Actemra Injection

Rheumatoid Arthritis (RA)
Actemra, in combination with methotrexate (MTX) is indicated for:

• the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate (MTX).
• the treatment of moderate to severe active rheumatoid arthritis in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, Actemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. Actemra has been shown to reduce the rate of progression of joint damage as measured by modified total Sharp-Genant radiographic score and to improve physical function when given in combination with MTX.

Polyarticular Juvenile Idiopathic Arthritis (pJIA)
Actemra, in combination with MTX, is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older. Actemra can be given alone in patients intolerant to MTX or where the treatment response with MTX is inadequate.

Systemic Juvenile Idiopathic Arthritis (sJIA)
Actemra is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids. Actemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.

Method of Administration
Treatment should be initiated by medical practitioners experienced in the diagnosis and treatment of RA, pJIA or sJIA.

Rheumatoid Arthritis (RA)
The recommended dose of Actemra for adult patients is 8 mg/kg body weight, given once every four weeks as an IV infusion over one hour. For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended. See Pharmacokinetic properties. Doses above 1,2 g have not been evaluated in clinical studies.

Dose adjustments due to laboratory abnormalities. See section 4.4

• Liver enzyme abnormalities
  Laboratory value Action
  > 1 to 3x Upper Limit of Normal (ULN) Dose modify concomitant MTX if appropriate. For persistent increases in this range, reduce Actemra dose to 4 mg/kg or interrupt Actemra until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised. Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate.
  > 3 to 5x ULN (confirmed by repeat testing. See section 4.4) Interrupt Actemra dosing until < 3x ULN. When values reach 3x ULN, discontinue Actemra.
  > 5x ULN Discontinue Actemra.
• Low absolute neutrophil count (ANC)
  In patients not previously treated with Actemra, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 10 9 /u2113. Laboratory value (cells x 10 9 /u2113) Action
  ANC > 1 Maintain dose.
  ANC 0,5 to 1 Interrupt Actemra dosing. When ANC increases > 1 x 10 9 /u2113 resume Actemra at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.
  ANC < 0,5 Discontinue Actemra.
• Low platelet count
  Laboratory value (cells x 10 3 /u03bcu2113) Action
  50 to 100 Interrupt Actemra dosing. When platelet count > 100 x 10 3 /u03bcu2113 resume Actemra at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.
  < 50 Discontinue Actemra.

Polyarticular Juvenile Idiopathic Arthritis (pJIA)
The recommended dose of Actemra for patients with pJIA is:

• 10 mg/kg once every four weeks for patients weighing < 30 kilograms (kg) as an IV infusion.
• 8 mg/kg once every four weeks for patients weighing u2265 30 kg as an IV infusion. A change in dose should only be based on a consistent change in the patientu2019s body weight over time. Actemra can be used alone or in combination with MTX.

Systemic Juvenile Idiopathic Arthritis (sJIA)
The recommended dose of Actemra for patients with sJIA is:

• 12 mg/kg once every two weeks in patients weighing < 30 kg as an IV infusion.
• 8 mg/kg once every two weeks in patients weighing u2265 30 kg as an IV infusion. The dose should be calculated on the patientu2019s body weight at each administration. A change in dose should only be based on a consistent change in the patientu2019s body weight over time.

Available data suggest that clinical improvement is observed within 6 weeks for sJIA patients or 12 weeks for pJIA patients following initiation of treatment with Actemra. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.

Hypersensitivity to the tocilizumab or to any of the excipients. Active, severe infections. See section 4.4

Infections
Serious and sometimes fatal infections have been reported in patients receiving Actemra. See section 4.8. Actemra treatment should not be initiated in patients with active infections. Administration of Actemra should be interrupted if a patient develops a serious infection until the infection is controlled. See section 4.3 and S4.8.

Medical practitioners should exercise caution when considering the use of Actemra in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes) 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, pJIA or sJIA as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reactants. The effects of Actemra on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients (including RA and younger children with pJIA or sJIA who may be less able to communicate their symptoms) and parents/guardians of pJIA or sJIA patients should be instructed to contact their medical practitioner immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Tuberculosis
RA, pJIA and sJIA patients should be screened for latent tuberculosis (TB) infection prior to starting Actemra therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating Actemra.

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

Hypersensitivity reactions
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with infusion of Actemra. In the post marketing setting, events of serious hypersensitivity and anaphylaxis have occurred in patients treated with a range of doses of Actemra, with or without concomitant arthritis therapies, premedication, and/or a previous hypersensitivity reaction. In the post marketing setting, cases with a fatal outcome have been reported with intravenous Actemra. These events have occurred as early as the first infusion of Actemra, see section 4.3 and 4.8.

Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during administration of Actemra. If an anaphylactic reaction or other serious hypersensitivity/serious infusion related reaction occurs, administration of Actemra should be stopped immediately and Actemra should be permanently discontinued.

Active hepatic disease and hepatic impairment
Treatment with Actemra, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases. See section 4.8. Therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment, as the safety of Actemra in these patients has not been adequately studied. See Special Dosage Instructions.

Hepatic transaminase elevations
In clinical trials, transient or intermittent mild and moderate elevations of hepatic transaminases have been observed with Actemra treatment, without progression to hepatic injury. See section 4.8. An increased frequency of these elevations was observed when potentially hepatotoxic medicines (e.g. MTX) were used in combination with Actemra. Caution should be exercised when considering initiation of Actemra treatment in patients with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1,5x upper limit of normal (ULN). In patients with baseline ALT or AST > 5x ULN, treatment is not recommended. ALT and AST levels should be monitored in RA patients 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 - 5x ULN, confirmed by repeat testing, Actemra treatment should be interrupted. Once the patientu2019s hepatic transaminases are below 3x ULN, treatment with Actemra may recommence at 4 or 8 mg/kg.

Neutropenia
Decreases in neutrophil counts have occurred following treatment with Actemra 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. Caution should be exercised when considering initiation of Actemra treatment in patients with a low absolute neutrophil count (ANC) < 2 x 10 9 /u2113. In patients with an ANC < 0,5 x 10 9 /u2113, treatment is not recommended. Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with Actemra to date. Neutrophils should be monitored in RA 4 to 8 weeks after start of therapy and thereafter according to good clinical practice. For recommended dose modifications based on ANC counts, see section 4.2. In pJIA and sJIA patients, neutrophils should be monitored at the time of the second infusion and thereafter according to good clinical practice. See section 4.2.

Thrombocytopenia
Treatment with Actemra was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials. See section 4.8. Caution should be exercised when considering initiation of Actemra treatment in patients with a platelet count below 100 x 10 3 /u03bcu2113. In patients with a platelet count < 50 x 10 3 /u03bcu2113, treatment is not recommended.

Lipid parameters
Elevations of lipid parameters including total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides were observed in patients treated with Actemra. 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. Assessment of lipid parameters should be performed in RA, pJIA and sJIA patients 4 to 8 weeks following initiation of Actemra therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia. The long term effect of the raised lipids is still unknown.

Demyelinating disorders
Medical practitioners should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with Actemra is currently unknown.

Malignancy
The risk of malignancy is increased in patients with RA. Immunomodulatory medicines, such as Actemra may increase the risk of malignancy.

Vaccinations
Live and live attenuated vaccines should not be given concurrently with Actemra as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Actemra. In a randomised open-label study, adult RA patients treated with Actemra and MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is recommended that all patients, particularly pJIA and sJIA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines, prior to initiating Actemra therapy. The interval between live vaccinations and initiation of Actemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

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

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.

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

Sodium
Actemra contains 1,17 mmol (or 26,55 mg) sodium per maximum dose of 1 200 mg. Information to be taken into consideration by patients on a controlled sodium diet. Doses below 1 025 mg of Actemra contain less than 1 mmol sodium (23 mg), i.e. essentially u201csodium freeu201d.

Sugar
Actemra contains sucrose. Patients with the rare hereditary conditions of galactose intolerance lactase deficiency, glucose-galactose malabsorption intolerance should not take Actemra Actemra contains sucrose which may have an effect on the glycaemic control of patients with diabetes mellitus.

Concomitant administration of a single dose of 10 mg/kg Actemra with 10 - 25 mg MTX once weekly had no clinically significant effect on MTX exposure. Population pharmacokinetic analysis did not detect any effect of MTX, non-steroidal anti-inflammatory drugs and corticosteroids on Actemra clearance. The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 may be reversed when potent cytokine inhibitory therapy, such as Actemra, is introduced. In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Actemra normalises expression of these enzymes. The effect of Actemra on CYP enzymes (except CYP2C19 and CYP2D6) is clinically relevant for CYP450 substrates with a narrow therapeutic index, and/or where the dose is individually adjusted.

In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57 % one week following a single dose of Actemra, to the level similar or slightly higher than those observed in healthy subjects. When starting or stopping therapy with Actemra, patients taking medicinal products which are individually dose-adjusted and are metabolised via CYP450 3A4, 1A2, or 2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t u00bd ), the effect of Actemra on CYP450 enzyme activity may persist for several weeks after stopping therapy.

Combination with TNF antagonists
There is no experience with the use of Actemra in combination with TNF antagonists or other biological treatments for RA or sJIA patients. Actemra is not recommended for use with other biological agents.

Pregnancy
Safety and efficacy has not been established. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose. Actemra should not be used in pregnancy.

Breastfeeding/Lactation
It is unknown whether ACTEMRA is excreted in human breast milk. The excretion of Actemra in milk has not been studied in animals. Breastfeeding should be discontinued during treatment with Actemra.

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.

Clinical Trials
A total of 3 778 patients received at least one dose of Actemra 4 mg/kg or 8 mg/kg. The adverse drug reactions (ADRs) presented in Table 1 are based on the safety of Actemra studied in 4 placebo-controlled studies (Studies II, III, IV and V) and 1 MTX-controlled study (Study I). The control period in 4 of the studies was 6 months and in 1 study was up to 2 years. In these studies 774 patients received Actemra 4 mg/kg in combination with MTX, 1 870 patients received Actemra 8 mg/kg in combination with MTX or other DMARDs and 288 patients received Actemra 8 mg/kg monotherapy. The long-term exposure population includes all patients who received at least one dose of Actemra either in the double-blind control period or open-label extension phase in studies. Of the 4 009 patients in this population, 3 577 received treatment for at least 6 months, 3 296 for at least one year; 2 806 received treatment for at least two years and 1 222 for three years.

The most commonly reported ADRs (occurring in u2265 5 % of patients treated with Actemra 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 (u2265 1/10), common (u2265 1/100 to < 1/10) or uncommon (u2265 1/1 000 to < 1/100).

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

System Organ Class
Very Common
Common
Uncommon
Infections and infestations
Upper respiratory tract infections
Cellulitis, pneumonia, oral herpes simplex, herpes zoster
Diverticulitis
Gastrointestinal disorders
Abdominal pain, mouth ulceration, gastritis
Stomatitis, gastric ulcer
Skin and subcutaneous tissue disorders
Rash, pruritus, urticaria
Nervous system disorders
Headache, dizziness
Investigations
Increased hepatic transaminases, increased weight, increased total bilirubin*
Vascular disorders
Hypertension
Blood and lymphatic system disorders
Leucopenia, neutropenia
Metabolism and nutrition disorders
Hypercholesterolaemia* Hypertriglyceridaemia
General disorders and administration site conditions
Peripheral oedema, hypersensitivity reactions
Eye disorders
Conjunctivitis
Respiratory, thoracic and mediastinal disorders
Cough, dyspnoea
Renal disorders
Nephrolithiasis
Endocrine disorders
Hypothyroidism
* Includes elevations collected as part of routine laboratory monitoring (see text below)

Infections: In the controlled studies the rate of all infections reported with Actemra 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 Actemra was 108 events per 100 patient-years exposure. In controlled clinical studies, the rate of serious infections with Actemra 8 mg/kg plus DMARDs was 5,3 events per 100 patient-years exposure compared to 3,9 events per 100 patient-years exposure in the placebo plus DMARD group. In the monotherapy study the rate of serious infections was 3,6 events per 100 patient-years of exposure in the Actemra group and 1,5 events per 100 patient-years of exposure in the MTX group. In the long-term safety population (core and extension studies) the rate of serious infections observed with Actemra plus DMARD treatment was 4,7 events per 100 patient-years exposure. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidiodomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis.

Gastrointestinal (GI) perforation:
During the six month controlled clinical trials, the overall rate of GI perforation was 0,26 events per 100 patient-years with Actemra therapy. In the long-term exposure population the overall rate of GI perforation was 0,28 events per 100 patient-years. Reports of GI perforation on Actemra were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistula and abscess.

Infusion reactions:
Adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6,9 % of patients in the Actemra 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 Actemra and requiring treatment discontinuation, were reported in a total of 13 out of 3 778 patients (0,3 %) treated with Actemra during the controlled and open-label clinical trials. These reactions were generally observed during the second to fifth infusions of Actemra. See section 4.4.

Immunogenicity:
A total of 2 876 patients have been tested for anti-tocilizumab antibodies in the 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. In 30 patients (1,1 %) who developed neutralising antibodies, no apparent correlation to clinical response was observed.

Early Rheumatoid Arthritis
Study VI1 (WA19926) evaluated 1 162 patients with early, moderate to severe RA who were nau00efve to treatment with both MTX and a biologic agent. The overall safety profile observed in the Actemra treatment groups was consistent with the known safety profile of Actemra (see Table 1).

Polyarticular Juvenile Idiopathic Arthritis
The safety of intravenous Actemra was studied in 188 paediatric patients, 2 to 17 years of age, with pJIA. The total patient exposure in the Actemra all exposure population was 184,4 patient years. In general, the types of adverse drug reactions in patients with pJIA were similar to those seen in RA and sJIA patients, see Table 1.

Infections
The rate of infections in the Actemra all exposure population was 163,7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing < 30 kg treated with 10 mg/kg tocilizumab (12,2 per 100 patient years) compared to patients weighing u2265 30 kg, treated with 8 mg/kg Actemra (4,0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing < 30 kg treated with 10 mg/kg Actemra (21,4 %) compared to patients weighing u2265 30 kg, treated with 8 mg/kg Actemra (7,6 %).

Infusion Reactions
In pJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the Actemra all exposure population, 11 patients (5,9 %) experienced infusion reactions during the infusion, and 38 patients (20,2 %) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension and within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and sJIA patients.

Immunogenicity
One patient in the 10 mg/kg < 30 kg group developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.

Systemic Juvenile Idiopathic Arthritis
The safety of Actemra in sJIA has been studied in 112 paediatric patients 2 to 17 years of age. In the 12 week double-blind, controlled phase, 75 patients received treatment with Actemra (8 or 12 mg/kg based upon body weight). After 12 weeks or at the time of switching to Actemra due to disease worsening, patients were treated in the on-going open-label extension phase. In general, the adverse drug reactions in patients with sJIA were similar in type to those seen in RA patients.

Infections: In the 12 week controlled trial the rate of all infections in the Actemra group was 344,7 per 100 patient-years and 287,0 per 100 patient-years in the placebo group. In the on-going open-label extension study (Part II) the overall rate of infections remained similar at 306,6 per 100 patient-years. In the 12 week controlled trial, the rate of serious infections in the Actemra group was 11,5 per 100 patient-years. In the on-going open-label extension study the overall rate of serious infection remained stable at 11,3 per 100 patient-years. Reported serious infections were similar to those seen in RA patients with the addition of varicella and otitis media.

Infusion reactions: For sJIA patients infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the 12 week controlled trial, 4,0 % of patients from the Actemra group experienced events occurring during infusion, one event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment. In the 12 week controlled trial, 16 % of patients in the Actemra group and 5,4 % of patients in the placebo group experienced an event within 24 hours of infusion. In the Actemra group, the events included, but were not limited to rash, urticaria, diarrhoea, epigastric discomfort, arthralgia and headache. One of these events (urticaria) was considered serious. Clinically significant hypersensitivity reactions associated with Actemra and requiring treatment discontinuation, were reported in 1 out of 112 patients (< 1 %) treated with Actemra during the controlled and open-label parts of the clinical trial.

Immunogenicity: All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies with one of these patients having a hypersensitivity reaction leading to withdrawal. The incidence of anti-tocilizumab antibody formation may be underestimated because of interference of Actemra with the assay and higher tocilizumab concentration observed in children compared to adults.

There are limited data available on overdose with Actemra. Side effects reported with the use of Actemra may occur but the frequency and/or severity thereof may be different from those reported with therapeutic use. Treatment is palliative and supportive.