyme activity

may persist for several weeks after stopping therapy.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential must use effective contraception during and up to 3 months after

treatment.

Pregnancy

There are no adequate data from the use of tocilizumab in pregnant women. A study in animals has

shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3).

The potential risk for humans is unknown.

Actemra should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is unknown whether tocilizumab is excreted in human breast milk. The excretion of tocilizumab in

milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or

to continue/discontinue therapy with Actemra should be made taking into account the benefit of

breast-feeding to the child and the benefit of Actemra therapy to the woman.

Fertility

Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.

4.7

Effects on ability to drive and use machines

Actemra has minor influence on the ability to drive and use machines (see section 4.8, dizziness).

4.8

Undesirable effects

Summary of the safety profile

The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab

monotherapy or in combination with DMARDs) were upper respiratory tract infections,

nasopharyngitis, headache, hypertension and increased ALT.

The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity

reactions.

RA Patients

The safety profile of tocilizumab has been studied in 4 placebo-controlled studies (studies II, III, IV

and V), 1 MTX-controlled study (study I) and their extension periods (see section 5.1).

The double-blind controlled period was 6 months in four studies (studies I, III, IV and V) and was up

to 2 years in one study (study II). In the double-blind controlled studies, 774 patients received

tocilizumab 4 mg/kg in combination with MTX, 1870 patients received tocilizumab 8 mg/kg in

combination with MTX or other DMARDs and 288 patients received tocilizumab 8 mg/kg

monotherapy.

The long-term exposure population includes all patients who received at least one dose of tocilizumab

either in the double-blind control period or open label extension phase in the studies. Of the 4009

patients in this population, 3577 received treatment for at least 6 months, 3296 for at least one year,

2806 received treatment for at least 2 years and 1222 for 3 years.

ADRs from clinical trials and/or post marketing experience with Actemra based on spontaneous case

reports, literature cases and cases from non-interventional study programs are listed in Table 1 and are

presented by MedDRA system organ class. The corresponding frequency category for each ADR is

based on the following convention: 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) or very rare (<1/10,000). Within each frequency

grouping, undesirable effects are presented in order of decreasing seriousness.

Roche Pharmaceuticals (Israel) Ltd

Drugs regulatory affairs

Hacharash St.

P.O.B. 6391

Hod Hasharon 4524079

Tel. + 972-9-9737777

Fax + 972-9-9737850

רבמבונ

2020

ה/אפור

/חקו

ה/רקי

לע םכעידוהל תשקבמ מ"עב )לארשי( הקיטבצמרפ שור תרבח לע ןכו רישכתל היוותה תפסות רפסמ רישכתה לש אפורל ןולעב ועצובש םינוכדע

וצמ וז העדוהב .הרמחה םיווהמ רשא םינוכדעו םייתוהמ םינוכדע קר םיני

יוותהה תו

מושרה תו

ל

רישכת :לארשיב

Actemra (tocilizumab) is indicated for reducing signs and symptoms in adult patients with

moderately to severely active rheumatoid arthritis who had an inadequate response to

one or more DMARDs (Disease Modifying Anti-Rheumatic Drugs) or TNF antagonists or

in whom DMARDs cannot be used. Actemra can be used alone or in combination with

methotrexate or other DMARDs.

Actemra has been shown to reduce the rate of progression of joint damage as measured

by X-ray and to improve physical function when given in combination with methotrexate.

Actemra is indicated for the treatment of active systemic juvenile idiopathic arthritis in

patients 2 years of age and older.

Actemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile

idiopathic polyarthritis (rheumatoid factor positive or negative and extended oligoarthritis)

in patients 2 years of age and older, who have responded inadequately to previous

therapy with MTX.

Actemra can be given as monotherapy in case of intolerance to MTX or where continued

treatment with MTX is inappropriate.

Actemra in combination with methotrexate (MTX) in indicated for the treatment of severe,

active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX.

Actemra is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced

severe or life-threatening cytokine release syndrome (CRS) in adults and paediatric patients

3 years of age and older.

:רבסה

יתחת וק םע טסקט

.ןולעל ףסוהש טסקט ןייצמ

הצוח וק םע טסקט

.ןולעה ןמ רסוהש טסקט ןייצמ

ל ןולעב ןייעל שי ףסונ עדימל אפור

יפכ חלשנש

תואירבה דרשמ

ולעה

כדועמה

חלשנ

ה דרשמ רתאבש תופורתה רגאמב םוסרפל לבקל ןתינו ,תואירב

ספדומ םי

י"ע

ד.ת ,מ"עב )לארשי( הקיטבצמרפ שור :םושירה לעבל היינפ

6391

ןורשה דוה ,

4524079

ןופלט

09-9737777

:טנרטניאב ונתבותכ .

www.roche.co.il

טורבסיו לטיבא

ימע איבל

דע

םושיר תקלחמ

הנוממ חקור

.

20 mg/ml I.V

®

Actemra

הרמטקא

20

ל"מ/ג"מ

I.V.

tocilizumab

Concentrate for solution for infusion

Actemra 20 mg/ml I.V.

Page 1 of 1

ןולעב םייתוהמ םינוכדע

ל

אפור

ףיעסב

4.1 Therapeutic indications

ןכדוע אבה עדימה

:

ctemra is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced

severe or life-threatening cytokine release syndrome (CRS) in adults and paediatric patients 3

years of age and older.

ףיעסב

4.2 Posology and method of administration

ןכדוע אבה עדימה

:

Treatment should be initiated by healthcare professionals experienced in the diagnosis and

treatment of RA, sJIA, pJIA or CRS.

[…]

Cytokine Release Syndrome (CRS) (adults and paediatrics)

The recommended posology for treatment of CRS given as a 60-minute intravenous infusion is

8 mg/kg in patients weighing greater than or equal to 30 kg or 12 mg/kg in patients weighing

less than 30 kg. Actemra can be given alone or in combination with corticosteroids.

If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to

3 additional doses of Actemra may be administered. The interval between consecutive doses

should be at least 8 hours. Doses exceeding 800 mg per infusion are not recommended in

CRS patients.

Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or

AST due to the underlying malignancy, preceding lymphodepleting chemotherapy or the CRS.

[…]

Reduction There are insufficient clinical data to assess the impact of a tocilizumab dose due to

reduction in sJIA patients who have experienced laboratory abnormalities has not been

studied in sJIA patients.

[…]

Elderly

No dose adjustment is required in elderly patients aged >65 years and older of age.

[…]

Method of administration

After dilution, Actemra for RA, sJIA, pJIA, and pJIA CRS patients should be administered as

an intravenous infusion over 1 hour.

RA, sJIA and, pJIA and CRS Patients ≥ 30 kg

Actemra should be diluted to a final volume of 100 mL with sterile, non-pyrogenic sodium

chloride 9 mg/ mL (0.9%) solution for injection using aseptic technique .

For instructions on dilution of the medicinal product before administration, see section 6.6 .

sJIA and ,pJIA and CRS Patients < 30 kg

Actemra should be diluted to a final volume of 50 mL with sterile, non-pyrogenic sodium

chloride 9 mg/ mL (0.9%) solution for injection using aseptic technique.

ףיעסב

4.8 Undesirable effects

ןכדוע אבה עדימה

:

CRS Patients

The safety of tocilizumab in CRS has been evaluated in a retrospective analysis of data from

clinical trials, where 51 patients were treated with intravenous tocilizumab 8 mg/kg (12 mg/kg

for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or

Actemra 20 mg/ml I.V.

Page 2 of 1

life-threatening CAR T-cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4

doses) was administered.

ףיעסב

5.1 Pharmacodynamic properties

ןכדוע אבה עדימה

:

The efficacy of Actemra for the treatment of CRS was assessed in a retrospective analysis of

data from clinical trials of CAR T-cell therapies (tisagenlecleucel and axicabtagene ciloleucel)

for hematological malignancies. Evaluable patients had been treated with tocilizumab 8 mg/kg

(12 mg/kg for patients < 30 kg) with or without additional high-dose corticosteroids for severe

or life-threatening CRS; only the first episode of CRS was included in the analysis. The

efficacy population for the tisagenlecleucel

cohort included 28 males and 23 females (total 51

patients) of median age 17 years (range, 3–68 years). The median time from start of CRS to

first dose of tocilizumab was 3 days (range, 0–18 days). Resolution of CRS was defined as

lack of fever and off vasopressors for at least 24 hours. Patients were considered responders

if CRS resolved within 14 days of the first dose of tocilizumab, if no more than 2 doses of

Actemra were needed, and no drugs other than Actemra and corticosteroids were used for

treatment. Thirty-nine patients (76.5%; 95% CI: 62.5%–87.2%) achieved a response. In an

independent cohort of 15 patients (range: 9–75 years old) with axicabtagene ciloleucel-

induced CRS, 53% responded.

ףיעסב

6.6 Special precautions for disposal and other handeling

ןכדוע אבה עדימה

:

RA and CRS Patients (≥ 30 kg)

Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for

injection from a 100 mL infusion bag, equal to the volume of Actemra concentrate required for

the patients dose, under aseptic conditions. The required amount of Actemra concentrate (0.4

mL/kg) should be withdrawn from the vial and placed in the 100 mL infusion bag. This should

be a final volume of 100 mL. To mix the solution, gently invert the infusion bag to avoid

foaming.

Use in the paediatric population

sJIA and, pJIA and CRS Patients ≥ 30 kg

Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for

injection from a 100 mL infusion bag, equal to the volume of Actemra concentrate required for

the patients dose, under aseptic conditions. The required amount of Actemra concentrate (0.4

mL/kg) should be withdrawn from the vial and placed in the 100 mL infusion bag. This should

be a final volume of 100 mL. To mix the solution, gently invert the infusion bag to avoid

foaming.

sJIA and CRS Patients < 30 kg

Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for

injection from a 50 mL infusion bag, equal to the volume of Actemra concentrate required for

the patients dose, under aseptic conditions. The required amount of Actemra concentrate (0.6

mL/kg) should be withdrawn from the vial and placed in the 50 mL infusion bag. This should be

a final volume of 50 mL. To mix the solution, gently invert the infusion bag to avoid foaming.

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