Actemra Larutan Injeksi 20 MG, ML (Infus) - Tokilizumab - DKI1135900149A1 - 2020

Draft_Actemra SC_PI_New Drug Application_CDS11.
0_EN_v1
Actemra®
Tocilizumab
Anti-human interleukin-6 (IL-6) receptor
1. DESCRIPTION
1.1 Therapeutic/Pharmacologic Class of Drug
Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal
antibody of the immunoglobulin (Ig) IgG1 subclass.
ATC Code: L04AC07
1.2 Type of Dosage Form

Intravenous (IV) formulation/Actemra IV: Concentrate solution for infusion
Subcutaneous (SC) formulation/Actemra SC: Ready-to-use sterile liquid solution in a single-use

pre-filled syringe (PFS) with needle safety device (NSD)
1.3 Route of Administration

Intravenous (IV) infusion
Subcutaneous (SC) injection
1.4 Sterile/Radioactive Statement

Sterile
1.5 Qualitative and Quantitative Composition

Active ingredient: tocilizumab
Actemra IV is a clear to opalescent, colourless to pale yellow liquid, supplied in preservative-
free, non-pyrogenic single-use vials. Actemra IV is supplied in vials containing 4 mL or 20 mL
of tocilizumab (20 mg/mL)
Excipients:
Each 80 mg vial contains 0.10 mmol (2.21 mg) sodium
Each 400 mg vial contains 0.39 mmol (8.85 mg) sodium
Actemra SC is a yellowish, preservative-free liquid supplied in a ready-to-use, single-use pre-

filled syringe with needle safety device (PFS+NSD). Each device delivers 0.9 mL (162 mg) of
tocilizumab
2. CLINICAL PARTICULARS
2.1 Therapeutic Indication(s)
Rheumatoid Arthritis (RA) [IV and SC formulation]
Actemra, in combination with methotrexate (MTX) is indicated for the treatment of moderate to
severe active rheumatoid arthritis (RA) in adult patients who have either responded
inadequately to, or who were intolerant to, previous therapy with one or more disease-
modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists, in
these patients, Actemra can be given as monotherapy in case of intolerance to or inappropriate
with MTX, DMARD, anti TNF and other established drugs for RA. Actemra has been shown to
inhibit progression of joint damage as measured by X-ray and to improve physical function
when given in combination with MTX.
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Draft_Actemra SC_PI_New Drug Application_CDS11.0_EN_v1
Polyarticular Juvenile Idiopathic Arthritis (pJIA) [IV formulation only]

Actemra IV is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in
patients 2 years of age and older, with an inadequate response to methotrexate, due to lack of
efficacy or toxicity, who were receiving standard of care, either with or without non-
steroidal anti-inflammatory drugs (NSAIDs), either with or without low-dose corticosteroids,
and either with or without concomitant methotrexate therapy.
Systemic Juvenile Idiopathic Arthritis (sJIA) [IV formulation only]

Actemra is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients
2 years of age and older, who have responded inadequately to previous therapy with MTX or
non-steroidal anti-inflammatory drugs and systemic corticosteroids.
2.2 Dosage and Administration

General
Substitution by any other biological medicinal product requires the consent of the prescribing
physician.
For adult patients with RA, Actemra may be administered as an IV infusion or a SC injection.
For patients with pJIA, Actemra is administered as an IV infusion.
Intravenous Administration
Actemra IV is not intended for Subcutaneous administration.
Actemra IV should be diluted by healthcare professionals with sterile 0.9% w/v sodium
chloride solution using aseptic technique (see section 4.2 Special Instructions for Use, Handling
and Disposal). The recommended duration of IV infusion is 1 hour.
Subcutaneous Administration
Actemra SC is not intended for intravenous administration.
Actemra SC is administered with a single-use PFS+NSD. The first injection should be

performed under the supervision of a qualified health care professional. A patient can self-inject
ACTEMRA SC only if the physician determines that it is appropriate and the patient agrees to
medical follow-up as necessary and has been trained in proper injection technique. The
recommended injection sites (abdomen, thigh and upper arm) should be rotated and injections
should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or
not intact.
Patients who transition from Actemra IV therapy to Actemra SC administration should

administer the first SC dose at the time of the next scheduled IV dose under the supervision of a
qualified health care professional.
Rheumatoid Arthritis [IV and SC formulation]

Intravenous Dosing Regimen:
The recommended dose of Actemra IV for adult patients is 8 mg/kg given once every four
weeks as an IV infusion.
Actemra can be used alone or in combination with MTX and/or other DMARDs.
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For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion
are not recommended (see section 3.2 Pharmacokinetic Properties).
Subcutaneous Dosing Regimen:
The recommended dose of Actemra SC for adult patients is 162 mg given once every week as a
Subcutaneous injection. Actemra SC can be used alone or in combination with MTX and/or
other DMARDs.
Dose Modification Recommendations for RA:

(see section 2.4.4 Laboratory Tests)
• Liver enzyme abnormalities
Lab Value Action
> 1 to 3x ULN Dose modify concomitant DMARDs if appropriate.
For patients on Actemra SC with persistent increases in this range,

reduce Actemra SC injection frequency to every other week or
interrupt Actemra SC until ALT/AST have normalized. Resume
ACTEMRA at every other week and increase frequency to every
week as clinically appropriate.
For patients on Actemra IV (RA only) with persistent increases in

this range, reduce Actemra IV dose to 4 mg/kg or interrupt
Actemra IV until ALT/AST have normalized. Restart with 4
mg/kg or 8 mg/kg, as clinically appropriate.
> 3 to 5x ULN Interrupt Actemra dosing until < 3x ULN and follow
recommendations above for > 1 to 3x ULN
For persistent increases > 3x ULN (confirmed by repeat testing),

discontinue Actemra
> 5x ULN Discontinue Actemra
• Low absolute neutrophil count (ANC)

Lab Value Action
(cells x 109/L)
ANC > 1 Maintain dose
ANC 0.5 to 1 Interrupt Actemra dosing
For patients on Actemra SC, when ANC > 1 x 109/L resume

Actemra SC injection every other week and increase frequency to
every week, as clinically appropriate.
For patients on Actemra IV (RA only), when ANC increases > 1 x

109/L resume Actemra IV at 4 mg/kg and increase to 8 mg/kg, as
clinically appropriate
ANC < 0.5 Discontinue Actemra
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• Low platelet count

Lab Value Action
(cells x 103/µL)
50 to 100 Interrupt Actemra dosing
For patients on Actemra SC, when platelet count is > 100 x 103/µL
resume Actemra SC injection every other week and increase
frequency to every week, as clinically appropriate.
For patients on Actemra IV (RA only), when platelet count > 100
x 103/μL resume Actemra IV at 4 mg/kg and increase to 8 mg/kg,
as clinically appropriate
< 50 Discontinue Actemra
Polyarticular Juvenile Idiopathic Arthritis (pJIA) [IV formulation only]
The recommended dose of Actemra IV for patients with pJIA is:

• 10 mg/kg for patients < 30 kilograms
• 8 mg/kg for patients ≥ 30 kilograms
given once every four weeks as an IV infusion. A change in dose should only be based on a
consistent change in the patient’s body weight over time. Actemra IV can be used alone or in
combination with MTX.
Systemic Juvenile Idiopathic Arthritis (sJIA) [IV formulation only]

A change in dose should only be based on a consistent change in the patient’s body weight over
time. Actemra is to be used in combination with MTX or non-steroidal inflammatory drugs and
systemic corticosteroid.
The recommended dose of IV tocilizumab for patients with sJIA is:

• 12 mg/kg for patients below 30 kg
• 8 mg/kg for patients ≥ 30 kg
given once every two weeks as an IV infusion.
Dose Modification Recommendations for pJIA and sJIA:

Dose reduction of Actemra IV has not been studied in the pJIA or sJIA population. Dose
interruptions of Actemra IV for laboratory abnormalities are recommended in patients with
pJIA or sJIA and are similar to what is outlined above for patients with RA (also see section
2.4.1 Warnings and Precautions, General). If appropriate, concomitant methotrexate and/or
other medications should be dose modified or stopped and Actemra IV dosing interrupted until
the clinical situation has been evaluated. In pJIA or sJIA the decision to discontinue Actemra
IV for a laboratory abnormality should be based upon the medical assessment of the individual
patient.
2.2.1 Special Dosage Instructions

Pediatric use: The safety and efficacy of Actemra in children with conditions other than pJIA
have not been established. The safety and efficacy in patients aged less than 2 years with IV
TCZ in sJIA have not been established.
Geriatric use: No dose adjustment is required in elderly patients > 65 years of age.
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Renal impairment: No dose adjustment is required in patients with mild renal impairment (see
section 3.2.6 Pharmacokinetics in Special Populations). Actemra has not been studied in
patients with moderate to severe renal impairment. Renal function should be monitored closely
in these patients.
Hepatic impairment: The safety and efficacy of Actemra has not been studied in patients with
hepatic impairment (see section 2.4.1 Warnings and Precautions, General). Therefore, no dose
recommendations can be made.
2.3 Contraindications
Known hypersensitivity to Actemra or to any of the excipients.
Active, severe infections.
2.4 Warnings and Precautions

2.4.1 General
In order to improve the traceability of biological medicinal products, the trade name and batch
number of the administered product should be clearly recorded (or stated) in the patient file.
All indications
Infections
Serious and sometimes fatal infections have been reported in patients receiving
immunosuppressive agents including Actemra (see section 2.6.1 Undesirable Effects). Actemra
treatment should not be initiated in patients with active infections. Administration of Actemra
should be interrupted if a patient develops a serious infection until the infection is controlled.
Healthcare professionals should exercise caution when considering the use of Actemra in
patients with a history of recurring infection or with underlying conditions (e.g. diverticulitis,
diabetes) which may predispose patients to infections.
Vigilance for the timely detection of serious infection is recommended for patients receiving
immunosuppressive agents, such as tocilizumab, as signs and symptoms of acute inflammation
may be lessened, due to suppression of the acute phase reactants. Patients (which include
younger children who may be less able to communicate their symptoms) and parents/guardians
of minors with pJIA or sJIA should be instructed to contact a healthcare professional
immediately when any symptoms suggesting infection appear, in order to assure rapid
evaluation and appropriate treatment.
Complications of diverticulitis
Events of diverticular perforation as complications of diverticulitis have been reported in

patients treated with Actemra. 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, should be evaluated promptly
for early identification of gastrointestinal perforation.
Tuberculosis
As recommended for other biologic therapies, all patients should be screened for latent
tuberculosis (TB) infection prior to starting Actemra therapy. Patients with latent TB should be
treated with standard antimycobacterial therapy before initiating Actemra.
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Vaccinations
Live and live attenuated vaccines should not be given concurrently with Actemra as clinical
safety has not been established.
No data are available on the secondary transmission of infection from persons receiving live
vaccines to patients receiving Actemra.
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 paediatric or elderly patients, if possible, be

brought up to date with all immunizations in agreement with current immunization 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.
Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with
Actemra (see section 2.6.1 Undesirable Effects, Clinical Trials). In the post marketing setting,
events of serious hypersensitivity and anaphylaxis have occurred in patients treated with a range
of doses of Actemra, with or without concomitant therapies, premedication, and/or a previous
hypersensitivity reaction. In the post marketing setting, cases with a fatal outcome have been
reported with Actemra IV. These events have occurred as early as the first infusion of Actemra
(see sections 2.3 Contraindications, 2.6.2 Post Marketing). Appropriate treatment should be
available for immediate use in the event of an anaphylactic reaction during infusion with
Actemra. If an anaphylactic reaction or other serious hypersensitivity reaction occurs,
administration of Actemra should be stopped immediately and Actemra should be permanently
discontinued (see section 2.2 Dosage and Administration).
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 2.2.1 Special Dosage Instructions, 2.6.1.1 Laboratory Abnormalities).
Hepatic transaminase elevations
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 2.6.1 Undesirable effect). An increased frequency of these elevations was observed
when potentially hepatotoxic drugs (e.g. MTX) were used in combination with Actemra.
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.
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 based on
transaminases see section see Section Dosage and method of administration.
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Haematological abnormalities
Decreases in neutrophil and platelet counts have occurred following treatment with Actemra IV
8 mg/kg in combination with MTX (See section 2.6.1 Undesirable effect). There may be an
increased risk of neutropenia in patients who have previously been treated with a TNF
antagonist.
Caution should be exercised when considering initiation of Actemra treatment in patients with a
low neutrophil or platelet count (i.e. ANC < 2 x 109/L or platelet count below 100 x 103/μL). In
patients with an ANC < 0.5 x 109/L or a platelet count < 50 x 103/μL treatment is not
recommended.
In RA, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and
thereafter according to standard good clinical practice. For recommended dose modifications
based on ANC and platelet counts, see section section 2.2 Dosage and Administration.
In pJIA, neutrophils and platelets should be monitored at the time of the second infusion and
thereafter according to good clinical practice (see section 2.2 Dosage and Administration, Dose
modifications).
In sJIA, neutrophils and platelets counts should be monitored at the time of the second infusion
and thereafter according to good clinical practice (See section 2.2 Dosage and Administration,
Dose modifications).
Viral reactivation
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for
rheumatoid arthritis. In clinical studies with Actemra, patients who screened positive for
hepatitis were excluded.
Demyelinating 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.
Lipid parameters
Elevations in lipid parameters including total cholesterol, triglycerides and/or low-density

lipoprotein (LDL) cholesterol have been observed (see section 2.6.1Undesirable Effects,
Clinical Trials). In the majority of patients, there was no increase in atherogenic indices, and
elevations in total cholesterol responded to treatment with lipid lowering agents.
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.
Malignancy
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal

products may increase the risk of malignancy.
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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 patient. 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’.
2.4.2 Drug Abuse and Dependence

No studies on the effects on the potential for Actemra to cause dependence have been
performed. However, there is no evidence from the available data that Actemra treatment
results in dependence.
2.4.3 Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machine have been performed.
However, given that dizziness has been commonly reported, patients who experience this
adverse reaction should be advised not to drive or use machines until it has resolved.
2.4.4 Laboratory Tests

Rheumatoid Arthritis and pJIA, sJIA
Neutropenia
Treatment with Actemra was associated with a higher incidence of neutropenia. Treatment-
related neutropenia was not associated with serious infection in clinical trials (see section
2.6.1.1 Laboratory Abnormalities).
low neutrophil count i.e. absolute neutrophil count (ANC) <2 x 109/L. In patients with an
absolute neutrophil count <0.5 x 109/L treatment is not recommended.
In RA, neutrophils should be monitored 4 to 8 weeks after start of therapy and thereafter
according to good clinical practice. For recommended dose modifications based on ANC
results, see section 2.2 Dosage and Administration.
In pJIA and sJIA, neutrophils should be monitored at the time of the second infusion and
modifications).
Thrombocytopenia
Treatment with Actemra was associated with a reduction in platelet counts. Treatment-related
reduction in platelets was not associated with serious bleeding events in clinical trials (see
section 2.6.1.1 Laboratory Abnormalities).
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platelet count below 100 x 103/µL. In patients with a platelet count <50 x 103/µL treatment is
not recommended.
In RA, platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according
to good clinical practice. For recommended dose modifications based on platelet counts, see
section 2.2 Dosage and Administration.
In pJIA and sJIA, platelets should be monitored at the time of the second infusion and
modifications).
Hepatic Transaminase Elevations
In clinical trials, mild and moderate elevations of hepatic transaminases have been observed
with Actemra treatment, without progression to hepatic injury (see section 2.6.1.1 Laboratory
Abnormalities). Increased frequency of these elevations was observed when potential
hepatotoxic drugs (e.g. methotrexate (MTX)) were used in combination with Actemra.
Caution should be exercised when considering initiation of Actemra treatment in patients with
elevated transaminases ALT or AST > 1.5x ULN. In patients with elevated ALT or AST > 5x
ULN treatment is not recommended.
In RA, ALT and AST should be monitored 4 to 8 weeks after start of therapy and thereafter
according to good clinical practice. For recommended dose modifications based on
transaminases, see section 2.2 Dosage and Administration.
In pJIA and sJIA, ALT and AST should be monitored at the time of the second infusion and
modifications).
Lipids parameters
Elevations of lipid parameters such as total cholesterol, triglycerides and/or low density
lipoprotein (LDL) cholesterol have been observed (see section 2.6.1.1 Laboratory
Abnormalities).
In patients treated with Actemra, 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.
Systemic Juvenile Idiopathic Arthritis
Macrophage activation syndrome (MAS)
MAS is a serious life-threatening disorder that may develop in patients with sJIA. In clinical
trials, tocilizumab has not been studied in patients during an episode of active MAS
2.4.5 Interactions with other Medicinal Products and other Forms of Interaction
Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-
inflammatory drugs or corticosteroids on Actemra clearance.
Concomitant administration of a single dose of 10 mg/kg Actemra IV with 10-25 mg MTX

once weekly had no clinically significant effect on MTX exposure.
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Actemra has not been studied in combination with other biological DMARDs.
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 Actemra is introduced.
In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in
CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Actemra normalizes
expression of these enzymes.
The effect of Actemra on CYP enzymes (except CYP2C19 and CYP2D6) is clinically relevant
for CYP450 substrates with a narrow therapeutic index, and/or where the dose is individually
adjusted.
In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week
following a single dose of Actemra, to the level similar or slightly higher than those observed in
healthy subjects.
When starting or stopping therapy with Actemra, patients taking medicinal products, which are
individually dose-adjusted and are metabolised via CYP450 3A4, 1A2, or 2C9 (e.g.
atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin, or
benzodiazepines) should be monitored as doses of these products may need to be adjusted to
maintain their therapeutic effect. Given its long elimination half-life (t1/2), the effect of Acterma
on CYP450 enzyme activity may persist for several weeks after stopping therapy.
2.5 Use in Special Populations

2.5.1 Pregnancy
There are no adequate data from the use of Actemra in pregnant women. A study in monkeys
did not indicate any dysmorphogenic potential but has yielded a higher number of spontaneous
abortion/embryo-foetal death at a high dose (see section 3.3.5 Preclinical Safety, Other). The
relevance of these data for humans is unknown.
Women of child bearing potential must use effective contraception during and up to 6 months
after treatment.
Actemra should not be used during pregnancy unless clearly indicated by medical need.
2.5.2 Labour and Delivery

No text
2.5.3 Nursing Mothers

Although endogenous immunoglobulin of IgG isotope are secreted into human milk, it is
unknown whether Actemra is excreted in human breast milk. 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.
2.5.4 Paediatric Use

See section 2.2.1 Special Dosage Instructions
2.5.5 Geriatric Use

See sections 2.2.1 Special Dosage Instructions, 3.2.6 Pharmacokinetics in Special Populations
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2.5.6 Renal Impairment

2.5.7 Hepatic Impairment

2.6 Undesirable Effects

2.6.1 Clinical Trials
Rheumatoid Arthritis
Patient Treated with Intravenous Actemra:

The safety of Actemra has been studied in 5 Phase III, double-blind controlled trials and their
extension periods.
The all control population includes all patients from the double-blind phases of each core study
from randomization until either the first change in the treatment regimen, or two years is
reached. The control period in 4 of the studies was 6 months and in 1 study was up to 2 years.
In the double-blind controlled studies 774 patients received Actemra 4 mg/kg in combination
with MTX, 1,870 patients received Actemra 8 mg/kg in combination with MTX/other
DMARDs and 288 patients received Actemra 8 mg/kg monotherapy.
The all exposure population includes all patients who received at least one dose of Actemra
either in the double-blind control period or open label extension phase in 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 listed according to clinical importance to the patient. Frequency are defined as very
common (≥ 1/10); common (≥ 1/100 to < 1/10) or uncommon (≥ 1/1000 to < 1/100).
Table 1 Summary of ADRs occurring in patients treated with Actemra

System Organ Class Very Common Common Uncommon
Cellulitis, Pneumonia,
Infections and Upper respiratory
Oral herpes simplex, Diverticulitis
infestations tract infections
Herpes zoster
Gastrointestinal Abdominal pain, Mouth Stomatitis, Gastric
disorders ulceration, Gastritis ulcer
Skin and Subcutaneous
Rash, Pruritus, Urticaria
tissue disorders
Nervous system
Headache, Dizziness
disorders
Hepatic transaminases
Total bilirubin
Investigations increased, Weight
increased
increased
Vascular disorders Hypertension
Blood and lymphatic
Leucopenia, Neutropenia
system disorders
Metabolism and
nutrition disorders Hypercholesterolaemia Hypertriglyceridemia
General disorders and Peripheral oedema,

administration site Hypersensitivity reaction,
conditions Injection site reaction
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System Organ Class Very Common Common Uncommon

Respiratory, thoracic
and mediastinal Cough, Dyspnoea
disorders
Eye disorders Conjunctivitis
Renal disorders Nephrolithiasis
Endocrine disorders Hypothyroidism
Description of selected adverse drug reactions from clinical trials:
Patients Treated with Intravenous Tocilizumab:
Infections
In the 6 month controlled trials, the rate of all infections reported with Actemra IV 8 mg/kg plus
DMARD treatment was 127 events per 100 patient years compared to 112 events per 100
patient years in the placebo plus DMARD group. In the all exposure population the overall rate
of infections with Actemra was 108 events per 100 patient years exposure.
In 6 month controlled clinical studies the rate of serious infections (bacterial, viral and fungal)
with Actemra IV 8 mg/kg plus DMARDs was 5.3 events per 100 patient years exposure
compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In
the monotherapy study the rate of serious infections was 3.6 events per 100 patient years of
exposure in the Actemra group and 1.5 events per 100 patient years of exposure in the MTX
group.
In the all exposure population the overall rate of serious infections was 4.7 events per 100
patient years. Reported serious infections, some with fatal outcome, included pneumonia,
cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of
opportunistic infections have also been reported.
Complications of diverticulitis
During the six month controlled trials, complications of diverticulitis including generalised
purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess have been reported
uncommonly with Actemra therapy.
Gastrointestinal Perforation
During the 6 month controlled clinical trials, the overall rate of gastrointestinal perforation was
0.26 events per 100 patient years with Actemra therapy. In the all exposure population the
overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of
gastrointestinal perforation on Actemra were primarily reported as complications of
diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and
abscess.
Infusion reactions
In the 6 month controlled trials adverse events associated with infusion (selected events
occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the
Actemra IV 8 mg/kg plus DMARD group and 5.1% of patients in the placebo plus DMARD
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group. Events reported during the infusion were primarily episodes of hypertension; events
reported within 24 hours of finishing an infusion were headache and skin reactions (rash,
urticaria). These events were not treatment limiting.
The rate of anaphylactic (occurring in a total of 6/3778 patients) was several fold higher in the 4
mg/kg arm in comparison to the 8 mg/kg dose. Clinically significant hypersensitivity reactions
associated with Actemra and requiring treatment discontinuation, were reported in a total of 13
out of 3778 patients (0.3%) treated with Actemra during the controlled and open label clinical
trials. These reactions were generally observed during the second to fifth infusions of Actemra
(see section 2.4.1 Warnings and Precautions, General).
Immunogenicity
A total of 2876 patients have been tested for anti-tocilizumab antibodies in the 6 month
controlled clinical trials. Forty-six (46) patients (1.6%) developed positive anti-tocilizumab
antibodies of whom 5 had an associated medically significant hypersensitivity reaction leading
to withdrawal. Thirty (30) patients (1.1%) developed neutralizing antibodies.
Haematological abnormalities
Decreases in neutrophil counts below 1 x 109/L occurred in 3.4% of patients on Actemra IV 8

mg/kg plus DMARDs compared to < 0.1% of patients on placebo plus DMARDs.
Approximately half of the patients who developed an ANC < 1 x 109/L did so within 8 weeks
after starting therapy. Decreases below 0.5 x 109/L were reported in 0.3% patients receiving
Actemra IV 8 mg/kg plus DMARDs. There was no clear association between decreases in
neutrophils and the occurrence of serious infections.
Decreases in platelet counts below 100 x 103/μL occurred in 1.7% of patients on Actemra IV 8
mg/kg plus DMARDs compared to < 1% on placebo plus DMARDs. These decreases occurred
without associated bleeding events.
Hepatic transaminase elevations
Transient elevations in ALT/AST > 3 x ULN were observed in 2.1% of patients on Actemra IV
8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg
Actemra IV plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.
The addition of potentially hepatotoxic drugs (e.g. MTX) to Actemra monotherapy resulted in
increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in
0.7% of Actemra monotherapy patients and 1.4% of Actemra plus DMARD patients, the
majority of whom were discontinued permanently from Actemra 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.
Lipid parameters
During the six month controlled trials, increases of lipid parameters such as total cholesterol,
triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly.
Approximately 24% of patients receiving Actemra in clinical trials experienced sustained
elevations in total cholesterol ≥ 6.2 mmol/L, with 15% experiencing a sustained increase in
LDL to ≥ 4.1 mmol/L. Elevations in lipid parameters responded to treatment with lipid-
lowering agents.
Page 13 of 35
Malignancies
The clinical data are insufficient to assess the potential incidence of malignancy following
exposure to Actemra. Long-term safety evaluations are ongoing.
Monotherapy: Actemra IV versus adalimumab
In a 24 week double-blinded, parallel study (monotherapy with Actemra IV 8 mg/kg q4w

(N=162) compared to adalimumab 40 mg SC q2w (N=162)), the overall clinical adverse event
profile was similar between Actemra IV and adalimumab. The proportion of patients with
serious adverse events was balanced between the treatment groups (Actemra IV 11.7% vs.
adalimumab 9.9%) with the most common event being infections (3.1% each). Both study
treatments induced the same pattern of changes in laboratory safety parameters (decreases in
neutrophil and platelet counts, increases in ALT, AST and lipids), however, the magnitude of
change and the frequency of marked abnormalities was higher with Actemra IV compared with
adalimumab. Four (2.5%) patients in the Actemra IV arm and two (1.2%) patients in the
adalimumab arm experienced CTC grade 3 or 4 neutrophil count decreases. Eleven (6.8%)
patients in the Actemra IV arm and five (3.1%) patients in the adalimumab arm experienced
ALT increases of CTC grade 2 or higher. The mean LDL increase from baseline was 0.64
mmol/L (25 mg/dL) for patients in the Actemra IV arm and 0.19 mmol/L (7 mg/dL) for patients
in the adalimumab arm. The safety observed in the Actemra IV arm was consistent with the
known safety profile of Actemra IV and no new or unexpected adverse drug reactions were
observed (see Table 1) (see section 3.1.2 Clinical/Efficacy Studies).
Patients Treated with Actemra SC:
The safety of Actemra SC in RA was study in SC-I. The study compared the efficacy and
safety of Actemra SC 162 mg administered every week versus Actemra IV 8 mg/kg in 1262
subjects with adult RA. All patients in the study received background non-biologic DMARD(s).
The safety and immunogenicity observed for Actemra SC was consistent with the known safety
profile of Actemra IV and no new or unexpected adverse drug reactions were observed (see
Table 1). A higher frequency of injection site reactions was observed in the SC arms compared
with placebo SC injections in the IV arms (see section 3.1.2 Clinical/Efficacy Studies).
Injection Site Reactions
During the 6 month controlled period, in SC-I, the frequency of injection site reactions was
10.1% (64/631) and 2.4% (15/631) for the Actemra SC and the SC placebo (IV group) weekly
injections, respectively. These injection site reactions (including erythema, pruritus, pain and
haematoma) were mild to moderate in severity. The majority was resolved without any
treatment and none necessitated drug discontinuation.
Immunogenicity
In SC-I, a total of 625 patients treated with Actemra SC 162 mg weekly were tested for anti-
tocilizumab antibodies in the 6 month controlled period. Five patients (0.8%) developed
positive anti-tocilizumab antibodies; of these, all developed neutralizing anti-tocilizumab
antibodies.
A total of 1454 Actemra SC all exposure patients have been tested for anti-tocilizumab
antibodies, thirteen patients (0.9%) developed positive anti-tocilizumab antibodies, and of these
12 patients (0.8%) developed neutralizing anti-tocilizumab antibodies.
Page 14 of 35
No correlation of antibody development to clinical response or adverse events was observed.
Polyarticular Juvenile Idiopathic Arthritis
The safety profile of Actemra was studied in 240 paediatric patients with pJIA. In Study
WA19977, 188 patients (2 to 17 years of age) were treated with Actemra IV. The total patient
exposure to Actemra in the pJIA all exposure population was 184.4 patient years for Actemra
IV. In general, the safety profile observed in patients with pJIA was consistent with the known
safety profile of Actemra with the exception of ISRs (see Table 1).
Infections
Infections are the most commonly observed events in pJIA. The rate of infections in the pJIA
Actemra IV all exposure population was 163.7 per 100 patient years. The most common events
observed were nasopharyngitis and upper respiratory tract infections. The rate of serious
infections was numerically higher in patients weighing below 30 kg treated with 10 mg/kg
Actemra IV (12.2 per 100 patient years) compared to patients weighing ≥ 30 kg, treated with 8
mg/kg Actemra IV (4.0 per 100 patient years). The incidence of infections leading to dose
interruptions was also numerically higher in patients weighing below 30 kg treated with 10
mg/kg Actemra IV (21.4%) compared to patients weighing ≥ 30 kg, treated with 8 mg/kg
Actemra IV (7.6%).
Infusion Reactions
In pJIA patients, infusion related reactions are defined as all events occurring during or within
24 hours of an infusion with Actemra IV. In the Actemra all exposure population, 11 patients
(5.9%) experienced infusion reactions during the infusion, and 38 patients (20.2%) experienced
an event within 24 hours of an infusion. The most common events occurring during infusion
were headache, nausea and hypotension and within 24 hours of infusion were dizziness and
hypotension. In general, the adverse drug reactions observed during or within 24 hours of an
infusion were similar in nature to those seen in RA patients (see section 2.6 Undesirable Effects
section).
No clinically significant hypersensitivity reactions associated with Actemra and requiring

treatment discontinuation were reported.
Injection Site Reactions
A total of 28.8% (15/52) pJIA patients experienced ISRs to Actemra SC. These ISRs occurred
in 44% of patients ≥ 30 kg compared to 14.8% of patients below 30 kg. The most common
ISRs were injection site erythema, swelling, hematoma, pain and pruritis. All ISRs reported
were non-serious Grade 1 events, and none of the ISRs required patient withdrawal from
treatment or dose interruption.
Immunogenicity
Across the two studies in pJIA patients, a total of four patients (0.5% [1/188] in the IV Study
WA19977) developed positive neutralizing anti-tocilizumab antibodies without developing a
serious or clinically significant hypersensitivity reaction. Of these 4 patients, 2 subsequently
withdrew from the study. No correlation between antibody development and clinical response
or adverse events was observed.
Page 15 of 35
The safety profile of tocilizumab in sJIA was studied in 163 paediatric patients. In Study
WA18221 (12-week trial and long term extension), 112 patients (2 to 17 years of age) were
treated with IV tocilizumab and in Study WA28118 (52-week trial), 51 patients (1 to 17 years
of age) were treated with SC tocilizumab. In general, the adverse drug reactions in patients with
sJIA were similar in type to those seen in RA patients (See section 2.6 Undesirable effect).
Infections
In the 12 week controlled trial (Study WA18221), the rate of all infections in the IV tocilizumab
group was 344.7 per 100 patient years and 287.0 per 100 patient years in the placebo group. In
the open label extension study (Part II) the overall rate of infections remained similar at 306.6
per 100 patient years.
In the 12 week controlled trial (Study WA18221), the rate of serious infections in the IV
tocilizumab group was 11.5 per 100 patient years. In the open label extension study the overall
rate of serious infections remained stable at 11.3 per 100 patient years. Reported serious
infections were similar to those seen in RA patients with the addition of varicella and otitis
media.
Infusion Reactions
For sJIA patients, infusion related reactions are defined as all events occurring during or within
24 hours of an infusion with IV tocilizumab. In the 12 week controlled trial (Study WA18221),
four percent (4.0%) of patients from the tocilizumab group experienced events occurring during
infusion, one event (angioedema) was considered serious and life-threatening, and the patient
was discontinued from study treatment.
In the 12 week controlled trial experience, 16% of patients in the IV tocilizumab group and
5.4% of patients in the placebo group experienced an event within 24 hours of infusion. In the
tocilizumab group, the events included, but not limited to rash, urticaria, diarrhoea, epigastric
discomfort, arthralgia and headache. One of these events, (urticaria) was considered serious.
Clinically significant hypersensitivity reactions associated with IV tocilizumab and requiring

treatment discontinuation, were reported in 1 out of 112 patients (below 1%) treated with IV
tocilizumab during the controlled and open-label parts of the clinical trial.
Immunogenicity
In Study WA18221, all 112 patients were tested for anti-tocilizumab antibodies at baseline.
Two patients developed positive anti-tocilizumab antibodies with one of these patients having a
hypersensitivity reaction leading to withdrawal.
2.6.1.1 Laboratory Abnormalities

Haematology abnormalities:
Neutrophils
Intravenous Administration:
In the 6 month controlled trials decreases in neutrophil counts below 1 x 109/L occurred in 3.4%
of patients on Actemra IV 8 mg/kg + DMARD compared to < 0.1% of patients on
placebo+DMARD. Approximately half of the instances of ANC below 1 x 109/L occurred
Page 16 of 35
within 8 weeks of starting therapy. Decreases below 0.5 x 109/L were reported in 0.3% patients
receiving Actemra IV 8 mg/kg + DMARD (see sections 2.2 Dosage and Administration, 2.4. 1
Laboratory Tests). There was no clear relationship between decreases in neutrophils below 1 x
109/L and the occurrence of serious infections.
In the all control and all exposure population, the pattern and incidence of decreases in
neutrophil counts remained consistent with what was seen in the 6 month controlled clinical
trials.
Subcutaneous Administration:
During routine laboratory monitoring in the Actemra SC 6-month controlled period of clinical
trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on
Actemra SC 162 mg weekly.
There was no clear relationship between decreases in neutrophils below 1 x 109/L and the
occurrence of serious infections.

During routine laboratory monitoring in the Actemra all exposure population, a decrease in
neutrophil count below 1 × 109/L occurred in 3.7% of patients treated with Actemra IV.

During routine laboratory monitoring in the 12-week controlled trial (Study WA18221), a
decrease in neutrophil counts below 1 × 109/L occurred in 7% of patients in the Actemra IV
group, and in none in the placebo group.
In the open-label extension study (WA18221), decreases in neutrophil counts below 1 x 109/L,
occurred in 15% of the IV tocilizumab group.
Platelets
In the 6 month controlled trials decreases in platelet counts below 100 x 103/μL occurred in
1.7% of patients on Actemra IV 8 mg/kg plus traditional DMARDs compared to < 1% of
patients on placebo plus traditional DMARDs, without associated bleeding events (see sections
2.2 Dosage and Administration, 2.4.4 Laboratory Tests).
In the all control and all exposure population, the pattern and incidence of decreases in platelet
counts remained consistent with what was seen in the 6 month controlled clinical trials.
trial SC-I, none of the patients had a decrease in platelet count to ≤ 50 × 103/μL.

During routine laboratory monitoring in the Actemra all exposure population, a decrease in
platelet count to ≤ 50 × 103/μL occurred in 1% patients treated with Actemra IV, without
associated bleeding events and in no patients treated with Actemra SC.
Page 17 of 35

During routine laboratory monitoring in the 12-week controlled trial (Study WA18221), 3% of
patients in the placebo group and 1% in the IV tocilizumab group had a decrease in platelet
count to ≤ 100 × 103/μL.
In the open-label extension study (WA18221), decreases in platelet counts below 100 x 103/μL
occurred in 3% of patients of the IV tocilizumab group, without associated bleeding events.
Liver enzyme elevations
During the 6 month controlled trials transient elevations in ALT/AST > 3 x ULN were observed
in 2.1% of patients on Actemra IV 8 mg/kg compared to 4.9% of patients on MTX, and in 6.5%
of patients who received Actemra IV 8 mg/kg + DMARD compared to 1.5% of patients on
placebo+DMARD. The addition of potentially hepatotoxic drugs (e.g. MTX) to Actemra IV
monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 x
ULN were observed in 0.7% of Actemra IV monotherapy patients and 1.4% of Actemra IV +
DMARD patients, the majority of whom were discontinued from Actemra treatment (see
sections 2.2 Dosage and Administration, 2.4.4 Laboratory Tests). These elevations were not
associated with any clinically relevant increases in direct bilirubin, nor were they associated
with clinical evidence of hepatitis or hepatic insufficiency. During routine laboratory
monitoring, the incidence of indirect bilirubin greater than the upper limit of normal was 6.2%
in patients treated with Actemra IV 8 mg/kg + DMARD in the all control population.
In the all control and all exposure population, the pattern and incidence of elevations in
ALT/AST remained consistent with what was seen in the 6 month controlled clinical trials.
trial SC-I, elevation in ALT or AST ≥ 3 x ULN occurred in 6.5% and 1.4% of patients,
respectively on SC weekly.

During routine laboratory monitoring in the Actemra all exposure population, elevation in ALT
or AST ≥ 3 x ULN occurred in 3.7% and below 1% of patients treated with Actemra IV.

During routine laboratory monitoring in the 12-week controlled trial (Study WA18221),
elevation in ALT or AST ≥ 3 x ULN occurred in 5% and 3% of patients, respectively, in the IV
tocilizumab group, and in 0% of placebo patients.
In the open-label extension study (WA18221), elevation in ALT or AST ≥ 3 x ULN occurred in
12% and 4% of patients, respectively, in the IV tocilizumab group.
Elevations in lipid parameters
During routine laboratory monitoring in the 6 month controlled trials, elevations in lipid
parameters (total cholesterol, LDL, HDL, triglycerides) were observed in patients treated with
Actemra IV. Approximately 24% of patients receiving Actemra IV in clinical trials experienced
sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL), with 15% experiencing a
sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL).
Page 18 of 35
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 the all control and all exposure population, the pattern and incidence of elevations in lipid
parameters remained consistent with what was seen in the 6 month controlled clinical trials.
During routine laboratory monitoring in the Actemra SC 6 month controlled period of clinical
trial SC-I, 19% of patients on Actemra SC weekly experienced sustained elevations in total
cholesterol > 6.2 mmol/L (240 mg/dL), with 9% experiencing a sustained increase in LDL to ≥
4.1 mmol/L (160 mg/dL) on Actemra SC weekly.

During routine laboratory monitoring in the Actemra all exposure population, elevation in total
cholesterol > 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL > 1.5-2 x ULN
in one patient (0.5%).

During routine laboratory monitoring in the 12-week controlled trial (Study WA18221), 13.4%
and 33.3% of patients experienced a post-baseline elevation of their LDL-cholesterol value to
≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL, respectively .
In the open-label extension study (WA18221), 13.2% and 27.7% of patients experienced a post-
baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to
≥ 200 mg/dL, respectively.
2.6.2 Post Marketing

The safety profile in post marketing experience is consistent with clinical trial data with the
exception of reports of fatal anaphylaxis during intravenous Actemra treatment (see sections 2.3
Contraindications, 2.4.1 Warnings and Precautions, General). Stevens-Johnson Syndrome
(SJS) has been reported during treatment with Actemra.
2.6.2.1 Laboratory Abnormalities

No text
2.7 Overdose
There are limited data available on overdosage with Actemra. One case of accidental overdose
was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg IV.
No adverse drug reactions were observed. No serious adverse drug reactions were observed in
healthy volunteers who received a single dose up to 28 mg/kg IV, although dose-limiting
neutropenia was observed.
2.8 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those
mentioned in the list excipients.
3. PHARMACOLOGICAL PROPERTIES AND EFFECTS

3.1 Pharmacodynamic Properties
In clinical studies with Actemra, rapid decreases in C-reactive protein (CRP), erythrocyte
sedimentation rate (ESR) and serum amyloid A were observed. Increases in haemoglobin levels
were observed, through Actemra decreasing the IL-6 driven effects on hepcidin production to
increase iron availability.
Page 19 of 35
In healthy subjects administered Actemra in doses from 2 to 28 mg/kg, absolute neutrophil

counts decreased to their lowest 3 to 5 days following administration. Thereafter, neutrophils
recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients
demonstrated a similar pattern of absolute neutrophil counts following Actemra administration
(see section 2.4.4 Laboratory Tests).
3.1.1 Mechanism of Action

Actemra is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal
antibody of the immunoglobulin (Ig) IgG1 subclass. Actemra binds specifically to both soluble
and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit
sIL-6R and mIL-6R-mediated signaling. IL-6 is a multi-functional cytokine, produced by a
variety of cell types involved in local paracrine function as well as regulation of systemic
physiological and pathological processes such as induction of immunoglobulin secretion, T-cell
activation, induction of hepatic acute phase proteins and stimulation of haematopoiesis. IL-6
has been implicated in the pathogenesis of diseases including inflammatory diseases,
osteoporosis, and neoplasia.
In clinical studies with Actemra, rapid decreases in CRP, erythrocyte sedimentation rate (ESR)
and serum amyloid (SAA) were observed. Consistent with the effect on acute phase reactants,
treatment with Actemra was associated with reduction in platelet count within the normal range.
Increases in haemoglobin levels were observed, through Actemra decreasing the IL-6 driven
effects on hepcidin production to increase iron availability. In Actemra-treated patients,
decreases in the levels of CRP to within normal ranges were seen as early as week 2, with
decreases maintained while on treatment.
3.1.2 Clinical/Efficacy Studies

The efficacy of Actemra IV in alleviating the signs and symptoms of rheumatoid arthritis was
assessed in five randomized, double-blind, multicentre studies. Studies I-V required patients ≥
age 18 with active rheumatoid arthritis diagnosed according to American College of
Rheumatology (ACR) criteria who had at least 8 tender and 6 swollen joints at baseline.
Actemra IV was administered intravenously every 4 weeks as monotherapy (Study I), in

combination with MTX (Studies II, III, V) or with other disease-modifying anti-rheumatic
drugs (DMARDs) (Study IV).
Study I evaluated 673 patients who had not been treated with MTX within 6 months prior to
randomization, and who had not discontinued previous MTX treatment as a result of clinically
important toxic effects or lack of response. The majority (67%) of patients were MTX naïve.
Doses of 8 mg/kg of Actemra IV were given every four weeks as monotherapy. The comparator
group was weekly MTX (dose titrated from 7.5 to a maximum of 20 mg weekly over an 8 week
period). The primary endpoint was the proportion of patients who achieved an ACR20 response
at week 24.
Study II, an ongoing two year study with a planned interim analyses at week 24 and week 52,
evaluated 1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8
mg/kg of Actemra IV or placebo were given every four weeks as blinded therapy for 52 weeks,
in combination with stable MTX (10 mg to 25 mg weekly). The primary endpoint at week 24
was the proportion of patients who achieved an ACR 20 response criteria. At week 52 the co-
primary endpoints were prevention of joint damage and improvement in physical function.
Study III evaluated 623 patients who had an inadequate clinical response to MTX. Doses of 4 or
8 mg/kg Actemra IV or placebo were given every four weeks, in combination with stable MTX
(10 mg to 25 mg weekly). Study IV evaluated 1220 patients who had an inadequate response to
Page 20 of 35
their existing rheumatologic therapy, including one or more DMARDs. Doses of 8 mg/kg
Actemra IV or placebo were given every four weeks in combination with stable DMARDs.
Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to
one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to
randomization. Doses of 4 or 8 mg/kg Actemra IV or placebo were given every four weeks, in
combination with stable MTX (10 mg to 25 mg weekly). The primary endpoint for studies III-V
was the proportion of patients who achieved an ACR20 response at week 24.
The percent of patients achieving ACR20, 50 and 70 responses in Studies I to V are shown in
Table 2.
The efficacy of Actemra SC was assessed in a double-blind, controlled, multicentre study in

patients with active RA. The study (SC-I) required patients to be > 18 years of age with active
rheumatoid arthritis diagnosed according to ACR criteria and who had at least 4 tender and 4
swollen joints at baseline. All patients received background non-biologic DMARD(s).
Study SC-I evaluated patients with moderate to severe active rheumatoid arthritis who had an
inadequate clinical response to their existing rheumatologic therapy, including one or more
DMARD(s). Approximately 20% had a history of inadequate response to at least one TNF
inhibitor. In SC-I, 1262 patients were randomized 1:1 to receive Actemra SC 162 mg every
week or Actemra IV 8 mg/kg every four weeks in combination with non-biologic DMARD(s).
The primary endpoint in the study was the difference in the proportion of patients who achieved
an ACR20 response at week 24. The results from study SC-I is shown in Table 4.
Table 2 ACR responses in MTX/Placebo-Controlled Trials (Percent of Patients)
Study I Study II Study III Study IV Study V

AMBITION LITHE OPTION TOWARD RADIATE
TCZ MTX TCZ PBO TCZ PBO TCZ PBO TCZ PBO
8mg/kg 8mg/kg + 8mg/kg + 8mg/kg + 8mg/kg +
Response + MTX + MTX + DMARD + MTX
Rate MTX MTX DMARD MTX
N= 286 N= 284 N=398 N=393 N=205 N=204 N=803 N=413 N=170 N=158
ACR20
Week 24 70%*** 52% 56%*** 27% 59%*** 26% 61%*** 24% 50%** 10%
*
Week 52 56%*** 25%
ACR 50
Week 24 44%** 33% 32%*** 10% 44%*** 11% 38%*** 9% 29%** 4%
*
Week 52 36%*** 10%
ACR 70
Week 24 28%** 15% 13%*** 2% 22%*** 2% 21%*** 3% 12%** 1%
Week 52 20%*** 4%
MCR † by 7% 1%
week 52
TCZ - Actemra IV
MTX - Methotrexate
PBO - Placebo
DMARD - Disease modifying anti-rheumatic drug
*p< 0.05, TCZ vs. PBO + MTX/DMARD
**p< 0.01, TCZ vs. PBO + MTX/DMARD
***p< 0.0001, TCZ vs. PBO + MTX/DMARD
† MCR = major clinical response, defined as an ACR70 response maintained for any 24 consecutive weeks or more.
Page 21 of 35
In all studies, patients treated with Actemra IV 8 mg/kg had statistically significant higher
ACR20, 50, 70 response rates at 6 months compared to control. The treatment effect was
similar in patients independent of rheumatoid factor status, age, gender, race, number of prior
treatments or disease status. Time to onset was rapid (as early as week 2) and the magnitude of
response continued to improve with duration of treatment. Continued durable responses were
seen for over 3 years in the ongoing open label extension studies I-V.
In the patients treated with Actemra IV 8 mg/kg significant improvements were noted on all
individual components of the ACR response (tender and swollen joint counts, patients and
physician global assessment, disability index scores, pain assessment and CRP compared to
patients receiving placebo+ MTX/DMARDs in all studies.
Actemra IV 8 mg/kg treated patients had a statistically significantly greater reduction in disease
activity score (DAS28) than patients treated with placebo + DMARD. A good to moderate
EULAR response was achieved by significantly more Actemra treated patients compared to
patients treated with placebo + DMARD (Table 3).
Table 3 Cross-Study Comparison of DAS and EULAR Responses at Week 24

MTX Naive Inadequate Response Inadequate Response Inadequate Response Inadequate
to MTX to MTX to DMARD Response to TNF
Blocking Agent
TCZ MTX TCZ Placebo TCZ Placebo TCZ Placebo TCZ Placebo
8 mg/kg 8 mg/kg + 8 mg/kg + 8 mg/kg + 8 mg/kg +
+ MTX + MTX + DMARD + MTX
MTX MTX DMARD MTX
N=286 N=284 N= 398 N=393 N= 205 N=204 N=803 N=413 N=170 N=158
Change in DAS28 [mean (Adjusted mean (SE))]
Week 24 -3.31 -2.05 -3.11 -1.45 -3.43 -1.55 -3.17 -1.16 -3.16 -0.95
(0.12) (0.12) (0.09)*** (0.11) (0.12)*** (0.15) (0.07)*** (0.09) (0.14) (0.22)
***
DAS < 2.6 response (%)
≠
Week 24 33.6% 12.1% 33.3%*** 3.8% 27.5%*** 0.8% 30.2%*** 3.4% 30.1% 1.6%
***
EULAR response (%)
None 18% 35% 26% 65% 20% 65% 20% 62% 32% 84%
Moderate 42% 48% 34% 29% 41% 32% 40% 33% 31% 15%
Good† 40% 17% 41%*** 6% 38%*** 3% 40%*** 4% 37%*** 2%
TCZ = Actemra IV
†The p value compares across all the EULAR categories
* p < 0.05, TCZ vs. placebo+MTX/DMARD
** p < 0.01, TCZ vs. placebo+MTX/DMARD
*** p < 0.0001, TCZ vs. placebo+MTX/DMARD
≠ In study II, 47% of patients achieved a DAS28 < 2.6 at 52 weeks compared to 33% of patients at week 24.
Page 22 of 35
Table 4 Clinical Response at Week 24 in Actemra SC Trial (Percent of Patients)
SC-Ia
Actemra SC 162 mg every week Actemra IV 8 mg/kg
+ DMARD(s) + DMARD(s)
N=558 N=537
ACR20
Week 24 69.4% 73.4%
Weighted difference (95% CI) -4.0 (-9.2, 1.2)
ACR50
Week 24 47.0% 48.6%
ACR70
Week 24 24.0% 27.9%
Change in DAS28 [adjusted mean]
Week 24 -3.5 -3.5
Adjusted mean difference 0 (-0.2, 0.1)
(95% CI)
DAS28 < 2.6
Week 24 38.4% 36.9%
Weighted difference (95% CI) 0.9 (-5.0, 6.8)
EULAR response (%)
None 3.3% 4.8%
Moderate 41.7% 42.7%
Good 55.0% 52.4%
a = Per Protocol Population
Major Clinical Response

After 2 years of treatment with Actemra/MTX, 14% of patients achieved a major clinical
response (maintenance of an ACR70 response for 24 weeks or more).
Radiographic Response – Intravenous Administration

In Study II, in patients with an inadequate response to MTX, inhibition of structural joint
damage was assessed radiographically and expressed as change in modified Sharp score and its
components, the erosion score and joint space narrowing score. Inhibition of joint structural
damage was shown with significantly less radiographic progression in patients receiving
Actemra compared to control.
In the open-label extension of Study II the inhibition of progression of structural damage in

Actemra/MTX-treated patients was maintained in the second year of treatment
Table 5 Radiographic mean changes at 52 weeks and 104 weeks in Study II
PBO + MTX TCZ 8 mg/kg + MTX

(+ option of TCZ from
week 16)
Changes from baseline to Week 52

n 294 353
Total Sharp-Genant score 1.17 0.25
Erosion score 0.76 0.15
JSN score 0.41 0.10
Page 23 of 35
PBO + MTX TCZ 8 mg/kg + MTX

(+ option of TCZ from
week 16)
Change from week 52 to week104

n 294 353
Total Sharp-Genant score 0.79 0.12
Erosion score 0.48 0.07
JSN score 0.31 0.05
PBO - Placebo
MTX - Methotrexate
TCZ – Actemra IV
JSN - Joint space narrowing
All data presented was read together in campaign 2 which consists of the evaluations of the baseline, week 24, week
52, week 80, week 104 and early withdrawal or escape therapy readings taken up to week 104 visit
Following 1 year of treatment with Actemra/MTX, 83% of patients had no progression of

structural damage, as defined by a change in the TSS score of zero or less, compared with 67%
of placebo/MTX-treated patients. This remained consistent following 2 years of treatment
(83%). Ninety-three percent (93%) of patients had no progression between week 52 and week
104.
Haemoglobin levels
Statistically significant improvements in haemoglobin levels were observed with tocilizumab

compared with DMARDs (p< 0.0001) at week 24. Mean haemoglobin levels increased by week
2 and remained within normal range through to week 24.
Radiographic Response – Subcutaneous Administration
The radiographic response of Actemra SC was assessed in a double-blind, controlled,

multicentre study in patients with active RA. This study (SC-II) evaluated patients with
moderate to severe active rheumatoid arthritis who had an inadequate clinical response to their
existing rheumatologic therapy, including one or more DMARD(s) where approximately 20%
had a history of inadequate response to at least one TNF inhibitor. Patients were required to
be > 18 years of age with active rheumatoid arthritis diagnosed according to ACR criteria and
who had at least 8 tender and 6 swollen joints at baseline. In SC-II, 656 patients were
randomized 2:1 to Actemra SC 162 mg every other week or placebo, in combination with non-
biologic DMARD(s).
In study SC-II, inhibition of structural joint damage was assessed radiographically and
expressed as a change from baseline in the van der Heijde modified mean total Sharp score
(mTSS). At week 24, inhibition of structural damage was shown, with significantly less
radiographic progression in patients receiving Actemra SC compared with placebo (mTSS of
0.62 vs. 1.23, p=0.0149 (van Elteren). These results are consistent with those observed in
patients treated with Actemra IV.
Quality of Life Outcomes – Intravenous Administration
Clinically significant improvements in disability index (HAQ-DI, Health Assessment

Questionnaire Disability Index), fatigue (FACIT-Fatigue, Functional Assessment of Chronic
Illness Therapy Fatigue) and improvement in both the physical (PCS, Physical Component
Summary) and mental health (MCS, Mental Component Summary) domains of the SF-36
Page 24 of 35
(Short Form 36) were observed in patients treated with Actemra IV 8 mg/kg (monotherapy or
combination with DMARDs) compared to patients treated with MTX/DMARDs (Table 6).
At week 24, the proportion of Actemra IV 8 mg/kg treated patients showing a clinically
relevant improvement in HAQ-DI (defined as an individual total score decrease of > 0.25), was
significantly higher than among patients receiving placebo + MTX/DMARDs in all studies.
During the open-label period of Study II the improvement in physical function has been
maintained for up to 2 years.
Table 6 Comparison of SF-36, HAQ and FACIT-Fatigue Responses at Week 24

MTX-Naïve Inadequate Response Inadequate Response Inadequate Response to Inadequate Response
to MTX to MTX DMARD to TNF Blocking
Agent
TCZ MTX TCZ Placebo TCZ Placebo TCZ Placebo TCZ Placebo
8 mg/kg 8 mg/kg + 8 mg/kg + 8 mg/kg + 8 mg/kg +
+ MTX + MTX + DMARD + MTX
MTX MTX DMARD MTX
N=286 N=284 N= 398 N=393 N= 205 N=204 N= 803 N=413 N=170 N=158
Change in PCS [mean (Adjusted mean (SE))]
10.2 8.4 8.1 5.6 9.5 5.0 8.9 4.1 8.0 2.2
(0.7) (0.7) (0.6)** (0.7) (0.8)*** (1.0) (0.4)*** (0.6) (0.9)** (1.3)
Change in MCS [mean (Adjusted mean (SE))]
6.7 5.0 4.2 2.8 7.3 2.7 5.3 2.3 4.1 4.1
(0.9) (0.9) (0.8) (0.9) (1.1)** (1.3) (0.6)** (0.7) (1.3) (1.9)
Change in HAQ-DI [mean (Adjusted mean (SE))]
-0.70 -0.52 -0.5 -0.3 -0.55 -0.34 -0.47 -0.2 -0.39 -0.05
(0.05) (0.05) (0.04)** (0.04) (0.06)** (0.07) (0.03)*** (0.03) (0.05)*** (0.07)
Change in FACIT-Fatigue [mean (Adjusted mean (SE))]
9.3 7.0 6.4 5.4 8.6 4.0 8.0 3.6 8.8 4.2
(0.8) (0.8) (0.7) (0.8) (0.9)*** (1.0) (0.5)*** (0.7) (1.0)* (1.6)
TCZ = Actemra IV
* p<0.05, TCZ vs. placebo+MTX/DMARD
** p<0.01, TCZ vs. placebo+MTX/DMARD
*** p<0.0001, TCZ vs. placebo+MTX/DMARD
In study II, changes in PCS, MCS and FACIT-Fatigue at 52 weeks were 10.1***, 5.4 and 8.4**,
respectively, in the Actemra IV 8 mg/kg + MTX group compared to 5.6, 3.8 and 5.5,
respectively, in the Placebo plus MTX group. At Week 52, the mean change in HAQ-DI was -
0.58 in the Actemra IV 8 mg/kg + MTX group compared with -0.39 in the placebo + MTX
group. The mean change in HAQ-DI was maintained at Week 104 in the Actemra IV 8 mg/kg
+ MTX group (-0.61).
Quality of Life Outcomes – Subcutaneous Administration
In study SC-I, the mean decrease in HAQ-DI from baseline to week 24 was 0.6 for both
Actemra SC 162 mg weekly and Actemra IV 8 mg/kg every 4 weeks. The proportion of patients
achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baseline of ≥
0.3 units) was comparable in the Actemra SC every week group (65.2%) versus the Actemra IV
8 mg/kg group (67.4%), with a weighted difference in proportions of -2.3% (95% CI -8.1, 3.4).
The SF-36 summary was split into mental and physical components. The mental component
Page 25 of 35
scores were similar between the groups, with a mean change from baseline at week 24 of 6.22
for the SC group and 6.54 for the IV group. The physical component scores were also similar
between the groups, with mean change from baseline at week 24 of 9.49 for the SC group and
9.65 for the IV group.
Laboratory Evaluations
Treatment with Actemra IV 8 mg/kg in combination with DMARD/MTX or as monotherapy

resulted in a highly statistically significant improvement in haemoglobin levels compared with
placebo + MTX/DMARD (p<0.0001) at week 24. The greatest improvement was observed in
patients with chronic anaemia associated with RA; mean haemoglobin levels increased by week
2 and remained within normal range through week 24.
A marked decrease in mean levels of acute phase reactants, CRP, ESR, and serum amyloid A
occurred rapidly after Actemra administration. Consistent with the effect on acute phase
reactants, treatment with Actemra was associated with reduction in platelet count within the
normal range.
Monotherapy: Actemra versus adalimumab
Study WA19924 evaluated 326 patients with RA who were intolerant of MTX or where
continued treatment with MTX was considered inappropriate (including MTX inadequate
responders). Patients in the Actemra arm received an Actemra IV (8 mg/kg) every 4 weeks
(q4w) and a Subcutaneous (SC) placebo injection every 2 weeks (q2w). Patients in the
adalimumab arm received an adalimumab SC injection (40 mg) q2w plus an IV placebo
infusion q4w.
A statistically significant superior treatment effect was seen in favour of Actemra over
adalimumab in control of disease activity from baseline to week 24 for the primary endpoint of
change in DAS28 and for all secondary endpoints (Table 7).
Table 7 Efficacy Results for Study WA 19924
ADA + Placebo
(IV) TCZ + Placebo (SC)
N = 162 N = 163 p-value(a)
Primary Endpoint - Mean Change from baseline at Week 24
DAS28 (adjusted mean) -1.8 -3.3
Difference in adjusted mean (95% CI) -1.5 (-1.8, -1.1) <0.0001
Secondary Endpoints - Percentage of Responders at Week 24 (b)
DAS28 < 2.6, n (%) 18 (10.5) 65 (39.9) <0.0001
DAS28 ≤ 3.2, n (%) 32 (19.8) 84 (51.5) <0.0001
ACR20 response, n (%) 80 (49.4) 106 (65.0) 0.0038
ACR50 response, n (%) 45 (27.8) 77 (47.2) 0.0002
ACR70 response, n (%) 29 (17.9) 53 (32.5) 0.0023
a
p value is adjusted for region and duration of RA for all endpoints and additionally baseline value for
all continuous endpoints.
b
Non-responder Imputation used for missing data. Multiplicity controlled using Bonferroni-Holm Procedure

The efficacy of Actemra IV was assessed in a three-part study including an open-label
extension in children with active polyarticular juvenile idiopathic arthritis (pJIA). Part I
consisted of a 16 week active Actemra IV treatment lead in period (n=188) followed by Part II,
a 24 week randomized double blind placebo controlled withdrawal period (ITT, n=163),
followed by Part III, a 64 week open label period. Eligible patients ≥ 30 kg received Actemra
Page 26 of 35
IV at 8 mg/kg for 4 doses. Patients < 30 kg were randomized 1:1 to receive either Actemra IV
8 mg/kg or 10 mg/kg IV every 4 weeks for 4 doses. Patients who completed Part I of the study
and achieved at least a JIA ACR30 response at week 16 compared to baseline entered the
blinded withdrawal period (Part II) of the study. In Part II, patients were randomized to
Actemra IV (same dose received in Part I) or placebo in a 1:1 ratio was stratified by concurrent
methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the
study until Week 40 or until the patient satisfied JIA ACR30 flare criteria (relative to Week 16)
and qualified for escape.
The primary endpoint was the proportion of patients with a JIA ACR30 flare at week 40
relative to week 16. Forty eight percent (48.1%, 39/81) of the patients treated with placebo
flared compared with 25.6% (21/82) of Actemra-treated patients. These proportions were
statistically significantly different (p=0.0024).
At the conclusion of Part I, JIA ACR 30/50/70/90 responses were 89.4%, 83.0%, 62.2%, and
26.1%, respectively.
During the withdrawal phase (Part II), the percent of patients achieving JIA ACR 30, 50, and 70
responses at Week 40 relative to baseline are shown in the table below.
Table 8 JIA ACR Response Rates at Week 40 Relative to Baseline (Percent of Patients)
TCZ Placebo
Response Rate
N=82 N=81
JIA ACR 30 74.4%† 54.3%†
JIA ACR 50 73.2%† 51.9%†
JIA ACR 70 64.6%† 42.0%†
†
p<0.01, Actemra IVvs. placebo

The efficacy of intravenous tocilizumab for the treatment of active sJIA was assessed in a 12-
week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients
(treated with or without MTX) were randomized (TCZ:placebo = 2:1) to one of two treatment
groups, 75 patients received tocilizumab infusions every two weeks either 8 mg/kg for patients
≥ 30kg or 12 mg/kg for patients below 30 kg and 37 patients were assigned to receiving placebo
infusions every two weeks. Corticosteroid tapering could occur from week six for patients who
achieved a JIA ACR70 response. After 12 weeks or at the time of escape, due to disease
worsening, patients were treated in the open-label extension phase at weight appropriate dosing.
The primary endpoint was the proportion of patients with at least 30% improvement in JIA
ACR core set (JIA ACR30 response) at Week 12 and absence of fever (no temperature
recording ≥ 37.5°C in the preceding 7 days). Eighty five percent (64/75) of the patients treated
with TCZ and 24.3% (9/37) of placebo patients achieved this endpoint. These proportions were
highly significantly different (p <0.0001).
The percent of patients achieving JIA ACR 30, 50, 70 and 90 responses are shown in the table
below. Responses are maintained in the open label extension.
Page 27 of 35
Table 9 JIA ACR Response Rates at Week 12 (Percent of Patients)
Response Rate TCZ Placebo

N=75 N=37
ACR 30 90.7%* 24.3%
ACR 50 85.3%* 10.8%
ACR 70 70.7%* 8.1%
ACR 90 37.3%* 5.4%
* p<0.0001, tocilizumab vs. placebo
Systemic Features
In those patients treated with tocilizumab, 85% who had fever due to sJIA at baseline were free
of fever (no temperature recording ≥ 37.5°C in the preceding 14 days) at week 12 versus only
21% of placebo patients (p<0.0001) and 64% of tocilizumab treated patients with rash
characteristic of sJIA at baseline were free of rash at week 12 versus 11% of placebo patients
(p=0.0008).
There was a highly statistically significant reduction in pain for tocilizumab treated patients at
week 12 in comparison to placebo patients. The adjusted mean change in the pain VAS after 12
weeks of tocilizumab treatment was a reduction of 41 points on a scale of 0 -100 compared to a
reduction of 1 for placebo patients (p <0.0001).
The responses for systemic features are maintained in the open label extension.
Corticosteroid Tapering
Of the 31 placebo and 70 tocilizumab patients receiving oral corticosteroids at baseline, 8

placebo and 48 tocilizumab patients achieved a JIA ACR70 response at week 6 or 8 enabling
corticosteroid dose reduction. Seventeen (24%) tocilizumab patients versus 1 (3%) placebo
patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a
subsequent JIA ACR30 flare or occurrence of systemic symptoms to week 12 (p=0.028).
Reductions in corticosteroids continued, with 44 patients off oral corticosteroids, at week 44,
while maintaining ACR responses.
Quality of Life
At week 12, the proportion of tocilizumab treated patients showing a minimally clinically
important improvement in CHAQ-DI (defined as an individual total score decrease of ≥ 0.13)
was significantly higher than in patients receiving placebo, 77% versus 19% (p<0.0001).
Responses are maintained in the open label extension.
Laboratory Parameters
Fifty out of seventy five (67%) patients treated with tocilizumab had a haemoglobin below LLN
at baseline. Forty (80%) of these patients with decreased haemoglobin had an increase in their
haemoglobin to within the normal range at week 12, in comparison to only 2 out of 29 (7%) of
placebo patients with haemoglobin below LLN at baseline (p<0.0001). Forty four (88%)
tocilizumab patients with decreased haemoglobin at baseline had an increase in their
haemoglobin by ≥ 10 g/L at week 6 versus 1 (3%) placebo patient (p < 0.0001).
The proportion of tocilizumab treated patients with thrombocytosis at baseline who had a
normal platelet count at week 12 was significantly higher than in the placebo patients, 90 %
versus 4%, (p < 0.0001).
Page 28 of 35
A marked decrease in mean levels of acute phase reactants, CRP, ESR, and serum amyloid A
occurred rapidly after tocilizumab administration.
3.2 Pharmacokinetic Properties

The pharmacokinetics of Actemra IV were determined using a population pharmacokinetic

analysis on a database composed of 1793 RA patients treated with a one-hour infusion of 4 and
8 mg/kg Actemra IV every 4 weeks for 24 weeks.
The pharmacokinetic parameters of Actemra IV did not change with time. A more than dose-
proportional increase in area under the curve (AUC) and trough concentration (Cmin) was
observed for doses of 4 and 8 mg/kg every 4 weeks. Maximum concentration (Cmax) increased
dose-proportionally. At steady-state, predicted AUC and Cmin were 2.7 and 6.5 fold higher at
8 mg/kg as compared to 4 mg/kg, respectively.
The following parameters are valid for a dose of Actemra IV 8 mg/kg given every 4 weeks.
Predicted mean (± SD) steady-state area under curve (AUC), Cmin and Cmax of Actemra IV were
35000 ± 15500 mcg•h μg/mL, 9.74 ± 10.5 μg/mL, and 183 ± 85.6 μg/mL, respectively.The
accumulation ratios for AUC and Cmax were small, 1.22 and 1.06, respectively. The
accumulation ratio was higher for Cmin (2.35), which was expected based on the non-linear
clearance contribution at lower concentrations. Steady-state was reached following the first
administration and after 8 and 20 weeks for Cmax, AUC and Cmin, respectively. Actemra IV
AUC, Cmin and Cmax increased with increase of body weight. At body weight ≥ 100 kg, the
predicted mean (± SD) steady-state AUC, Cmin and Cmax of Actemra IV were 55500 ± 14100
mcg•h/mL, 19.0 ± 12.0 mcg/mL, and 269 ± 57 mcg/mL, respectively, which are higher than
mean exposure values for the patient population. Therefore, Actemra IV doses exceeding 800
mg per infusion are not recommended in patients ≥ 100 kg (see section 2.2 Dosage and
Administration).
The following parameters are valid for a dose of Actemra IV 4 mg/kg given every 4 weeks.
Predicted mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 13000 ± 5800
mcg•h/mL, 1.49 ± 2.13 mcg/mL, and 88.3 ± 41.4 mcg/mL, respectively. The accumulation
ratios for AUC and Cmax were small; 1.11 and 1.02, respectively. The accumulation ratio was
higher for Cmin (1.96). Steady-state was reached following the first administration for Cmax and
AUC, respectively, and after 16 weeks for Cmin.
The pharmacokinetics of Actemra SC were determined using a population pharmacokinetic

analysis on a database composed of 1759 rheumatoid arthritis patients treated with Actemra SC
162 mg every week, Actemra SC 162 mg every other week, and Actemra IV 8 mg/kg every 4
weeks for 24 weeks.
The pharmacokinetic parameters of Actemra SC did not change with time. For the Actemra SC
162 mg every week dose, the predicted mean (±SD) steady-state AUC1week, Cmin and Cmax of
tocilizumab were 8200 ± 3600 mcg•h/mL, 44.6 ± 20.6 mcg/mL, and 50.9 ± 21.8 mcg/mL,
respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.83, 6.37, and 5.47,
respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax.
For the Actemra SC 162 mg every other week dose, the predicted mean (±SD) steady-state
AUC2week, Cmin, and Cmax of Actemra SC were 3200 ± 2700 mcg•h/mL, 5.6 ± 7.0 mcg/mL, and
Page 29 of 35
12.3 ± 8.7 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67,
5.6, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and Cmin, and
after 10 weeks for Cmax.

The pharmacokinetics of Actemra in pJIA patients was characterized by a population
pharmacokinetic analysis which included 237 patients who were treated with Actemra IV 8
mg/kg every 4 weeks (patients weighing ≥ 30 kg), Actemra IV 10 mg/kg every 4 weeks
(patients weighing below 30 kg).
Table 10 Predicted mean ± SD PK parameters at steady-state after IV

IV
8 mg/kg Q4W 10 mg/kg Q4W
TCZ PK Parameter
≥ 30 kg below 30 kg
Cmax (µg/mL) 183 ± 42.3 168 ± 24.8
Ctrough (µg/mL) 6.55 ± 7.93 1.47 ± 2.44
Cmean (µg/mL) 42.2 ± 13.4 31.6 ± 7.84
Accumulation Cmax 1.04 1.01
Accumulation Ctrough 2.22 1.43

Accumulation Cmean or
1.16 1.05
AUCτ *
*τ = 4 weeks for IV regimens
After Actemra IV dosing, approximately 90% of the steady-state was reached by Week 12 for
the 10 mg/kg (BW < 30 kg), and by Week 16 for the 8 mg/kg (BW ≥ 30 kg) dose.

The pharmacokinetics of tocilizumab in sJIA patients was characterized by a population
pharmacokinetic analysis which included 140 patients who were treated with 8 mg/kg IV every
2 weeks (patients weighing ≥ 30 kg), 12 mg/kg IV every 2 weeks (patients weighing below 30
kg).
Table 11 Predicted mean ± SD PK parameters at steady-state after IV dosing in

sJIA
IV
TCZ PK 8 mg/kg Q2W 12 mg/kg Q2W
Parameter ≥ 30 kg below 30 kg
Cmax (µg/mL) 256 ± 60.8 274 ± 63.8
Ctrough (µg/mL) 69.7 ± 29.1 68.4 ± 30.0
Cmean (µg/mL) 119 ± 36.0 123 ± 36.0
Accumulation Cmax 1.42 1.37

Accumulation Ctrough 3.20 3.41
Accumulation Cmean 2.01 1.95
or AUCτ *
*τ = 2 weeks for IV regimens
After IV dosing, approximately 90% of the steady-state was reached by Week 8 for both the 12
mg/kg and 8 mg/kg Q2W regimens.
Page 30 of 35
3.2.1 Absorption
Following SC dosing in rheumatoid arthritis patients, the absorption half-life was around 4
days. The bioavailability for the SC formulation was 0.8.
3.2.2 Distribution
Following IV dosing, Actemra undergoes biphasic elimination from the circulation. In
rheumatoid arthritis patients the central volume of distribution was 3.5 L, the peripheral volume
of distribution was 2.9 L resulting in a volume of distribution at steady state of 6.4 L.
In paediatric patients with pJIA, the central volume of distribution was 1.98 L, the peripheral
volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.
3.2.3 Metabolism
No text
3.2.4 Elimination
The total clearance of Actemra was concentration-dependent and is the sum of the linear and
non-linear clearance. The linear clearance was estimated as a parameter in the population
pharmacokinetic analysis and was 12.5 mL/h in rheumatoid arthritis patients and 5.8 mL/h in
paediatric patients with polyarticular juvenile idiopathic arthritis and 5.7 mL/h in paediatric
patients with Systemic Juvenile Idiopathic Arthritis. The concentration-dependent non-linear
clearance plays a major role at low Actemra concentrations. Once the non-linear clearance
pathway is saturated, at higher Actemra concentrations, clearance is mainly determined by the
linear clearance.
In RA patients, for intravenous administration, the t1/2 of Actemra IV was concentration-

dependent in rheumatoid arthritis, the concentration-dependent apparent t1/2 is up to 11 days for
4 mg/kg and 13 days for 8 mg/kg every 4 weeks in patients with RA at steady-state. For
subcutaneous administration, the concentration-dependent apparent t1/2 is up to 13 days for
Actemra SC 162 mg every week and 5 days for Actemra SC 162 mg every other week in
patients with RA at steady-state. At high serum concentrations, when total clearance of Actemra
SC is dominated by linear clearance, a terminal t1/2 of approximately 21.5 days was derived
from the population parameter estimates.
In children with pJIA, the effective t1/2 of Actemra IV is up to 17 days for the two body weight
categories (8 mg/kg for body weight ≥ 30 kg or 10 mg/kg for body weight below 30 kg) during
a dosing interval at steady state.
In children with sJIA, the effective t1/2 of IV tocilizumab is up to 16 days for both the 12 mg/kg
and 8 mg/kg Q2W regimens during a dosing interval at steady-state.
3.2.5 Linearity
Pharmacokinetic parameters of Actemra did not change with time. A more than dose-
proportional increase in the AUC and Cmin was observed for doses of Actemra IV 4 and 8 mg/kg
every 4 weeks. Cmax increased dose-proportionally. At steady-state, predicted AUC and Cmin
were 2.7 and 6.5 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.
3.2.6 Pharmacokinetics in Special Populations

Renal impairment: No formal study of the effect of renal impairment on the pharmacokinetics
of Actemra has been conducted.
Most of the patients in the RA studies population pharmacokinetic analysis had normal renal
function or mild renal impairment. Mild renal impairment (creatinine clearance based on
Page 31 of 35
Cockcroft-Gault < 80 mL/min and ≥ 50 mL/min) did not impact the pharmacokinetics of
Actemra. No dose adjustment is required in patients with mild renal impairment.
Hepatic impairment: No formal study of the effect of hepatic impairment on the

pharmacokinetics of Actemra has been conducted.
Age, gender and ethnicity: Population pharmacokinetic analyses in adult RA patients, showed
that age, gender and ethnic origin did not affect the pharmacokinetics of Actemra. No dose
adjustment is necessary for these demographic factors
3.3 Nonclinical Safety

3.3.1 Carcinogenicity
A carcinogenicity study of tocilizumab has not been conducted. Available preclinical data,
showed the contribution of the pleiotropic cytokine IL-6 to malignant progression and apoptosis
resistance of various cancer types. These data do not suggest a relevant risk for cancer initiation
and progression under therapy with Actemra. Accordingly, proliferate lesions have not been
observed in a chronic cynomolgus monkey 6-month toxicity study nor were they described in
IL-6 knock-out mice under chronic IL-6 depletion.
3.3.2 Genotoxicity
Standard genotoxicity studies with Actemra in both prokaryotic and eukaryotic cells were all
negative.
3.3.3 Impairment of Fertility

Nonclinical data do not suggest an effect on fertility under treatment with an analogue of
Actemra. Effects on endocrine active organs or on organs of the reproductive system were not
seen in a chronic cynomolgus monkey toxicity study, nor was the reproductive performance
affected in IL-6 deficient male and female mice.
3.3.4 Reproductive Toxicity

When Actemra was administered intravenously to cynomolgus monkeys during early gestation,
no direct or indirect harmful effects on pregnancy or embryo-foetal development were
observed.
3.3.5 Other
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity and genotoxicity.
In an embryo-foetal toxicity study conducted in cynomolgus monkeys a slight increase of

abortion/embryonal-foetal death was observed with high systemic cumulative exposure (>100 x
human exposure) in the 50 mg/kg/day high-dose group compared to placebo and other low-dose
groups. The abortion incidence was within the historical background for the cynomolgus
monkey in captivity and the individual cases of abortions/embryo-foetal death did not show any
consistent relationship to dosing or duration of dosing with Actemra. Although IL-6 does not
seem to be a critical cytokine for either foetal growth or the immunological control of the
maternal/foetal interface, a relation of this finding to Actemra cannot be excluded.
Transfer of a murine analogue of Actemra into the milk of lactating mice has been observed.
Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there
was no impairment of skeletal growth, immune function and sexual maturation.
The non-clinical safety profile of Actemra in the cynomolgus monkey does not suggest a
difference between IV and SC routes of administration.
Page 32 of 35
4. PHARMACEUTICAL PARTICULARS
4.1 Storage
Actemra IV:
Diluted product: After dilution, the prepared solution for infusion is physically and chemically
stable in sodium chloride 9 mg/mL (0.9%) solution for injection at 30ºC for 24 hours.
From a microbiological point of view, the prepared solution for infusion should be used
immediately. If not used immediately, in use storage times and conditions prior to use are the
responsibility of the user and would normally not be longer than 24 hours at 2°C – 8°C, unless
dilution has taken place in controlled and validated aseptic conditions.
Actemra is supplied as a sterile concentrate that does not contain preservatives.
Special precautions for storage

Store vials in a refrigerator 2°C–8°C. Do not freeze.
Keep the vial(s) in the outer carton in order to protect from light.
Actemra SC:
The medicine should not be used after the expiry date shown on the PFS and the pack. Store
the PFS in a refrigerator at a temperature of 2°C–8°C. Do not freeze, keep in carton to protect
from light, and keep dry.
4.2 Special Instructions for Use, Handling and Disposal

Actemra IV:
Instructions for dilution prior to administration
Parenteral medicinal products should be inspected visually for particulate matter or
discoloration prior to administration. Only solutions which are clear to opalescent, colourless to
pale yellow and free of visible particles must be infused.
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.
Actemra is for single-use only.
Any unused product or waste material should be disposed of in accordance with local
requirements.
pJIA and sJIA Patients ≥ 30 kg:

From a 100 mL infusion bag, withdraw a volume of 0.9% sodium chloride solution equal to the
volume of the Actemra solution required for the patient’s dose. Withdraw the required amount
of Actemra (0.4 mL/kg) under aseptic conditions and dilute to a calculated Actemra
concentration in a 100 mL infusion bag containing sterile, non-pyrogenic 0.9% sodium chloride
solution. To mix the solution, gently invert the bag to avoid foaming.
Page 33 of 35
sJIA patients below 30 kg:

From a 50 mL infusion bag, withdraw a volume of 0.9% sodium chloride solution equal to 0.6
mL/kg of the patient’s body weight and discard. This volume should be replaced in the saline
bag with an equal volume of tocilizumab under aseptic conditions. To mix the solution, gently
invert the bag to avoid foaming.
pJIA Patients < 30 kg:

From a 50 mL infusion bag, withdraw a volume of 0.9% sodium chloride solution equal to 0.5
mL/kg of the patient’s body weight and discard. This volume should be replaced in the saline
bag with an equal volume of Actemra under aseptic conditions. To mix the solution, gently
invert the bag to avoid foaming.
Actemra SC:
Do not use if the medicine is cloudy or contains particles, is any colour besides colourless to
yellowish, or any part of the PFS+NSD appears to be damaged.
Disposal of syringes/sharps
The following points should be strictly adhered to regarding the use and disposal of the
PFS+NSD:
• Syringes should never be reused.
• Place all used syringes into a sharps container (puncture-proof disposable container).
• Keep this container out of the reach of children.
• Placing used sharps containers in the household waste should be avoided.
• Dispose of the full container according to local requirements or as instructed by your
healthcare provider.
For home use, patients should procure a puncture resistant container for the disposal of used
syringes.
Disposal of unused/expired medicines

The release of pharmaceuticals in the environment should be minimized. Medicines should not
be disposed of via wastewater, and disposal through household waste should be avoided. Use
established ‘collection systems' if available in your location.
Packs
Actemra IV:
Box, 1 Vial @ 80 mg (4 mL) Reg.No.: DKI1135900149A1
Box, 1 Vial @ 400 mg (20 mL) Reg.No.: DKI1135900149A1
Actemra SC:
Box, 4 prefilled syringes @ 0.9 mL Reg.No.:
Medicine: keep out of reach of children

Obat: Jauhkan dari jangkauan anak-anak
On medical prescription only
Harus dengan resep dokter
Pada proses pembuatannya bersinggungan dengan bahan

bersumber babi
Page 34 of 35
Made by:
Actemra IV:
Chugai Pharma Manufacturing Co, Ltd, Utsunomiya-City, Japan
Actemra SC:
Vetter Pharma-Fertigung GmbH & Co. KG, Ravensburg, Germany
For:
F. Hoffmann-La Roche Ltd, Basel, Switzerland
Imported by:
PT Boehringer Ingelheim Indonesia, Bogor, Indonesia
Distributed by:
PT Roche Indonesia, Jakarta, Indonesia
Page 35 of 35
Draft_ACTEMRA SC_PIL_New Drug Application_ID_v1
INFORMASI PRODUK UNTUK PASIEN
ACTEMRA
Tocilizumab
20 mg/mL konsentrat untuk cairan infus intravena/ACTEMRA IV

162 mg cairan injeksi dalam alat suntik siap pakai untuk pemberian subkutan/ACTEMRA SC
Bacalah seluruh brosur ini dengan saksama sebelum Anda mulai menggunakan obat ini karena
brosur ini berisi informasi yang penting bagi Anda.
• Simpan brosur ini. Anda mungkin perlu membacanya kembali.

• Jika Anda memiliki pertanyaan lebih lanjut, tanyakan pada dokter, apoteker, atau perawat Anda.
• Obat ini hanya diresepkan untuk Anda. Jangan memberikannya kepada orang lain. Obat ini mungkin
dapat membahayakan mereka, walaupun tanda-tanda penyakit mereka serupa dengan penyakit Anda.
• Jika Anda mengalami efek samping, bicarakanlah dengan dokter, apoteker, atau perawat Anda. Hal ini
termasuk efek samping yang mungkin terjadi di luar dari apa yang tercantum pada brosur ini. Lihat
bagian 4.
Apa yang terdapat dalam brosur ini

1. Apa itu ACTEMRA dan kegunaannya
2. Apa yang perlu Anda ketahui sebelum diberikan ACTEMRA
3. Cara pemberian ACTEMRA
4. Efek samping yang mungkin terjadi
5. Cara penyimpanan ACTEMRA
6. Isi dalam kemasan dan informasi lainnya
7. Petunjuk penggunaan ACTEMRA SC
1. Apa itu ACTEMRA dan kegunaannya
Apa itu ACTEMRA
ACTEMRA mengandung zat aktif tocilizumab, yaitu protein yang terbuat dari sel-sel imun spesifik
(antibodi monoklonal), yang menghambat aktivitas protein tertentu (sitokin) berupa interleukin-6. Protein
ini berperan dalam proses peradangan dalam tubuh dan penghambatan protein ini dapat mengurangi
peradangan dalam tubuh Anda.
Apa kegunaan ACTEMRA
ACTEMRA digunakan untuk mengobati:
• Artritis reumatoid untuk formulasi intravena (ACTEMRA IV) dan subkutan (ACTEMRA SC)
 orang dewasa dengan artritis reumatoid (AR) aktif derajat sedang hingga berat, yaitu suatu
penyakit autoimun, apabila terapi sebelumnya tidak memberi respons yang cukup baik.
 orang dewasa dengan artritis reumatoid (AR) yang berat, aktif, dan progresif.
ACTEMRA membantu mengurangi gejala-gejala AR seperti nyeri dan bengkak pada persendian
Anda, dan dapat pula meningkatkan performa Anda dalam melakukan aktivitas harian.
ACTEMRA telah terbukti memperlambat kerusakan tulang lunak dan tulang pada persendian
yang diakibatkan oleh penyakit tersebut dan meningkatkan kemampuan Anda untuk melakukan
aktivitas harian seperti biasanya.
Page 1 of 16
• Artritis Juvenil Poliartikular Idiopatik untuk formulasi Intravena (ACTEMRA IV)
 ACTEMRAdigunakan untuk mengobati anak dengan pJIA. ACTEMRA digunakan untuk

anak berusia 2 tahun ke atas yang mengalami artritis juvenil poliartikular idiopatik [polyarticular
juvenile idiopathic arthritis (pJIA)], yaitu suatu penyakit autoimun yang menyebabkan nyeri dan
bengkak pada satu atau lebih sendi. ACTEMRA digunakan untuk memperbaiki gejala-gejala
pJIA dan dapat diberikan baik secara kombinasi dengan metotreksat atau secara tunggal.
• Artritis Juvenil Sistemik Idiopatik
 ACTEMRA digunakan untuk mengobati anak dengan sJIA. ACTEMRA digunakan untuk
anak berusia 2 tahun ke atas yang mengalami artritis juvenil sistemik idiopatik [systemic juvenile
idiopathic arthritis (sJIA)], yaitu suatu penyakit autoimun yang menyebabkan nyeri dan bengkak
pada satu atau lebih sendi disertai demam dan ruam. ACTEMRA digunakan untuk memperbaiki
gejala-gejala sJIA pada pasien yang sudah tidak merespons pengobatan dengan metotreksat atau
obat antiinflamasi non steroid dan kortikosteroid sistemik.
2. Apa yang perlu Anda ketahui sebelum Anda diberikan ACTEMRA
Anda tidak boleh menggunakan ACTEMRA bila:

• Anda alergi terhadap tocilizumab atau bahan-bahan lain dalam obat ini (tercantum pada bagian
6).
• Anda mengalami infeksi berat dalam kondisi aktif.
Apabila salah satu dari hal tersebut sesuai dengan kondisi Anda, Anda dilarang menggunakan ACTEMRA
atau informasikan kepada dokter atau perawat yang memberikan obat Anda.
Jika Anda ragu-ragu tentang hal ini, silakan Anda berkonsultasi dengan dokter, apoteker atau perawat
Anda sebelum menggunakan ACTEMRA.
Peringatan dan Perhatian

Informasikan kepada dokter, apoteker atau perawat Anda sebelum Anda menggunakan ACTEMRA bila:
• Anda mengalami reaksi alergi seperti dada terasa sesak, mengi (napas berbunyi), pusing berat
atau pening, bengkak pada bibir, atau ruam pada kulit selama atau setelah pemberian obat, maka
segeralah informasikan kepada dokter Anda.
• Khusus untuk penggunaan ACTEMRA SC, apabila sebelumnya Anda mengalami gejala reaksi
alergi apa pun setelah pemberian ACTEMRA, jangan menyuntikkan dosis selanjutnya hingga
Anda telah menginformasikan hal ini kepada dokter Anda DAN dokter Anda telah
menyampaikan kepada Anda untuk menyuntikkan dosis selanjutnya.
• Anda mengalami infeksi apa pun, baik jangka pendek maupun jangka panjang, atau apabila Anda
sering mengalami infeksi, segera informasikan kepada dokter Anda apabila Anda merasa tidak
sehat. ACTEMRA dapat menurunkan kemampuan tubuh Anda untuk memberikan respons
terhadap infeksi dan mungkin memperburuk infeksi yang telah ada sebelumnya atau meningkatkan
peluang terjadinya infeksi baru.
• Anda pernah mengalami tuberkulosis, informasikan kepada dokter Anda. Dokter Anda akan
memeriksa adanya gejala dan tanda tuberkulosis sebelum memberikan ACTEMRA. Apabila
gejala tuberkulosis (batuk yang tak kunjung sembuh, penurunan berat badan, lesu, demam
ringan), atau infeksi lainnya muncul selama atau setelah terapi, segera informasikan kepada
dokter Anda.
• Anda mengalami ulkus usus (luka pada usus) atau divertikulitis, informasikan kepada dokter
Anda. Gejala-gejalanya dapat berupa nyeri perut dan perubahan kebiasaan buang air besar tanpa
Page 2 of 16
sebab yang jelas yang disertai dengan demam.
• Anda mengalami penyakit hati, informasikan kepada dokter Anda. Sebelum Anda menerima
ACTEMRA, dokter Anda mungkin akan melakukan pemeriksaan darah untuk menilai fungsi
hati Anda.
• Pasien baru saja mendapatkan vaksinasi (baik dewasa maupun anak), atau memiliki rencana
untuk mendapatkan vaksinasi, informasikan kepada dokter Anda. Seluruh pasien, terutama anak-
anak, sebaiknya telah menerima semua vaksinasinya sebelum memulai pengobatan dengan
ACTEMRA. Terdapat beberapa jenis vaksin yang tidak boleh diberikan selama menjalani
pengobatan dengan ACTEMRA.
• Anda mengalami kanker, informasikan kepada dokter Anda. Dokter Anda akan menentukan
apakah Anda masih dapat diberikan ACTEMRA.
• Anda memiliki faktor risiko kardiovaskular seperti peningkatan tekanan darah dan kadar
kolesterol, informasikan kepada dokter Anda. Faktor-faktor tersebut perlu dipantau saat Anda
menerima ACTEMRA.
• Anda mengalami gangguan fungsi ginjal derajat sedang hingga berat, dokter Anda akan
memantau Anda.
• Anda mengalami sakit kepala yang tak kunjung reda.
Dokter Anda akan melakukan pemeriksaan darah sebelum Anda diberikan ACTEMRA, dan selama
pengobatan Anda, untuk menentukan apakah Anda memiliki jumlah sel darah putih yang rendah, jumlah
trombosit yang rendah, atau enzim hati yang tinggi.
Anak dan remaja

ACTEMRA tidak direkomendasikan untuk diberikan kepada anak yang berusia di bawah 2 tahun.
Terkait penggunaan ACTEMRA IV pada pasien anak, apabila pasien memiliki riwayat sindrom
aktivasi makrofag, (aktivasi dan proliferasi yang tak terkendali dari sel darah tertentu), informasikan
kepada dokter Anda. Dokter Anda akan menentukan apakah ACTEMRA masih dapat diberikan.
Obat-obatan lain dan ACTEMRA

Informasikan kepada dokter Anda apabila Anda (atau anak Anda, bila mereka yang menjadi pasien)
sedang atau akhir-akhir ini mengonsumsi obat-obatan lainnya. Hal ini termasuk obat-obatan yang
diperoleh tanpa resep. ACTEMRA dapat memengaruhi cara kerja beberapa jenis obat sehingga dosis
untuk obat tersebut mungkin perlu disesuaikan. Bila Anda sedang menggunakan obat yang mengandung
bahan aktif seperti yang tercantum di bawah ini, informasikan kepada dokter Anda:
• metilprednisolon, deksametason, digunakan untuk mengurangi peradangan

• atorvastatin, digunakan untuk menurunkan kadar kolesterol
• penghambat kanal kalsium (contohnya adalah amlodipin), digunakan untuk mengobati
peningkatan tekanan darah
• teofilin, digunakan untuk mengobati asma
• warfarin atau phenprocoumon, digunakan sebagai zat pengencer darah
• fenitoin, digunakan untuk mengobati kejang
• siklosporin, digunakan untuk menekan sistem imun Anda saat transplantasi organ
• benzodiazepin (contohnya adalah temazepam), digunakan untuk meringankan kecemasan.
Karena masih kurangnya pengalaman klinis, ACTEMRA tidak direkomendasikan untuk digunakan
bersamaan dengan obat-obatan biologis lainnya baik untuk pengobatan Artritis Reumatoid maupun
Artritis Juvenil Poliartikular Idiopatik dan Artritis Juvenil Sistemik Idiopatik.
Page 3 of 16
Kehamilan, menyusui, dan kesuburan

ACTEMRA tidak boleh digunakan saat hamil kecuali bila memang sangat penting untuk diberikan.
Informasikan kepada dokter Anda apabila Anda hamil, mungkin sedang hamil, atau memiliki rencana
untuk hamil.
Perempuan dalam usia subur harus menggunakan kontrasepsi yang efektif selama pengobatan hingga
3 bulan setelah selesai menjalani pengobatan.
Berhentilah menyusui apabila Anda diberikan ACTEMRA, dan bicarakanlah dengan dokter Anda.
Berikan waktu minimal 3 bulan setelah pengobatan selesai sebelum Anda mulai menyusui. Belum
diketahui apakah ACTEMRA masuk ke dalam air susu ibu.
Data yang tersedia hingga saat ini tidak menunjukkan pengaruh apa pun dari pengobatan ini terhadap
kesuburan.
Berkendara dan mengoperasikan mesin

Obat ini dapat menyebabkan pusing. Apabila Anda merasa pusing, jangan berkendara atau
mengoperasikan mesin.
ACTEMRA IV mengandung natrium

ACTEMRA IV mengandung 26,55 mg natrium per dosis maksimum 1200 mg. Pertimbangkan hal ini
apabila Anda sedang menjalani diet rendah natrium. Meski demikian, dosis di bawah 1025 mg dari obat
ini mengandung kurang dari 23 mg natrium, sehingga mereka dapat dikatakan bebas natrium.
3. Cara pemberian ACTEMRA
 ACTEMRA IV (formulasi intravena)
Obat ini hanya dapat diberikan dengan resep obat yang dituliskan oleh dokter Anda.
ACTEMRA akan diberikan kepada Anda dalam bentuk infus ke dalam pembuluh darah vena oleh
dokter atau perawat. Mereka akan mengencerkan larutan tersebut, mempersiapkan infus intravena, dan
memantau Anda selama dan setelah pengobatan.
Pasien dewasa dengan Artritis Reumatoid

Dosis umum ACTEMRA adalah 8 mg/kg berat badan. Tergantung pada respons tubuh Anda, dokter
Anda mungkin akan menurunkan dosis Anda menjadi 4 mg/kg berat badan lalu menaikkannya kembali ke
8 mg/kg berat badan apabila diperlukan.
Orang dewasa akan diberikan ACTEMRA setiap 4 minggu sekali infus intravena selama satu jam.
Anak-anak dengan pJIA (usia 2 tahun ke atas)

Dosis umum ACTEMRA disesuaikan dengan berat badan pasien bila:
• Berat badan pasien kurang dari 30 kg: dosis yang diberikan adalah 10 mg/kg berat badan.
• Berat badan pasien 30 kg atau lebih: dosis yang diberikan adalah 8 mg/kg berat badan.
Dosis tersebut dihitung berdasarkan berat badan pasien pada setiap pemberian.
Pasien anak dengan pJIA akan diberikan ACTEMRA setiap 4 minggu sekali melalui infus intravena
selama satu jam.
Page 4 of 16
Anak-anak dengan sJIA (usia 2 tahun ke atas)

Dosis umum ACTEMRA disesuaikan dengan berat badan pasien bila:
• Berat badan pasien kurang dari 30 kg: dosis yang diberikan adalah 12 mg/kg berat badan.
• Berat badan pasien 30 kg atau lebih: dosis yang diberikan adalah 8 mg/kg berat badan.
Dosis tersebut dihitung berdasarkan berat badan pasien pada setiap pemberian.
Pasien anak dengan sJIA akan diberikan ACTEMRA setiap 2 minggu sekali melalui infus intravena
selama satu jam.
 ACTEMRA SC (formulasi subkutan)
Pasien dewasa dengan Artritis Reumatoid

Selalu gunakan obat ini persis seperti yang dianjurkan oleh dokter, apoteker, atau perawat Anda. Anda
sebaiknya melakukan konfirmasi kepada dokter, apoteker, atau perawat Anda apabila Anda tidak yakin.
Pengobatan akan diresepkan dan dimulai oleh tenaga kesehatan yang telah berpengalaman dalam
mendiagnosis dan menangani AR.
Rekomendasi dosis
Dosis untuk orang dewasa yang menderita AR adalah 162 mg (dalam bentuk alat suntik siap pakai) yang
diberikan seminggu sekali.
ACTEMRA diberikan melalui suntikan di bawah kulit (subkutan). Awalnya, dokter atau perawat Anda
mungkin menyuntikkan ACTEMRA. Namun, dokter Anda mungkin akan memutuskan bahwa Anda
dapat menyuntikkan ACTEMRA sendiri. Pada kasus tersebut, Anda akan mendapatkan pelatihan
tentang cara penyuntikan ACTEMRA secara mandiri. Orang tua dan orang yang merawat pasien akan
mendapatkan pelatihan tentang cara penyuntikan ACTEMRA untuk pasien yang tidak dapat menyuntik
dirinya sendiri.
Bicaralah dengan dokter Anda apabila Anda memiliki pertanyaan seputar cara menyuntik diri sendiri.
Anda akan menemukan “instruksi penyuntikan” yang terperinci di bagian akhir brosur ini.
Apabila Anda melewatkan atau lupa dosis ACTEMRA

ACTEMRA IV diberikan oleh seorang dokter atau perawat, kecil kemungkinannya Anda akan
melewatkan satu dosis. Namun, bila Anda khawatir, bicaralah dengan dokter atau perawat Anda.
Sangat penting untuk menggunakan ACTEMRA SC persis seperti yang ditentukan oleh dokter Anda.
Pantau terus dosis berikutnya bila:
• Anda melewatkan dosis mingguan dalam 7 hari, Anda harus mengambil dosis Anda pada hari
yang dijadwalkan berikutnya.
• Anda melewatkan dosis Anda lebih dari 7 hari, atau Anda tidak yakin kapan harus menyuntikkan
ACTEMRA SC, segera hubungi dokter atau apoteker Anda.
Apabila Anda diberikan ACTEMRA lebih banyak dari yang seharusnya

Karena ACTEMRA IV diberikan dalam suntikan oleh dokter atau perawat Anda dan ACTEMRA SC
diberikan dalam satu alat suntik siap pakai, kecil kemungkinannya Anda akan diberikan dosis yang lebih
banyak dari seharusnya. Namun, bila Anda khawatir, bicaralah dengan dokter Anda.
Apabila Anda telah berhenti diberikan ACTEMRA

Anda sebaiknya tidak menghentikan penggunaan ACTEMRA tanpa mendiskusikannya dengan dokter
Anda terlebih dahulu.
Apabila Anda memiliki pertanyaan lebih lanjut tentang penggunaan obat ini, tanyakanlah kepada dokter,
apoteker, atau perawat Anda.
Page 5 of 16
4. Efek samping yang mungkin terjadi

Seperti semua obat-obatan, ACTEMRA dapat menyebabkan beberapa efek samping, meskipun tidak
semua orang mengalaminya. Efek samping dapat timbul hingga setidaknya 3 bulan setelah pemberian
dosis ACTEMRA yang terakhir.
Efek samping serius yang mungkin dapat terjadi (dapat terjadi pada hingga 1 dari setiap 10 orang):
segera informasikan kepada dokter, apoteker, atau perawat Anda.
Reaksi alergi selama atau setelah penyuntikan, terutama reaksi penyuntikan ACTEMRA SC:
• kesulitan bernapas, dada terasa sesak, atau pening
• ruam, gatal, biduran, bengkak pada bibir, lidah, atau wajah
Tanda-tanda infeksi serius

• demam dan menggigil
• lepuh pada mulut atau kulit
• sakit perut
Apabila Anda mengalami hal-hal tersebut, informasikan kepada dokter, apoteker, atau perawat Anda
sesegera mungkin.
Efek samping lain dari penggunaan ACTEMRA
Efek samping yang sangat umum (dapat terjadi pada lebih dari 1 dari setiap 10 orang)
• infeksi saluran napas atas dengan gejala-gejala khas seperti batuk, hidung tersumbat, hidung
berair, nyeri tenggorokan, dan sakit kepala.
• reaksi pada lokasi penyuntikan/administrasi (terutama untuk ACTEMRA SC)
Efek samping yang umum (dapat terjadi pada hingga 1 dari setiap 10 orang)
• infeksi paru (pneumonia)
• ruam saraf (herpes zoster)
• cold sores (herpes simpleks oralis), lepuh
• infeksi kulit (selulitis) yang kadang disertai demam dan menggigil
• ruam dan gatal, biduran
• reaksi alergi (hipersensitivitas)
• infeksi mata (konjungtivitis)
• sakit kepala, pusing
• tekanan darah tinggi
• ulkus (luka) pada mulut
• nyeri pada perut
• retensi cairan (edema) pada kaki bagian bawah
• peningkatan berat badan
• batuk
• sesak napas
• jumlah sel darah putih yang rendah, ditunjukkan dengan pemeriksaan darah (neutropenia,
leukopenia)
• hasil yang abnormal dari pemeriksaan fungsi hati (peningkatan enzim transaminase)
• kadar lemak (kolesterol) darah yang tinggi.
Efek samping yang tidak umum (dapat terjadi pada hingga 1 dari setiap 100 orang)
• divertikulitis (demam, mual, diare, sembelit, nyeri lambung)
• seriawan
Page 6 of 16
• lemak darah (trigliserida) yang tinggi

• ulkus (tukak) lambung
• batu ginjal
• penurunan aktivitas kelenjar tiroid
• peningkatan bilirubin, ditunjukkan dengan pemeriksaan darah
Efek samping yang sangat jarang (dapat terjadi pada hingga 1 dari setiap 10000 orang)
• jumlah yang rendah dari sel darah merah, dan trombosit dalam pemeriksaan darah
• sindrom Stevens-Johnson (ruam kulit, yang dapat menyebabkan terjadinya lepuh berat dan
terkelupasnya kulit)
Pelaporan efek samping

Apabila Anda mengalami efek samping apapun, beri tahu dokter, apoteker, atau perawat Anda. Hal ini
termasuk efek samping lainnya yang tidak tercantum dalam brosur ini. Dengan melaporkan efek samping,
Anda dapat membantu menyediakan informasi keselamatan lebih lanjut mengenai obat ini.
Anda juga dapat melaporkan efek samping secara langsung melalui:
PT Roche Indonesia – Local Safety Unit

Email: indonesia.safety@roche.com
Tel: 0-800-140-1579 (bebas pulsa)
Pusat Farmakovigilans
c.q. Direktorat Pengawasan Keamanan, Mutu, dan Ekspor Impor Obat, Narkotika, Psikotropika, Prekursor,
dan Zat Adiktif
Badan Pengawas Obat dan Makanan Republik Indonesia

Melalui pos: Jl. Percetakan Negara No. 23, Jakarta Pusat, 10560
Email: pv-center@pom.go.id
Tel: +62-21-4244691 Ext. 1079
Website: http://e-meso.pom.go.id/
Anak-anak dengan pJIA

Secara umum, efek samping pada pasien pJIA hampir sama dengan orang dewasa dengan RA. Beberapa
efek samping terlihat lebih sering: hidung dan tenggorokan meradang, sakit kepala, merasa tidak enak
badan (mual) dan penurunan jumlah sel darah putih.
Anak-anak dengan sJIA

Secara umum, efek samping pada pasien sJIA hampir sama dengan orang dewasa dengan RA. Beberapa
efek samping terlihat lebih sering: hidung dan tenggorokan meradang, diare, penurunan jumlah sel darah
putih dan enzim hati yang lebih tinggi.
5. Cara penyimpanan ACTEMRA

Simpan di dalam lemari pendingin (2°C hingga 8°C). Jangan dibekukan.
Simpan vial di dalam karton pembungkus agar terlindung dari cahaya.
Jangan gunakan obat ini setelah melewati tanggal kedaluwarsa yang tertera pada karton.
Jangan gunakan obat ini setelah melewati tanggal kedaluwarsa yang tertera pada label dan karton alat
Page 7 of 16
suntik siap pakai (EXP). Tanggal kedaluwarsa mengacu pada hari terakhir pada bulan tersebut.
Simpan di dalam lemari pendingin (2°C hingga 8°C). Jangan dibekukan.
Simpan alat suntik siap pakai di dalam karton pembungkus agar terlindung dari cahaya dan kelembapan.
Setelah dikeluarkan dari lemari pendingin, ACTEMRA harus digunakan dalam waktu 8 jam dan
sebaiknya tidak disimpan pada suhu lebih dari 300C.
Jangan gunakan apabila obat tersebut terlihat berkabut atau mengandung partikel, berwarna apa pun
selain bening hingga kekuningan, atau terdapat bagian dari alat suntik siap pakai yang terlihat rusak.
Alat suntik sebaiknya tidak dikocok. Setelah melepaskan penutup jarum, penyuntikan harus dilakukan
dalam waktu 5 menit untuk mencegah obat mengering dan jarum tersumbat. Apabila alat suntik siap pakai
tidak digunakan dalam waktu 5 menit setelah pelepasan penutup jarum, Anda harus membuangnya dalam
wadah tahan tusukan dan gunakan alat suntik siap pakai yang baru.
Apabila Anda tidak dapat menurunkan pompa pendorong setelah jarum masuk, Anda harus membuang
alat suntik siap pakai tersebut ke dalam wadah tahan tusukan dan gunakan alat suntik siap pakai yang
baru.
6. Isi dalam kemasan dan informasi lainnya

Apa yang terkandung di dalam ACTEMRA
Zat aktif berupa tocilizumab:
Setiap 4 mL vial mengandung 80 mg tocilizumab (20 mg/mL)
Setiap 20 mL vial mengandung 400 mg tocilizumab (20 mg/mL)

Zat aktif berupa tocilizumab.
Setiap alat suntik siap pakai mengandung 162 mg tocilizumab dalam 0,9 mL.
Seperti apakah ACTEMRA dan isinya dalam dus

ACTEMRA adalah konsentrat untuk larutan infus. Konsentrat ini berupa cairan jernih hingga
opak yang berwarna bening hingga sedikit kekuningan.
ACTEMRA tersedia dalam bentuk vial yang berisi 4 mL dan 20 mL konsentrat untuk larutan
infus. Kemasan berukuran 1 vial.

ACTEMRA adalah larutan untuk injeksi. Larutan ini berwarna bening hingga sedikit kekuningan.
ACTEMRA tersedia dalam bentuk alat suntik siap pakai 0,9 mL yang berisi 162 mg larutan
tocilizumab untuk injeksi.
Setiap dus berisi 4 alat suntik siap pakai.
Page 8 of 16
Kemasan
ACTEMRA IV
Dus, 1 vial @ 80 mg (4 mL) No. Registrasi: DKI1135900149A1
Dus, 1 vial @ 400 mg (20 mL) No. Registrasi: DKI1135900149A1
ACTEMRA SC
Dus, 4 alat suntik @ 0,9 mL No. Registrasi:
Medicine: keep out of reach of children

Obat: Jauhkan dari jangkauan anak-anak
On medical prescription only
Pada proses pembuatannya bersinggungan dengan bahan

bersumber babi
Diproduksi oleh:
ACTEMRA IV
Chugai Pharma Manufacturing Co, Ltd, Utsunomiya-City, Jepang
ACTEMRA SC
Vetter Pharma-Fertigung GmbH & Co. KG, Ravensburg, Jerman
Untuk:
F. Hoffmann-La Roche Ltd, Basel, Swiss
Diimpor oleh:
PT Boehringer Ingelheim Indonesia, Bogor, Indonesia
Didistribusikan oleh:
PT Roche Indonesia, Jakarta, Indonesia
Page 9 of 16
7. Petunjuk penggunaan ACTEMRA SC
Petunjuk Penggunaan ACTEMRA Subkutan

Alat suntik siap pakai
Apa yang perlu Anda ketahui agar dapat menggunakan ACTEMRA SC dalam alat suntik siap
pakai dengan aman?
Penting untuk membaca, mengerti, dan mengikuti instruksi ini sehingga Anda atau orang yang merawat
Anda dapat menggunakan alat suntik ACTEMRA dengan benar. Instruksi-instruksi ini tidak dapat
menggantikan pelatihan dari tenaga kesehatan Anda. Tenaga kesehatan Anda harus menunjukkan
kepada Anda cara mempersiapkan dan menyuntik dengan benar sebelum Anda menggunakan alat
suntik ACTEMRA secara mandiri untuk pertama kalinya. Tanyakan kepada tenaga kesehatan Anda
semua pertanyaan yang mungkin Anda miliki.
Jangan mencoba melakukan penyuntikan hingga Anda yakin bahwa Anda telah mengerti cara
menggunakan alat suntik ACTEMRA.
Mohon baca pula informasi produk untuk pasien yang menyertai alat suntik ACTEMRA untuk
informasi paling penting yang perlu Anda ketahui mengenai obat ini. Penting bagi Anda untuk tetap
berada di dalam perawatan tenaga kesehatan ketika Anda menggunakan ACTEMRA.
Informasi Penting:
• Jangan gunakan alat suntik apabila alat suntik terlihat rusak.

• Jangan gunakan obat apabila cairan di dalam alat suntik terlihat berawan, berkabut, berubah
warna, atau mengandung partikel-partikel
• Jangan pernah mencoba membongkar alat suntik sekalipun
• Jangan melepaskan pelindung jarum hingga Anda siap untuk melakukan penyuntikan.
• Jangan menyuntik melalui pakaian yang menutupi kulit.
• Jangan pernah menggunakan kembali alat suntik yang telah terpakai
• Jangan pernah menyentuh pemicu alat suntik karena dapat merusak alat suntik
Penyimpanan
Jauhkan alat suntik ACTEMRA dan semua obat-obatan dari pandangan dan jangkauan anak-anak.
Selalu simpan alat suntik di dalam lemari pendingin bersuhu 2-8°C. Lindungi alat suntik dari
pembekuan dan cahaya.
Simpan alat suntik siap pakai di dalam karton pembungkus untuk melindunginya dari cahaya dan
jagalah agar tetap kering.
Bagian-bagian alat suntik siap pakai

Pemicu
(jangan sentuh bagian ini karena dapat
Sebelum pemakaian: melepaskan pelindung jarum lebih awal)
Penutup jarum
Pompa
Setelah pemakaian: pendorong
Pelindung jarum
(memanjang dan terkunci)
Page 10 of 16
Anda akan memerlukan hal berikut untuk melakukan penyuntikan:

Disertakan di dalam kotak:
• Alat suntik siap pakai
Tidak disertakan di dalam kotak:

• Kasa alkohol
• Bola kapas atau kasa steril
• Wadah tahan tusukan atau wadah benda tajam untuk pembuangan tutup jarum dan alat suntik
bekas pakai yang aman
Tempat untuk mempersiapkan persediaan Anda:

• Carilah permukaan yang memiliki penerangan yang cukup, bersih, dan rata, misalnya
sebuah meja
Langkah 1. Periksalah alat suntik secara visual
• Keluarkan kotak yang berisi alat suntik dari dalam lemari pendingin dan buka kotak tersebut.
Jangan menyentuh pemicu alat suntik karena dapat merusak alat suntik.
• Keluarkan alat suntik dari kotak dan periksa alat suntik serta isi obat dalam alat suntik tersebut
secara visual. Langkah ini penting untuk memastikan bahwa alat suntik dan obat aman untuk
digunakan.
• Periksalah tanggal kedaluwarsa pada kotak dan alat suntik (Lihat Gambar. A) untuk
memastikan bahwa obat belum kedaluwarsa. Jangan gunakan alat suntik apabila tanggal
kedaluwarsa telah berlalu. Langkah ini penting untuk memastikan bahwa alat suntik aman
untuk digunakan.
Gambar A Tanggal kedaluwarsa pada alat suntik
Tanggal
kedaluwarsa pada
kotak
Buang alat suntik dan jangan gunakan apabila:

• obat tampak keruh
• obat mengandung partikel
• obat berwarna lain selain bening hingga kekuningan
• ada bagian dari alat suntik yang tampak rusak
Langkah 2. Berikan waktu bagi alat suntik untuk menyesuaikan dengan suhu ruangan
• Jangan melepaskan pelindung jarum pada alat suntik Anda sebelum mencapai Langkah 5.
Pelepasan pelindung jarum yang terlalu cepat dapat menyebabkan obat mengering dan jarum
tersumbat.
• Letakkan alat suntik pada permukaan yang rata dan bersih serta biarkan alat suntik berada pada
suhu ruang selama sekitar 25-30 menit untuk menghangatkannya. Tidak membiarkan alat
suntik berada pada suhu ruang dapat menyebabkan proses penyuntikan menjadi tidak nyaman
dan pompa pendorong dapat menjadi sulit ditekan.
• Jangan hangatkan alat suntik dengan cara lainnya.
Page 11 of 16
Langkah 3. Bersihkan tangan Anda
• Cucilah tangan Anda dengan sabun dan air.
Langkah 4. Pilihlah dan siapkan lokasi penyuntikan
• Lokasi penyuntikan yang direkomendasikan adalah sisi depan dan bagian tengah dari paha
Anda dan bagian bawah perut di bawah pusar kecuali pada daerah dalam radius lima
sentimeter di sekitar pusar. (Lihat Gambar B)
• Apabila orang yang merawat Anda yang akan memberikan suntikan, sisi luar dari lengan atas
dapat pula digunakan. (Lihat Gambar B)
Gambar B
depan belakang
Lokasi penyuntikan
• Anda sebaiknya menggunakan lokasi yang berbeda setiap kali Anda melakukan penyuntikan
pada diri Anda, minimal tiga sentimeter dari daerah yang telah Anda gunakan untuk
penyuntikan sebelumnya.
• Jangan menyuntik pada daerah yang dapat terganggu oleh ikat pinggang. Jangan menyuntikkan
obat pada tahi lalat, bekas luka, memar, atau daerah di mana kulit terasa nyeri, merah, keras,
atau tidak utuh.
• Bersihkan lokasi yang dipilih untuk penyuntikan dengan kasa alkohol (Lihat Gambar C), untuk
mengurangi risiko terjadinya infeksi.
Gambar C
• Biarkan kulit mengering selama kurang lebih 10 detik

• Pastikan untuk tidak menyentuh daerah yang telah dibersihkan sebelum penyuntikan dilakukan.
Jangan mengipas atau meniup daerah yang telah dibersihkan tersebut.
Page 12 of 16
Langkah 5. Lepaskan penutup jarum
• Jangan memegang alat suntik pada pompa pendorongnya ketika melepaskan penutup jarum.
• Pegang pelindung jarum dengan benar menggunakan satu tangan dan tarik penutup jarum
menggunakan tangan lainnya (Lihat Gambar D). Apabila Anda tidak dapat melepaskan penutup
jarum, Anda sebaiknya meminta pertolongan orang yang merawat Anda atau menghubungi
tenaga kesehatan.
Gambar D
• Jangan sentuh jarum atau membiarkan jarum menyentuh permukaan apa pun.
• Anda mungkin melihat tetesan cairan pada ujung jarum. Ini adalah hal yang normal.
• Buang penutup jarum ke dalam wadah tahan tusukan atau wadah benda tajam.
CATATAN: Setelah penutup jarum dibuang, alat suntik harus segera digunakan.
• Apabila alat suntik tidak digunakan dalam waktu 5 menit setelah penutup jarum dilepaskan,
maka alat suntik harus dibuang ke dalam wadah tahan tusukan atau wadah benda tajam dan alat
suntik baru harus digunakan. Apabila penutup jarum telah dilepaskan selama lebih dari 5 menit,
penyuntikan mungkin menjadi lebih sulit dilakukan karena obat dapat mengering dan jarum
tersumbat.
• Jangan pernah memasang kembali penutup jarum setelah dilepaskan.
Langkah 6. Penyuntikan
• Pegang alat suntik secara nyaman dengan tangan Anda.

• Untuk memastikan bahwa jarum dapat dimasukkan dengan tepat di bawah kulit, cubitlah kulit
yang longgar di sekitar daerah suntikan yang bersih dengan tangan Anda yang bebas.
Pencubitan pada kulit penting dilakukan untuk memastikan bahwa Anda melakukan
penyuntikan di bawah kulit (pada jaringan lemak) dan bukan pada jaringan yang lebih dalam
(pada otot). Penyuntikan pada otot dapat menyebabkan ketidaknyamanan saat penyuntikan.
• Jangan menahan atau menekan pompa pendorong ketika memasukkan jarum ke dalam kulit.
• Masukkan jarum ke dalam cubitan kulit dengan sudut antara 450 dan 900 dengan cepat dan
penuh keyakinan (Lihat Gambar E).
Page 13 of 16
Gambar E
Sangat penting untuk memilih sudut yang benar guna memastikan obat masuk ke bawah kulit (ke dalam
jaringan lemak). Bila tidak, suntikan dapat menyebabkan rasa nyeri dan obat mungkin tidak bekerja.
• Kemudian, jaga alat suntik pada posisi tersebut dan lepaskan cubitan kulit.
• Suntikkan seluruh obat dalam alat suntik secara perlahan-lahan dengan menekan pompa
pendorong ke bawah (Lihat Gambar F). Anda harus menekan pompa pendorong hingga paling
bawah untuk memastikan bahwa Anda mendapatkan dosis obat yang penuh dan untuk
memastikan bahwa pemicu telah tertekan sempurna ke samping.
Apabila pompa pendorong tidak tertekan secara sempurna, pelindung jarum tidak akan
memanjang untuk menutup ujung jarum saat alat suntik dikeluarkan dari dalam kulit. Apabila
jarum tidak terbungkus dengan benar, masukkan jarum ke dalam wadah tahan tusukan untuk
mencegah cedera akibat tertusuk jarum.
Gambar F
• Setelah pompa pendorong ditekan secara sempurna ke bawah, terus tekan pompa pendorong ke
bawah untuk memastikan seluruh obat telah disuntikkan sebelum mengeluarkan jarum dari
kulit.
• Teruskan menekan pompa pendorong ke bawah ketika Anda mengeluarkan jarum dari kulit
pada sudut yang sama dengan sudut saat Anda memasukkan jarum tersebut (Lihat Gambar G).
• Apabila pompa pendorong tidak dapat ditekan ke bawah setelah jarum dimasukkan, Anda harus
membuang alat suntik siap pakai tersebut pada wadah tahan tusukan dan gunakan alat suntik siap
pakai yang baru (mulai kembali dengan Langkah 2). Apabila Anda masih mengalami kesulitan,
Anda sebaiknya berkonsultasi kepada dokter, apoteker, atau perawat Anda.
Page 14 of 16
Gambar G
• Setelah jarum dikeluarkan dengan sempurna dari kulit, Anda dapat melepaskan pompa
pendorong agar pelindung jarum melindungi jarum (Lihat Gambar H).
Gambar H
• Apabila Anda melihat tetesan darah pada lokasi penyuntikan, Anda dapat menekan sisi atas
lokasi penyuntikan dengan bola kapas atau kasa steril selama 10 detik.
• Jangan menggosok lokasi penyuntikan.
Langkah 7. Buang alat suntik
• Jangan mencoba menutup kembali ujung alat suntik.

• Buanglah alat suntik yang telah terpakai pada wadah tahan tusukan atau wadah benda tajam.
Tanyakan kepada tenaga kesehatan atau apoteker Anda mengenai informasi di mana Anda bisa
mendapatkan wadah “benda tajam” atau jenis wadah tahan tusukan lain yang dapat Anda
gunakan untuk membuang alat suntik yang telah Anda gunakan secara aman, bila Anda tidak
memiliki wadah tersebut (Lihat Gambar I).
Page 15 of 16
Gambar I
Tanyakan kepada tenaga kesehatan mengenai instruksi tentang cara yang benar untuk membuang alat
suntik bekas pakai. Mungkin terdapat peraturan lokal atau undang-undang mengenai cara membuang alat
suntik bekas pakai.
Jangan membuang alat suntik bekas pakai atau wadah tahan tusukan dalam sampah rumah tangga dan
jangan mendaur ulangnya.
• Buanglah wadah yang telah penuh sesuai instruksi tenaga kesehatan atau apoteker Anda.
• Selalu jauhkan wadah tahan tusukan dari pandangan dan jangkauan anak-anak.
Saran bagi pasien mengenai reaksi hipersensitivitas (dikenal pula sebagai reaksi anafilaksis, bila
parah)
Apabila Anda mengalami gejala-gejala seperti, namun tidak terbatas pada ruam kulit, gatal, menggigil,
pembengkakan wajah, bibir, lidah atau tenggorokan, nyeri dada, mengi (napas berbunyi), kesulitan
bernapas atau menelan atau merasa pusing atau pingsan kapan pun ketika tidak sedang berada di klinik
selama atau setelah penggunaan injeksi ACTEMRA, Anda sebaiknya segera mencari pertolongan gawat
darurat.
Saran bagi pasien mengenai tanda awal dan terapi untuk membatasi risiko terjadinya infeksi yang
serius
Waspadalah terhadap tanda-tanda pertama dari infeksi, seperti:
• pegal-pegal, demam, menggigil

• batuk, rasa tidak nyaman/sesak pada dada, sesak napas
• kemerahan, panas, dan bengkak yang tidak biasa pada kulit atau sendi
• nyeri perut dan/atau perubahan dalam buang air besar
Hubungi dokter Anda dan segera cari pertolongan medis apabila Anda merasakan bahwa Anda mungkin
mengalami infeksi.
Apabila Anda memiliki pertanyaan mengenai alat suntik Anda, hubungi dokter, apoteker, atau
perawat Anda untuk memperoleh bantuan.
Page 16 of 16
Draft_Actemra SC_New Drug Application_Box_EN_v1
Indication, dosage and administration,

contraindication, undesirable effects,
drug interaction, warning and precaution:
see package insert On medical prescription only
mL
Reg. No. : DKIXXXXXXXXXX
Pada proses pembuatannya

bersinggungan dengan
bahan bersumber babi
mL
Made by Vetter Pharma-Fertigung GmbH & Co. KG, Ravensburg,

Germany for F. Hoffmann-La Roche Ltd, Basel, Switzerland
Imported by PT Boehringer Ingelheim Indonesia,
Bogor, Indonesia
Distributed by PT Roche Indonesia,
Jakarta, Indonesia
: (Rp.) HET
: Date Exp.
: Date Mfg.
: No. Batch
mL
Draft_Actemra SC_New Drug Application_Sticker_EN_v1
EXP
45 mm
L
Pada proses pembuatannya
bersinggungan dengan
On medical prescription only bahan bersumber babi
MFD
Reg. No.: DKIXXXXXXXXXX
HET (Rp.):
Made by Vetter Pharma-Fertigung GmbH & Co. KG, Ravensburg,

Germany for F. Hoffmann-La Roche Ltd, Basel, Switzerland
Imported by PT Boehringer Ingelheim Indonesia
Distributed by PT Roche Indonesia
Batch
31 mm

Actemra Larutan Injeksi 20 MG, ML (Infus) - Tokilizumab - DKI1135900149A1 - 2020

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Actemra Larutan Injeksi 20 MG, ML (Infus) - Tokilizumab - DKI1135900149A1 - 2020

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Draft_Actemra SC_PI_New Drug Application_CDS11.

Anti-human interleukin-6 (IL-6) receptor

ATC Code: L04AC07

1.2 Type of Dosage Form

Subcutaneous (SC) formulation/Actemra SC: Ready-to-use sterile liquid solution in a single-use

1.3 Route of Administration

Subcutaneous (SC) injection

1.4 Sterile/Radioactive Statement

1.5 Qualitative and Quantitative Composition

Actemra SC is a yellowish, preservative-free liquid supplied in a ready-to-use, single-use pre-

Polyarticular Juvenile Idiopathic Arthritis (pJIA) [IV formulation only]

Systemic Juvenile Idiopathic Arthritis (sJIA) [IV formulation only]

2.2 Dosage and Administration

For patients with pJIA, Actemra is administered as an IV infusion.

Actemra IV is not intended for Subcutaneous administration.

Actemra SC is not intended for intravenous administration.

Actemra SC is administered with a single-use PFS+NSD. The first injection should be

Patients who transition from Actemra IV therapy to Actemra SC administration should

Rheumatoid Arthritis [IV and SC formulation]

Subcutaneous Dosing Regimen:

Dose Modification Recommendations for RA:

For patients on Actemra SC with persistent increases in this range,

For patients on Actemra IV (RA only) with persistent increases in

For persistent increases > 3x ULN (confirmed by repeat testing),

• Low absolute neutrophil count (ANC)

For patients on Actemra SC, when ANC > 1 x 109/L resume

For patients on Actemra IV (RA only), when ANC increases > 1 x

ANC < 0.5 Discontinue Actemra

• Low platelet count

< 50 Discontinue Actemra

Polyarticular Juvenile Idiopathic Arthritis (pJIA) [IV formulation only]

The recommended dose of Actemra IV for patients with pJIA is:

Systemic Juvenile Idiopathic Arthritis (sJIA) [IV formulation only]

The recommended dose of IV tocilizumab for patients with sJIA is:

given once every two weeks as an IV infusion.

Dose Modification Recommendations for pJIA and sJIA:

2.2.1 Special Dosage Instructions

2.4 Warnings and Precautions

Events of diverticular perforation as complications of diverticulitis have been reported in

It is recommended that all patients, particularly paediatric or elderly patients, if possible, be

Active hepatic disease and hepatic impairment

Hepatic transaminase elevations

Elevations in lipid parameters including total cholesterol, triglycerides and/or low-density

Assessment of lipid parameters should be performed 4 to 8 weeks following initiation of

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

Combination with TNF antagonists

2.4.2 Drug Abuse and Dependence

2.4.3 Ability to Drive and Use Machines

2.4.4 Laboratory Tests

Hepatic Transaminase Elevations

In patients treated with Actemra, assessment of lipid parameters should be performed 4 to 8

Systemic Juvenile Idiopathic Arthritis

Macrophage activation syndrome (MAS)

Concomitant administration of a single dose of 10 mg/kg Actemra IV with 10-25 mg MTX

2.5 Use in Special Populations

2.5.2 Labour and Delivery

2.5.3 Nursing Mothers

2.5.4 Paediatric Use

2.5.5 Geriatric Use

2.5.6 Renal Impairment

2.5.7 Hepatic Impairment

2.6 Undesirable Effects

Patient Treated with Intravenous Actemra: