RoActemra 20 mg/ml concentrate for solution for infusion. *

Pharmacy Only: Prescription

EMEA/H/C/000955/IB/0100. Update the SmPC to include ‘use sterile needle and syringe to prepare Actemra’ into Section 6.6. Update the Annex IIIB Package Leaflet section This Information is Intended for Healthcare Professionals Only to include the following instruction: 'Use a sterile needle and syringe to prepare RoActemra'. Typographical change in Section 4.2 Posology and method of administration (Page 4): In the table ‘Low platelet count’, ‘> 100 x 10 3 / μ’ revised to ‘> 100 x 10 3 / μl’. QRD 10.2 template to add Northern Ireland as a representative. 21-May-2021: Local PI re-publication to incorporate QRD template 10.2 updates by the addition of Northern Ireland details in the ADRS reporting section in the SmPC and PIL and Legal representative section in the PIL, which ​was not included in the original publication as all applicable actions for responsibility handover had to take place first.

EMEA/H/C/000955/II/97 Minor update to RoActemra IV SmPC to account for the ARTHUR CSR results.

EMEA/H/C/000955/II/93G. G6 new drug substance manufacturing process for RoActemra IV and SC.

ACTEMRA, EMEA/H/C/000955/IB/0088/G

CDS Update - Safety, 18.0

Update safety information to include PRAC-agreed wording on Hepatotoxicity.

Addition of new ADR hypofibrinogenaemia

New indication: sJIA (II/76)

New Indication : Cytokine Release Syndrome (CRS) 

date of last renewal changed to 25 September 2013

MAH transfer from Roche Registration Limited (UK) to Roche Registration GmBH (Germany)

4.4     Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number

of the administered product should be clearly recorded.

[ … ]

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number

of the administered product should be clearly recorded.

Paediatric population

sJIA Patients

Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.

4.5     Interaction with other medicinal products and other forms of interaction

[ … ]

When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. . methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t_1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

4.8     Undesirable effects

[ … ]

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

10.     DATE OF REVISION OF THE TEXT

18 September 2017

4.4     Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded (or stated) in the patient file.

10.     DATE OF REVISION OF THE TEXT

24 May 2017

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

[...]

For  the full list of excipients, see section 6.1.

4.2    Posology and method of administration

[...]

 

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

No data are available.

[...]

The safety and efficacy of RoActemra in children below 2 years of age has not been

established.

No data are available.

[...]

Renal impairment

No dose adjustment is required in patients with mild renal impairment. RoActemra

has not been studied in patients with moderate to severe renal impairment (see section 5.2). Renal

function should be monitored closely in these patients.

4.8     Undesirable effects

[...]

The ADRs listed in Table 1 are presented by system organ class and frequency categories, defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10),  uncommon (≥ 1/1,000 to < 1/100), rare (>1/10,000 to <1/1,000) or very rare (<1/10,000) Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

[...]

Table 2:  Summary of ADRs occurring in patients with sJIA or pJIA receiving tocilizumab as  monotherapy or in combination with MTX.

1.  Infusion related reaction events in pJIA patients included but were not limited to headache, nausea and hypotension

2.  Infusion related reaction events in sJIA patients included but were not limited to rash, urticaria, diarrhoea, epigastric discomfort, arthralgia and headache

pJIA Patients

The safety of tocilizumab in pJIA has been studied in 188 patients from 2 to 17 years of age. The total patient exposure was 184.4 patient years. The frequency of ADRs in pJIA patients can be found in Table 2 . The types of ADRs in pJIA patients were similar to those seen in RA and sJIA patients, see section 4.8. When compared to the adult RA population, events of nasopharyngitis, headache, nausea, and decreased neutrophil count were more frequently reported in the pJIA population.  Events of cholesterol increased were less frequently reported in the pJIA population than in the adult RA population.

[...]

10.     DATE OF REVISION OF THE TEXT

29 July 2016

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5.2     Pharmacokinetic properties

RA Patients

AbsorptionIntravenous use

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 1,7933552 RA patients treated with a one‑hour infusion of 4 and or 8 mg/kg tocilizumab every 4 weeks for 24 weeks or with 162 mg tocilizumab given subcutaneously either once a week or every other week  for 24 weeks.

The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg tocilizumab given every 4 weeks: steady-state area under curve (AUC) = 35000 38000 ± 15500 13000 h µg/ml, trough concentration (C_min) = 9.7415.9 ± 10.513.1 mg/ml and maximum concentration (C_max) = 183 182 ± 85.650.4 µg/ml, and the accumulation ratios for AUC and C_max were small, 1.221.32 and 1.061.09, respectively. The accumulation ratio was higher for C_min (2.352.49), which was expected based on the non‑linear clearance contribution at lower concentrations. Steady-state was reached following the first administration for C_max and after 8 and 20 weeks for AUC and C_min, respectively. Tocilizumab AUC, C_min and C_max increased with increase of body weight. At body weight ≥ 100 kg, the predicted mean (± SD) steady-state AUC, C_min and C_max of tocilizumab were 55500 50000

 ± 14100 16800 μg•h/mL, 19.024.4 ± 12.017.5 μg/mL, and 269 226 ± 57 50.3 μg/mL, respectively, which are higher than mean exposure values for the patient population (i.e. all body weights) reported above. (AUC = 35000 ± 15500 h µg/ml, C_min = 9.74 ± 10.5 mg/ml and C_max = 183 ± 85.6 µg/ml). The dose-response curve for tocilizumab flattens at higher exposure, resulting in smaller efficacy gains for each incremental increase in tocilizumab concentration such that clinically meaningful increases in efficacy were not demonstrated in patients treated with > 800 mg of tocilizumab. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended (see section 4.2).

Distribution

In RA patients the central volume of distribution was 3.5 l3.72, the peripheral volume of distribution was 2.9 l3.35 resulting in a volume of distribution at steady state of 6.4 l7.07.

Elimination

Following intravenous administration, tocilizumab undergoes biphasic elimination from the circulation. The total clearance of tocilizumab 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 12.59.5 ml/h. The concentration-dependent non‑linear clearance plays a major role at low tocilizumab concentrations. Once the non‑linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.

The t_1/2 of tocilizumab was concentration-dependent. At steady‑state following a dose of 8 mg/kg every 4 weeks, the effective t_1/2 decreased with decreasing concentrations within a dosing interval from 14 18 days to 8 6 days.

Linearity

Pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in the AUC and C_min was observed for doses of 4 and 8 mg/kg every 4 weeks. C_max increased dose-proportionally. At steady-state, predicted AUC and C_min were 2.73.2 and 6.530 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.

Special populations

[  … ]

10.     DATE OF REVISION OF THE TEXT

26 March 2015

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4.1     Therapeutic indications

RoActemra, in combination with methotrexate (MTX), is indicated for:

·  the treatment of severe, active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX.

·          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.

[ … ]

RoActemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic polyarthritis (pJIA; rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

4.5     Interaction with other medicinal products and other forms of interaction

[ … ]

When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t_1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

4.8     Undesirable effects

[ … ]

The rate of anaphylactic reactions (occurring in a total of 68/34,778 009 patients, 0.2%) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 13 56 out of 34,778 009 patients (01.34%) treated with tocilizumab during the controlled and open label clinical studies. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation during treatment with tocilizumab (see section 4.4).

[ … ]

4.9       Overdose

There are limited data available on overdose with RoActemra. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg. No adverse reactions were observed.

No serious adverse reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg, although dose limiting neutropenia was observed.

Paediatric population

No case of an overdose in the paediatric population has been observed.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

[ … ]

MTX naïve, Early RA

Study VII (WA19926), a 2 year study with the planned primary analysis at week 52 evaluated 1162 MTX-naïve adult patients with moderate to severe, active early RA (mean disease duration ≤ 6 months). Approximately 20% of patients had received prior treatment with DMARDs other than MTX. This study evaluated the efficacy of IV tocilizumab 4 or 8 mg/kg every 4 weeks/MTX combination therapy, IV tocilizumab 8 mg/kg monotherapy and MTX monotherapy in reducing the signs and symptoms and rate of progression of joint damage for 104 weeks. The primary endpoint was the proportion of patients achieving DAS28 remission (DAS28 < 2.6) at week 24. A significantly higher proportion of patients in the tocilizumab 8 mg/kg + MTX and tocilizumab monotherapy groups met the primary endpoint compared with MTX alone. The tocilizumab 8 mg/kg + MTX group also showed statistically significant results across the key secondary endpoints. Numerically greater responses compared with MTX alone were observed in the tocilizumab 8 mg/kg monotherapy group in all secondary endpoints, including radiographic endpoints. In this study, ACR/EULAR remission (Boolean and Index) were also analysed as pre-specified exploratory endpoints, with higher responses observed in the tocilizumab groups. The results from study VII are shown in Table 6.

Table 6:           Efficacy Results for Study VII (WA19926) on MTX-naïve, early RA patients

mTSS                       - modified Total Sharp Score

JSN                          - Joint space narrowing

All efficacy comparisons vs Placebo + MTX. ***p≤0.0001; **p<0.001; *p<0.05;

‡p-value < 0.05 vs. Placebo + MTX, but endpoint was exploratory (not included in the hierarchy of statistical testing and has therefore not been controlled for multiplicity)

Paediatric population

[ … ]

The percent of patients achieving JIA ACR 30, 50, 70 and 90 responses are shown in Table 67.

Table 67. JIA ACR response rates at week 12 (% patients)

[ … ]

[ … ]

During the withdrawal phase (Part II), the percentage of patients achieving JIA ACR 30, 50, and 70 responses at Week 40 relative to baseline are shown in Table 78. In this statistical analysis, patients who flared (and escaped to TCZ) during Part II or who withdrew, were classified as non-responders.  An additional analyses of JIA ACR responses, considering observed data at Week 40, regardless of flare status, showed that by Week 40, 95.1% of patients who had received continuous TCZ therapy, had achieved JIA ACR30 or higher.

Table 78.  JIA ACR Response Rates at Week 40 Relative to baseline (Percentage of Patients)

[ … ]

The ACR response rates were numerically lower for patients with prior biologic treatment as shown in Table 89 below.

Table 89. Number and Proportion of Patients with a JIA ACR30 Flare and Proportion of Patients with JIA ACR30/50/70/90 Responses at Week 40, by Previous Biologic Use (ITT Population - Study Part II)

[ … ]

10.     DATE OF REVISION OF THE TEXT

24 July1 September 2014

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4.8     Undesirable effects

RA Patients

[ … ]

Skin Reactions

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

Paediatric population

The safety of tocilizumab in the pediatric population in the sections on pJIA and sJIA below.  In general, the ADRs in pJIA and sJIA patients were similar in type to those see in RA patients, see section 4.8.

[ … ]

Ireland

IMBHPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

email: medsafety@hpra.ie

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

[ … ]

10.     DATE OF REVISION OF THE TEXT

24 July 2014

Underlined text has been added, text with strike through deleted:

Section 4.4

[…]

Vaccinations

Live and live attenuated vaccines should not be given concurrently with RoActemra as clinical safety has not been established. In a randomized open-label study, adult RA patients treated with RoActemra and MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is recommended that all patients, particularly sJIA and pJIA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating RoActemra therapy. The interval between live vaccinations and initiation of RoActemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

 […]

Section 4.8

[…]

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via (see details below).

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

Section 10:

10.       DATE OF REVISION OF THE TEXT

23 January 2014

Text underlined has been added, text with strike through deleted:

2.            QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml concentrate contains 20 mg tocilizumab*.

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

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

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

*humanised IgG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

Excipients with known effects:

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

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

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

For a the full list of excipients, see section 6.1.

4.2    Posology and method of administration

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA, sJIA or pJIA.  All patients treated with RoActemra should be given the Patient Alert Card.

RA Patients

Posology

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

For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended (see Ssection 5.2).

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

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

·          Liver enzyme abnormalities

·          Low absolute neutrophil count (ANC)

In patients not previously treated with RoActemra, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 10⁹/l.

·          Low platelet count

Special populations

Paediatric patients: 

sJIA Patients

The safety and efficacy of RoActemra in children below 2 years of age has not been

established.

No data are available.

The recommended posology in patients above 2 years of age is 8 mg/kg once every 2 weeks in patients weighing greater than or equal

to 30 kg or 12 mg/kg once every 2 weeks in patients weighing less than 30 kg. The dose should be

calculated based on the patient’s body weight at each administration. A change in dose should only be

based on a consistent change in the patient’s body weight over time.

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

No data are available.

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

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

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

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

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

assessment of the individual patient.

·      Liver enzyme abnormalities

·      Low absolute neutrophil count (ANC)

·    Low platelet count

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

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

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

no improvement within this timeframe.

pJIA Patients

The safety and efficacy of RoActemra in children below 2 years of age has not been

established.

No data are available.

The recommended posology in patients above 2 years of age is 8 mg/kg once every 4 weeks in patients weighing greater than or equal to 30 kg or 10 mg/kg once every 4 weeks in patients weighing less than 30 kg. The dose should be calculated based on the patient’s body weight at each administration. A change in dose should only be based on a consistent change in the patient’s body weight over time.

The safety and efficacy of RoActemra in children below 2 years of age has not been

established.

No data are available.

Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in pJIA patients in the tables below. If appropriate, the dose of concomitant MTX and/or other medications should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co-morbid conditions that may effect laboratory values in pJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient.

·    Liver enzyme abnormalities

·    Low absolute neutrophil count (ANC)

·    Low platelet count

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

Available data suggest that clinical improvement is observed within 12 weeks of initiation of treatment with RoActemra. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.

Elderly patients

: No dose adjustment is required in patients aged 65 years and older.

Renal impairment

: No dose adjustment is required in patients with mild renal impairment. RoActemra

has not been studied in patients with moderate to severe renal impairment (see section 5.2). Renal

function should be monitored closely in these patients.

Hepatic impairment

: RoActemra has not been studied in patients with hepatic impairment. Therefore, no dose recommendations can be made.

Method of administration

After dilution, RoActemra for RA sJIA and pJIA patients should be administered as an intravenous infusion over 1 hour.

RA sJIA and pJIA Patients ≥ 30 kg

RoActemra should be diluted to a final volume of 100 ml with sterile, non-pyrogenic sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic technique.

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

sJIA and pJIA Patients < 30 kg

RoActemra should be diluted to a final volume of 50 ml with sterile, non-pyrogenic sodium chloride 9 mg/ml (0.9%) solution for injection using aseptic technique.

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

4.4     Special warnings and precautions for use

Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including RoActemra (see section 4.8, Uundesirable Eeffects). RoActemra treatment should must not be initiated in patients with active infections (see section 4.3). Administration of RoActemra should be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of RoActemra in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receiving biological treatments for moderate to severe RA sJIA or pJIA as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reaction. The effects of tocilizumab on C‑reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA patients, should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Tuberculosis

As recommended for other biological treatments, RA sJIA and pJIA patients should be screened for latent tuberculosis (TB) infection prior to starting RoActemra therapy. Patients with latent TB should be treated with standard anti‑mycobacterial therapy before initiating RoActemra. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.

Patients should be instructed to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with RoActemra. 

Viral reactivation

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical studies with tocilizumab, patients who screened positive for hepatitis were excluded.

Complications of diverticulitis

Events of diverticular perforations as complications of diverticulitis have been reported uncommonly with RoActemra in RA patients (see section 4.8). RoActemra should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever should be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.

Hypersensitivity reactions

Serious hypersensitivity reactions have been reported in association with infusion of RoActemra (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous infusions even if they have received premedication with steroids and antihistamines. Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment with RoActemra. If an anaphylactic reaction or other serious hypersensitivity / serious infusion related reaction occurs, administration of RoActemra should be stopped immediately and RoActemra should be permanently discontinued.

Active hepatic disease and hepatic impairment

Treatment with RoActemra, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases, therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).

Hepatic transaminase elevations

In clinical trials, transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with RoActemra treatment, without progression to hepatic injury (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with RoActemra. When clinically indicated, other liver function tests including bilirubin should be considered.

Caution should be exercised when considering initiation of RoActemra treatment in patients with elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x ULN, treatment is not recommended.

In RA patients, ALT and AST levels should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended modifications based on transaminases see section 4.2. For ALT or AST elevations > 3–5 x ULN, confirmed by repeat testing, RoActemra treatment should be interrupted.

In sJIA and pJIA patients, ALT and AST levels should be monitored at the time of the second infusion and thereafter according to good clinical practice, see section 4.2.

Haematological abnormalities

Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.

In patients not previously treated with RoActemra, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 10⁹/l. Caution should be exercised when considering initiation of RoActemra treatment in patients with a low platelet count (i.e. platelet count below 100 x 10³/ μl). In patients who develop an ANC < 0.5 x 10⁹/ l or a platelet count < 50 x 10³/μl, continued treatment is not recommended.

Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with RoActemra to date. 

In RA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see section 4.2.

In sJIA and pJIA patients, neutrophils and platelets should be monitored at the time of second infusion and thereafter according to good clinical practice, see section 4.2.

Lipid parameters

Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (see section 4.8). In the majority of patients, there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid lowering agents.

In sJIA, pJIA and RA patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of RoActemra therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.

Neurological disorders

Physicians should be vigilant for symptoms potentially indicative of new‑onset central demyelinating disorders. The potential for central demyelination with RoActemra is currently unknown.

Malignancy

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

increase the risk of malignancy.

Vaccinations

Live and live attenuated vaccines should not be given concurrently with RoActemra as clinical safety has not been established. It is recommended that all patients, particularly sJIA and pJIA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating RoActemra therapy. The interval between live vaccinations and initiation of RoActemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Cardiovascular risk

RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.

Combination with TNF antagonists

There is no experience with the use of RoActemra with TNF antagonists or other biological treatments for RA sJIA or pJIA patients. RoActemra is not recommended for use with other biological agents.

Sodium

This medicinal product contains 1.17 mmol (or 26.55 mg) sodium per maximum dose of 1200 mg. To be taken into consideration by patients on a controlled sodium diet. Doses below 1025 mg of this medicinal product contain less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium free’.

Paediatric population

sJIA and pJIA Patients

As described above.

sJIA Patients

Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.

4.5     Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.

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

anti-inflammatory drugs (NSAIDs) or corticosteroids on tocilizumab clearance.

The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL‑6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced.

In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes.

In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects.

When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t_1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Paediatric population

Interaction studies have only been performed in adults.

4.6     Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

There are no adequate data from the use of tocilizumab in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo‑foetal death at a high dose (see section 5.3). The potential risk for humans is unknown. Women of childbearing potential must use effective contraception during and up to 3 months after treatment.

RoActemra should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is unknown whether tocilizumab is excreted in human breast milk. The excretion of tocilizumab in milk has not been studied in animals. A decision on whether to continue/discontinue breast‑feeding or to continue/discontinue therapy with RoActemra should be made taking into account the benefit of breast‑feeding to the child and the benefit of RoActemra therapy to the woman.

Fertility

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

4.7     Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines 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.

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

4.8     Undesirable effects

RA Patients

Summary of the safety profile

The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

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

reactions.

SJIA Patients

Summary of safety profile

The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis and decreased neutrophil count.

The most serious ADRs were serious infections.

PJIA Patients

Summary of safety profile

The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis and headache.

The most serious ADRs were serious infections.

RA Patients

The safety of tocilizumab has been studied in 4 placebo‑controlled studies (studies II, III, IV and V), 1 MTX‑controlled study (study I) and their extension periods (see section 5.1).

The double-blind controlled period was 6 months in four studies (studies I, III, IV and V) and was up to 2 years in one study (study II). In the double-blind controlled studies, 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1870 patients received tocilizumab 8 mg/kg in combination with MTX or other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.

The long‑term exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in the studies. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3296 for at least one year, 2806 received treatment for at least 2 years and 1222 for 3 years.

The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The ADRs listed in Table 1 are presented by system organ class and frequency categories, defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10), or uncommon (≥ 1/1,000 to < 1/100), rare (>1/10,000 to <1/1,000) or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Summary of ADRs occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the double-blind controlled period

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

Infections

In the 6-month controlled studies the rate of all infections reported with tocilizumab 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 long‑term exposure population, the overall rate of infections with RoActemra was 108 events per 100 patient years exposure.

In 6-month controlled clinical studies, the rate of serious infections with tocilizumab 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 tocilizumab group and 1.5 events per 100 patient years of exposure in the MTX group.

In the long‑term exposure population, the overall rate of serious infections (bacterial, viral and fungal) was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.

Interstitial Lung Disease

Impaired lung function may increase the risk for developing infections. There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.

Gastrointestinal Perforation

During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on tocilizumab were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae 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 tocilizumab 8 mg/kg plus DMARD group and 5.1% of patients in the placebo plus DMARD 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 reactions (occurring in a total of 6/3,778 patients, 0.2%) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 13 out of 3,778 patients (0.3%) treated with tocilizumab during the controlled and open label clinical studies. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation during treatment with tocilizumab (see section 4.4).

Immunogenicity

A total of 2,876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6%) who developed anti-tocilizumab antibodies, 6 had an associated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuation of treatment. Thirty patients (1.1%) developed neutralising antibodies.

Haematological abnormalities:

Neutrophils

In the 6-month controlled trials decreases in neutrophil counts below 1 x 10⁹/ l occurred in 3.4% of patients on tocilizumab 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 tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported. 

During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.

Platelets

In the 6-month controlled trials decreases in platelet counts below 100 x 10³/ μl occurred in 1.7% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 1% on placebo plus DMARDs. These decreases occurred without associated bleeding events.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.

Very rare reports of pancytopenia have occurred in the post marketing setting.

Hepatic transaminase elevations

During the 6-month controlled trials transient elevations in ALT/AST > 3 x ULN were observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.

The addition of potentially hepatotoxic drugs (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab plus DMARD patients, the majority of whom were discontinued permanently from tocilizumab treatment. These elevations were not associated with clinically relevant increase in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment. During the double-blind controlled period, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routine laboratory parameter, is 6.2% in patients treated with 8 mg/kg tocilizumab + DMARD. A total of 5.8% of patients experienced an elevation of indirect bilirubin of > 1 to 2 x ULN and 0.4% had an elevation of > 2 x ULN.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.

Lipid parameters

During the 6-month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24% of patients receiving RoActemra 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.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled trials.

Malignancies

The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.

Paediatric population

The safety of toclizumab in the paediatric population in the sections on pJIA and sJIA below.  In general, the ADRs in pJIA and sJIA patients were similar in type to those see in RA patients, see section 4.8.

The ADRs in the pJIA and sJIA patients treated with tocilizumab are described below and are presented in the Table 2 by system organ class and frequency categories, defined using the following convention:  very common (≥ 1/10); common (≥ 1/100 to < 1/10) or uncommon (≥ 1/1,000 to <1/100)

Table 2:  Summary of ADRs occurring in patients with sJIA or pJIA receiving tocilizumab as monotherapy or in combination with MTX.