RoActemra 162 mg solution for injection in pre-filled syringe

Republished RoActemra SC PFS SmPC dated 20 Mar 2024 (IB-0122G) on 05 Apr 2024 as some symbols were incorrectly displaying in the originally published version.

EMEA/H/C/000955/II/0101. New Indication for COVID-19 (IV only). QRD 10.1 Annex IIIA alignment (removal of capitalisation for INN and removal of colons - all presentations). 

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

EMEA/H/C/000955/II/0091. Addition of pJIA/sJIA to the Pre-Filled Pen (Autoinjector) label. Additional small editorial changes also included in this variation.

EMEA/H/C/000955/II/0091. Addition of pJIA/sJIA to the Pre-Filled Pen (Autoinjector) label. Additional small editorial changes also included in this variation.

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/076)

New indication pJIA

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

4.1     Therapeutic indications

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

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·    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.

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RoActemra is indicated for the treatment of Giant Cell Arteritis (GCA) in adult patients.

4.2     Posology and method of administration

Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA and / or GCA. All patients treated with RoActemra should be given the Patient Alert Card. Suitability of the patient for subcutaneous home use should be assessed and instruct patients should be instructed to inform a healthcare professional if they experience symptoms of an allergic reaction before administering the next dose. Patients should seek immediate medical attention if they developing symptoms of serious allergic reactions (see section 4.4).

Posology

RoActemra subcutaneous formulation is not intended for intravenous administration.

RA

The recommended posology is subcutaneous 162 mg once every week.

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GCA

The recommended posology is subcutaneous 162 mg once every week in combination with a tapering course of glucocorticoids. RoActemra can be used alone following discontinuation of glucocorticoids.

RoActemra monotherapy should not be used for the treatment of acute relapses (see 4.4).

Based upon the chronic nature of GCA, treatment beyond 52 weeks should be guided by disease activity, physician discretion, and patient choice.

RA and GCA

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

·          Liver enzyme abnormalities

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Renal impairment:

No dose adjustment is required in patients with mild or moderate 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.

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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.

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

immunosupressive agents biological treatments such as RoActemra for moderate to severe RA or GCA as signs and symptoms of acute inflammation may be lessened, due to associated with suppression of the acute phase reactants.

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Tuberculosis

As recommended for other biological treatments, RA, all 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.

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Viral reactivation

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical studies with RoActemra 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 treated with RoActemra (see section 4.8). RoActemra should be used with caution in patients with previous history of intestinal ulceration or diverticulitis.

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In RA and GCA 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, RoActemra treatment should be interrupted.

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In patients not previously treated with RoActemra, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 10⁹/Ll. 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/ μLl). In patients who develop an ANC < 0.5 x 10⁹/ Ll or a platelet count < 50 x 10³/μLl, continued treatment is not recommended.

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In RA and GCA 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.

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In RA and GCA 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.

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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 elderly 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.

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Traceability

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

GCA

RoActemra monotherapy should not be used for the treatment of acute relapses as efficacy in this setting has not been established. Glucocorticoids should be given according to medical judgement and practice guidelines.

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 RoActemra 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 RoActemra tocilizumab clearance in RA patients. In GCA patients, no effect of cumulative corticosteroid dose on RoActemra exposure was observed.

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 RoActemra 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. RoActemra Tocilizumab normalises expression of these enzymes.

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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.

4.6     Fertility, pregnancy and lactation

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Pregnancy

There are no adequate data from the use of RoActemra 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.

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 RoActemra 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 RoActemra tocilizumab treatment.

4.8    Undesirable effects

Summary of the safety profile

The safety profile comes from 4158 patients exposed to RoActemra in clinical trials; the majority of these patients were participating in RA studies (n=4009), while the remaining experience comes from GCA (n=149) studies. The safety profile of RoActemra across these indications remains similar and undifferentiated.

The most commonly reported Adverse Drug Reactions (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.

Intravenous use

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.

Tabulated summary of adverse reactions

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, (³>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 treated with RoActemra. 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)

RA

Intravenous use

The safety of RoActemra 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 RoActemra 4 mg/kg in combination with MTX, 1870 patients received RoActemra 8 mg/kg in combination with MTX or other DMARDs and 288 patients received RoActemra 8 mg/kg monotherapy.

The long‑term exposure population includes all patients who received at least one dose of RoActemra 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.

Description of selected adverse reactions

Infections

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

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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 RoActemra tocilizumab were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.

Infusion reactions

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The rate of anaphylactic reactions (occurring in a total of 8/4,009 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 RoActemra tocilizumab and requiring treatment discontinuation were reported in a total of 56 out of 4,009 patients (1.4%) treated with RoActemra 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 intravenous RoActemra tocilizumab (see section 4.4).

Immunogenicity

A total of 2,876 patients have been tested for anti-RoActemra tocilizumab antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6%) who developed anti-RoActemra 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/ Ll occurred in 3.4% of patients on RoActemra 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/ Ll did so within 8 weeks after starting therapy. Decreases below 0.5 x 10⁹/ Ll were reported in 0.3% patients receiving RoActemra tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.

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Platelets

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

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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 RoActemra tocilizumab 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg RoActemra 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 RoActemra 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 RoActemra 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/ Ll, with 15% experiencing a sustained increase in LDL to ≥ 4.1 mmol/ Ll. Elevations in lipid parameters responded to treatment with lipid-lowering agents.

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Subcutaneous use

RA

The safety of subcutaneous RoActemra tocilizumab in RA includes a double-blind, controlled, multicenter study, SC-I. SC-I was a non-inferiority study that compared the efficacy and safety of RoActemra tocilizumab 162 mg administered every week versus 8 mg/kg intravenous in 1262 patients with RA. All patients received background non-biologic DMARD(s). The safety and immunogenicity observed for RoActemra tocilizumab administered subcutaneous was consistent with the known safety profile of intravenous RoActemra tocilizumab and no new or unexpected adverse drug reactions were observed (see Table 1). A higher frequency of injection site reactions was observed in the subcutaneous arms compared with placebo subcutaneous injections in the intravenous arms.

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Immunogenicity

In SC-I, a total of 625 patients treated with tocilizumab RoActemra 162mg weekly were tested for anti-RoActemra tocilizumab antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti-RoActemra tocilizumab antibodies; of these, all developed neutralizing anti-RoActemra tocilizumab antibodies. One patient was tested positive for IgE isotype (0.2%).

In SC-II, a total of 434 patients treated with tocilizumab 162mg every other week were tested for anti-RoActemra tocilizumab antibodies in the 6 month controlled period. Seven patients (1.6%) developed positive antiRoActemra-tocilizumab antibodies; of these, six (1.4%) developed neutralizing anti-RoActemra tocilizumab antibodies. Four patients were tested positive for IgE isotype (0.9%).

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Platelets

During routine laboratory monitoring in the tocilizumab 6 month clinical trial SC-I, none of the patients on the SC weekly dose had a decrease in platelet count to ≤50 × 10³ / μLl.

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Lipid parameters

During routine laboratory monitoring in the RoActemra tocilizumab 6 month controlled clinical trial SC-I, 19% of patients experienced sustained elevations in total cholesterol > 6.2 mmol/Ll (240 mg/dl), with 9% experiencing a sustained increase in LDL to ³ 4.1 mmol/lL (160 mg/dLl) on the subcutaneous weekly dose.

Subcutaneous use

GCA

The safety of subcutaneous RoActemra has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the RoActemra all exposure population was 138.5 patient years during the 12 month double blind, placebo controlled phase of the study. The overall safety profile observed in the RoActemra treatment groups was consistent with the known safety profile of RoActemra (see Table 1).

Infections

The rate of infection/serious infection events was balanced between the RoActemra weekly group (200.2/9.7 events per 100 patient years) vs. placebo plus 26 weeks prednisone taper (156.0/4.2 events per 100 patient years) and placebo plus 52 weeks taper (210.2/12.5 events per 100 patient years) groups.  

Injection site reactions

In the RoActemra subcutaneous weekly group, a total of 6% (6/100) patients reported an adverse reaction occurring at the site of a subcutaneous injection. No injection site reaction was reported as a serious adverse event or required treatment discontinuation.

Immunogenicity

In the RoActemra subcutaneous weekly group, one patient (1.1%, 1/95) developed positive neutralizing anti-RoActemra antibodies, though not of the IgE isotype. This patient did not develop a hypersensitivity reaction or injection site reaction.

Haematological abnormalities:

Neutrophils

During routine laboratory monitoring in the Roactemra 12 month controlled clinical trial, a decrease in neutrophil count below 1 × 10⁹/L occurred in 4% of patients in the RoActemra subcutaneous weekly group. This was not observed in either of the placebo plus prednisone taper groups.

Platelets

During routine laboratory monitoring in the RoActemra 12 month controlled clinical trial, one patient (1%, 1/100) in the  RoActemra subcutaneous weekly group had a single transient occurence of decrease in platelet count to <100 × 10³ / μL without associated bleeding events. A decrease in platelet count below 100 × 10³ / μL was not observed in either of the placebo plus prednisone taper groups.

Hepatic transaminase elevations

During routine laboratory monitoring in the RoActemra 12 month controlled clinical trial, elevation in ALT  ≥3 x ULN occurred in 3% of patients in the RoActemra subcutaneous  weekly group compared to  2% in the placebo plus 52 week prednisone taper group and none in the placebo plus 26 week prednisone taper group. An elevation in AST > 3 ULN occurred in 1% of patients in the RoActemra subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper groups.

Lipid parameters

During routine laboratory monitoring in the RoActemra 12 month controlled clinical trial, 34% of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L  (240 mg/dL), with 15% experiencing a sustained increase in LDL to ³ 4.1 mmol/L (160 mg/dL) in the RoActemra subcutaneous weekly group.

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 (see details below).

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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

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors; ATC code: L04AC07.

Mechanism of action

RoActemraTocilizumab binds specifically to both soluble and membrane-bound IL‑6 receptors (sIL‑6R and mIL‑6R). Tocilizumab has been shown to inhibit sIL‑6R and mIL‑6R-mediated signalling. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, monocytes and fibroblasts. IL-6 is involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, induction of hepatic acute phase protein synthesis and stimulation of haemopoiesis. IL-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis and neoplasia.

Pharmacodynamic effects

In RA clinical studies with RoActemra tocilizumab, rapid decreases in CRP, erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) were observed. Consistent with the effect on acute phase reactants, treatment with RoActemra tocilizumab was associated with reduction in platelet count within the normal range. Increases in haemoglobin levels were observed, through RoActemra tocilizumab decreasing the IL-6 driven effects on hepcidin production to increase iron availability. In RoActemra tocilizumab‑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.

In GCA clinical study WA28119, similar rapid decreases in CRP and ESR were observed along with slight increases in mean corpuscular haemoglobin concentration. In healthy subjects administered RoActemra tocilizumab in doses from 2 to 28 mg/kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to their lowest 2 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis RA and GCA patients demonstrate a comparable (to healthy subjects) decrease of absolute neutrophil counts following RoActemra tocilizumab administration (see section 4.8).

RA

Intravenous use

Clinical efficacy

The efficacy of tocilizumab in alleviating the signs and symptoms of RA was assessed in five randomised, double-blind, multi-centre studies. Studies I-V enrolled patients ³ 18 years of age with active RA diagnosed according to the American College of Rheumatology (ACR) criteria and who had at least eight tender and six swollen joints at baseline.

In Study I, RoActemra tocilizumab was administered intravenously every four weeks as monotherapy. In Studies II, III and V, RoActemra tocilizumab was administered intravenously every four weeks in combination with MTX vs. placebo and MTX. In Study IV, RoActemra tocilizumab was administered intravenously every 4 weeks in combination with other DMARDs vs. placebo and other DMARDs. The primary endpoint for each of the five studies was the proportion of patients who achieved an ACR 20 response at week 24.

Study I evaluated 673 patients who had not been treated with MTX within six months prior to randomisation 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 RoActemra tocilizumab were given every four weeks as monotherapy. The comparator group was weekly MTX (dose titrated from 7.5 mg to a maximum of 20 mg weekly over an eight week period).

Study II, a two year study with planned analyses at week 24, week 52 and week 104, evaluated 1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of RoActemra tocilizumab or placebo were given every four weeks as blinded therapy for 52 weeks in combination with stable MTX (10 mg to 25 mg weekly). After week 52, all patients could receive open-label treatment with RoActemra tocilizumab 8 mg/kg. Of the patients who completed the study who were originally randomised to placebo + MTX, 86% received open-label RoActemra tocilizumab 8 mg/kg in year 2. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At week 52 and week 104 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 RoActemra tocilizumab or placebo were given every four weeks, in combination with stable MTX (10 mg to 25 mg weekly).

Study IV evaluated 1,220 patients who had an inadequate response to their existing rheumatologic therapy, including one or more DMARDs. Doses of 8 mg/kg RoActemra tocilizumab or placebo were given every four weeks in combination with stable DMARDs.

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Clinical response

In all studies, patients treated with RoActemra tocilizumab 8 mg/kg had statistically significant higher ACR 20, 50, 70 response rates at 6 months compared to control (Table 2). In study I, superiority of RoActemra tocilizumab 8 mg/kg was demonstrated against the active comparator MTX.

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 patients treated with RoActemra tocilizumab 8 mg/kg, significant improvements were noted on all individual components of the ACR response including: tender and swollen joint counts; patients and physician global assessment; disability index scores; pain assessment and CRP compared to patients receiving placebo plus MTX or other DMARDs in all studies.

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In a pooled analysis of studies II, III and IV, the proportion of patients achieving an ACR 20, 50 and 70 response was significantly higher (59% vs. 50%, 37% vs. 27%, 18% vs. 11%, respectively) in the tocilizumab 8 mg/kg plus DMARD vs. the tocilizumab 4 mg/kg plus DMARD group (p< 0.03). Similarly the proportion of patients achieving a DAS 28 remission (DAS28 < 2.6) was significantly higher (31% vs. 16% respectively) in patients receiving RoActemra tocilizumab 8 mg/kg plus DMARD than in patients receiving RoActemra tocilizumab 4 mg/kg plus DMARD (p< 0.0001).

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Radiographic response

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 RoActemra tocilizumab compared to control (Table 3).

In the open-label extension of Study II the inhibition of progression of structural joint damage in tocilizumab plus MTX-treated patients was maintained in the second year of treatment. The mean change from baseline at week 104 in total Sharp-Genant score was significantly lower for patients randomised to RoActemra tocilizumab 8 mg/kg plus MTX (p<0.0001) compared with patients who were randomised to placebo plus MTX.

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Health‑related and quality of life outcomes

RoActemra Tocilizumab‑treated patients reported an improvement in all patient‑reported outcomes (Health Assessment Questionnaire Disability Index - HAQ-DI), Short Form-36 and Functional Assessment of Chronic Illness Therapy questionnaires. Statistically significant improvements in HAQ-DI scores were observed in patients treated with RoActemra compared with patients treated with DMARDs. During the open-label period of Study II, the improvement in physical function has been maintained for up to 2 years. At Week 52, the mean change in HAQ-DI was -0.58 in the RoActemra tocilizumab 8 mg/kg plus MTX group compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI was maintained at Week 104 in the RoActemra tocilizumab 8 mg/kg plus MTX group (-0.61).

Haemoglobin levels

Statistically significant improvements in haemoglobin levels were observed with RoActemra 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.

Tocilizumab versus adalimumab in monotherapy

Study VI (WA19924), a 24 week double-blinded study that compared RoActemra tocilizumab monotherapy with adalimumab monotherapy, 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 RoActemra tocilizumab arm received an intravenous (IV) infusion of RoActemra tocilizumab (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 RoActemra tocilizumab 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 4).

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The overall clinical adverse event profile was similar between tocilizumab and adalimumab. The proportion of patients with serious adverse events was balanced between the treatment groups (RoActemra tocilizumab 11.7% vs. adalimumab 9.9%). The types of adverse drug reactions in the tocilizumab arm were consistent with the known safety profile of RoActemra tocilizumab and adverse drug reactions were reported at a similar frequency compared with Table 1. A higher incidence of infections and infestations was reported in the RoActemra tocilizumab arm (48% vs. 42%), with no difference in the incidence of serious infections (3.1%). 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 RoActemra tocilizumab compared with adalimumab. Four (2.5%) patients in the RoActemra tocilizumab 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 RoActemra tocilizumab 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 RoActemra tocilizumab arm and 0.19 mmol/L (7 mg/dL) for patients in the adalimumab arm. The safety observed in the tocilizumab arm was consistent with the known safety profile of RoActemra  tocilizumab and no new or unexpected adverse drug reactions were observed (see Table 1).

Subcutaneous use

Clinical efficacy

The efficacy of subcutaneous administered RoActemra  tocilizumab in alleviating the signs and symptoms of RA and radiographic response, was assessed in two randomised, double-blind, controlled, multi-center studies.

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Clinical response

Study SC-I evaluated patients with moderate to severe active RA 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. In SC-I, 1262 patients were randomized 1:1 to receive RoActemra tocilizumab subcutaneous 162 mg every week or RoActemra tocilizumab intravenous 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 5.

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Radiographic response

The radiographic response of subcutaneous administered RoActemra tocilizumab was assessed in a double-blind, controlled, multicenter study in patients with active RA (SC-II). Study SC-II evaluated patients with moderate to severe active RA 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 RA diagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline. In SC-II, 656 patients were randomized 2:1 to RoActemra tocilizumab subcutaneous 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 RoActemra tocilizumab subcutaneous compared to placebo (mean mTSS of 0.62 vs. 1.23, p=0.0149 (van Elteren). These results are consistent with those observed in patients treated with intravenous tocilizumab.

In study SC-II, at week 24 there was ACR20 of 60.9%, ACR50 of 39.8% and ACR70 of 19.7% for patients treated with RoActemra tocilizumab subcutaneous every other week versus placebo ACR20 of 31.5%, ACR50 of 12.3% and ACR70 of 5.0%. Patients had mean DAS28 at baseline of 6.7 on subcutaneous and 6.6 on placebo arms. At week 24, a significant reduction in DAS28 from baseline of 3.1 was observed on subcutaneous and 1.7 on placebo arm, and for DAS28 < 2.6, 32.0% was observed on subcutaneous and 4.0% on placebo arm.

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GCA

Subcutaneous Use

Clinical efficacy

Study WA28119 was a randomized, multi-center, double-blind placebo-controlled Phase III superiority study conducted to assess the efficacy and safety of RoActemra in patients with GCA.

Two hundred and fifty one (251) patients with new-onset or relapsing GCA were enrolled and assigned to one of four treatment arms. The study consisted of a 52-week blinded period (Part 1), followed by a 104-week open-label extension (Part 2). The purpose of Part 2 was  to describe the long‑term safety and maintenance of efficacy after 52 weeks of RoActemra therapy, to explore the rate of relapse and the requirement for RoActemra therapy beyond 52 weeks, and to gain insight into the potential long-term steroid-sparing effect of RoActemra.

Two subcutaneous doses of RoActemra (162 mg every week and 162 mg every other week) were compared to two different placebo control groups randomised 2:1:1:1.

All patients received background glucocorticoid (prednisone) therapy. Each of the RoActemra-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen over 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen over 52 weeks, designed to be more in keeping with standard practice.

The duration of glucocorticoid therapy during screening and before RoActemra (or placebo) was initiated, was similar in all 4 treatment groups (see Table 6).

Table 6. Duration of Corticosteroid Therapy During Screening in Study WA28119

The primary efficacy endpoint assessed by the proportion of patients achieving steroid free  sustained remission at week 52 on RoActemra plus 26 weeks prednisone taper compared with placebo plus 26 weeks prednisone taper, was met (Table 7).

The key secondary efficacy endpoint also based on the proportion of patients achieving sustained remission at week 52, comparing tocilizumab plus 26 weeks prednisone taper with placebo plus 52 weeks prednisone taper, was also met (Table 7).  

A statistically significant superior treatment effect was seen in favour of RoActemra over placebo in achieving steroid-free sustained remission at week 52 on RoActemra plus 26 weeks prednisone taper compared with placebo plus 26 weeks prednisone taper and with placebo plus 52 weeks prednisone taper.

The percentage of patients achieving sustained remission at week 52, are shown in the Table 7.

Secondary Endpoints

The assessment of the time to first GCA flare showed a significantly lower risk of flare for the RoActemra subcutaneous weekly group compared to placebo plus 26 weeks prednisone and placebo plus 52 weeks prednisone taper groups and for the RoActemra subcutaneous every other weekly group compared to placebo plus 26 weeks prednisone (when compared at a 0.01 significance level)​. RoActemra subcutaneous weekly dose also showed a clinically meaningful decrease in the risk for flare compared to placebo plus 26 weeks prednisone in patients who entered the trial with relapsing GCA as well as those with new-onset disease (Table 7). 

Cumulative glucocorticoid dose

The cumulative prednisone dose at week 52 was significantly lower in the two RoActemra dose groups compared to the two placebo groups (Table 6). In a separate analysis of the patients who received escape prednisone to treat GCA flare during the first 52 weeks, the cumulative prednisone dose varied greatly.  The median doses for escape patients in the RoActemra weekly and every other weekly groups were 3129.75 mg and 3847 mg, respectively. Both considerably lower than in the placebo plus 26 weeks and the placebo plus 52 weeks prednisone taper groups, 4023.5 mg and 5389.5 mg respectively.

Table 7. Efficacy results from Study WA28119

*  p<0.0001

** p<0.005 (threshold for significance for primary and key secondary tests of superiority)

***Descriptive p value <0.005

****Flare: recurrence of GCA signs or symptoms and/or ESR ≥30 mm/h – Increase in the prednisone dose required

Remission: absence of flare and normalization of the CRP

Sustained remission: remission from week 12 to week 52 –Patients must adhere to the protocol-defined prednisone taper 

¹ analysis of the time (in days) between clinical remission and first disease flare

² p-values are determined using a Van Elteren analysis for non-parametric data

^§ statistical analyses has not been performed

N/A= Not applicable

HR = Hazard Ratio

CI = Confidence Interval

Quality of Life Outcomes

In study WA28119, the SF-36 results were separated into the physical and mental component summary scores (PCS and MCS, respectively). The PCS mean change from baseline to week 52 was higher (showing more improvement) in the RoActemra weekly and every other weekly dose groups [4.10, 2.76, respectively] than in the two placebo groups [placebo plus 26 weeks; -0.28, placebo plus 52 weeks; -1.49], although only the comparison between RoActemra weekly plus 26 weeks prednisone taper group and placebo plus 52 weeks prednisone taper group (5.59, 99% CI: 8.6, 10.32) showed a statistically significant difference (p=0.0024).  For MCS, the mean change from baseline to week 52 for both RoActemra weekly and every other weekly dose groups [7.28, 6.12, respectively] were higher than the placebo plus 52 weeks prednisone taper group [2.84] (although the differences were not statistically significant [weekly p=0.0252 for weekly, p=0.1468 for every other weekly]) and similar to the placebo plus 26 weeks prednisone taper group [6.67].

The Patient’s Global Assessment of disease activity was assessed on a 0-100mm Visual Analogue Scale (VAS). The mean change in Patient’s global VAS from baseline at week 52 was lower (showing greater improvement) in the RoActemra weekly and every other weekly dose groups [-19.0, -25.3, respectively] than in both placebo  groups [placebo plus 26 weeks -3.4, placebo plus 52 weeks -7.2], although only the RoActemra every other weekly plus 26 weeks prednisone taper group showed a statistically significant difference compared to placebo [placebo plus 26 weeks taper p=0.0059, and placebo plus 52 weeks taper p=0.0081].

FACIT-Fatigue change from baseline to week 52 scores were calculated for all groups.  The mean [SD] change scores were as follows: RoActemra weekly plus 26 weeks 5.61 [10.115], RoActemra every other weekly plus 26 weeks 1.81 [8.836], placebo plus 26 weeks 0.26 [10.702], and placebo plus 52 weeks -1.63 [6.753].

Change in EQ5D scores from baseline to week 52 were RoActemra weekly plus 26 weeks 0.10 [0.198], RoActemra every other weekly plus 26 weeks 0.05 [0.215], placebo plus 26 weeks 0.07 [0.293], and placebo plus 52 weeks -0.02 [0.159].

Higher scores signal improvement in both FACIT-Fatigue and EQ5D.

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5.2     Pharmacokinetic properties

The pharmacokinetics of RoActemra is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination.  The nonlinear part of RoActemra elimination leads to an increase in exposure that is more than dose-proportional.  The pharmacokinetic parameters of RoActemra do not change with time. Due to the dependence of total clearance on RoActemra serum concentrations, the half-life of RoActemra is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

RA

Intravenous use

The pharmacokinetics of RoActemra tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 3552 RA patients treated with a one‑hour infusion of 4 or 8 mg/kg RoActemra 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 RoActemra tocilizumab given every 4 weeks: steady-state area under curve (AUC) = 38000 ± 13000 h• µg/mLl, trough concentration (Cmin) = 15.9 ± 13.1 mg/mLl and maximum concentration (Cmax) = 182 ± 50.4 µg/mLl, and. the accumulation ratios for AUC and Cmax were small, 1.32 and 1.09, respectively. The accumulation ratio was higher for Cmin (2.49), which was expected based on the non‑linear clearance contribution at lower concentrations. Steady-state was reached following the first administration for Cmax and after 8 and 20 weeks for AUC and Cmin, respectively. RoActemra Tocilizumab 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 RoActemra tocilizumab were 50000 ± 16800 μg•h/mL, 24.4 ± 17.5 μg/mLl, and 226 ± 50.3 μg/mLl, respectively, which are higher than mean exposure values for the patient population (i.e. all body weights) reported above. The dose-response curve for tocilizumab flattens at higher exposure, resulting in smaller efficacy gains for each incremental increase in RoActemra tocilizumab concentration such that clinically meaningful increases in efficacy were not demonstrated in patients treated with > 800 mg of RoActemra tocilizumab. Therefore, RoActemra tocilizumab doses exceeding 800 mg per infusion are not recommended (see section 4.2).

Distribution

In RA patients the central volume of distribution was 3.72, the peripheral volume of distribution was 3.35 resulting in a volume of distribution at steady state of 7.07.

Elimination

Following intravenous administration, RoActemra tocilizumab undergoes biphasic elimination from the circulation. The total clearance of RoActemra 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 9.5 ml/h. The concentration-dependent non‑linear clearance plays a major role at low RoActemra tocilizumab concentrations. Once the non‑linear clearance pathway is saturated, at higher RoActemra tocilizumab concentrations, clearance is mainly determined by the linear clearance.

The t_1/2 of RoActemra 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 18 days to 6 days.

Linearity

Pharmacokinetic parameters of RoActemra 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 3.2 and 30 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.

Subcutaneous use

The pharmacokinetics of RoActemra tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 3552 RA patients treated with 162 mg subcutaneous every week, 162 mg subcutaneous every other week, and or 4 or 8 mg/kg intravenous every 4 weeks for 24 weeks.

The pharmacokinetic parameters of RoActemra tocilizumab did not change with time. For the 162 mg every week dose, the predicted mean (±SD) steady-state AUC1week, C_min and C_max of RoActemra tocilizumab were 7970 ± 3432 mcgµg•h/mL, 43.0 ± 19.8 mcgµg/mL, and 49.8 ± 21.0 mcgµg/mL, respectively. The accumulation ratios for AUC, C_min, and C_max were 6.32, 6.30, and 5.27, respectively. Steady state was reached after 12 weeks for AUC, C_min, and C_max.

For the 162 every other week dose, the predicted mean (±SD) steady-state AUC2week, C_min, and Cmax of RoActemra tocilizumab were 3430 ± 2660 mcgµg•h/mL, 5.7 ± 6.8 mcgµg/mL, and 13.2 ± 8.8 mcgµg/mL, respectively. The accumulation ratios for AUC, C_min, and C_max were 2.67, 6.02, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and C_min, and after 10 weeks for C_max.

Absorption

Following subcutaneous dosing in RA patients, the time to peak serum RoActemra tocilizumab concentrations t_max was 2.8 days. The bioavailability for the subcutaneous formulation was 79%.

Elimination

For subcutaneous administration, the concentration-dependent apparent t _1/2 is up to 12 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.

GCA

Subcutaneous use

The PK of RoActemra  in GCA patients were determined using a population PK model from an analysis dataset composed of 149 GCA patients treated with 162 mg subcutaneous every week or 162 mg subcutaneous every other week.  The developed model had the same structure as the population PK model developed earlier based on data from RA patients (see Table 8).

Table 8. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in GCA