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RoActemra 20mg/ml 400mg/ml 800mg/ml Concentrate for Solution for Infusion
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RoActemra 20mg/ml 400mg/ml 800mg/ml Concentrate for Solution for Infusion
1. Name of the medicinal product
RoActemra 20 mg/ml concentrate for solution for infusion.
2. Qualitative and quantitative composition
Each ml concentrate contains 20 mg tocilizumab*.
Each vial contains 80 mg of tocilizumab* in 4 ml (20 mg/ml).
Each vial contains 200 mg of tocilizumab* in 10 ml (20 mg/ml).
Each vial contains 400 mg of tocilizumab* in 20 ml (20 mg/ml).
*humanised IgG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.
Excipients with known effects:
Each 80 mg vial contains 0.10 mmol (2.21 mg) sodium.
Each 200 mg vial contains 0.20 mmol (4.43 mg) sodium.
Each 400 mg vial contains 0.39 mmol (8.85 mg) sodium.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Concentrate for solution for infusion (sterile concentrate).
Clear to opalescent, colourless to pale yellow solution.
4. Clinical particulars
4.1 Therapeutic indications
RoActemra, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
RoActemra has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.
RoActemra is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 2 years of age and older, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids. RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.
RoActemra in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic polyarthritis (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
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 section 5.2).
Doses above 1.2 g have not been eva luated in clinical studies (see section 5.1).
Dose adjustments due to laboratory abnormalities (see section 4.4).
• Liver enzyme abnormalities
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Laboratory Value
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Action
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> 1 to 3 x Upper Limit of Normal (ULN)
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Modify the dose of the concomitant MTX if appropriate
For persistent increases in this range, reduce RoActemra dose to 4 mg/kg or interrupt RoActemra until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised
Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate
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> 3 to 5 x ULN
(confirmed by repeat testing, see section 4.4).
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Interrupt RoActemra dosing until < 3 x ULN and follow recommendations above for > 1 to 3 x ULN
For persistent increases> 3 x ULN, discontinue RoActemra
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> 5 x ULN
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Discontinue RoActemra
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• 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.
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Laboratory Value
(cells x 109/ l )
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Action
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ANC > 1
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Maintain dose
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ANC 0.5 to 1
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Interrupt RoActemra dosing
When ANC increases > 1 x 109/ l resume RoActemra at 4 mg/kg and increase to 8 mg/kg as clinically appropriate
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ANC < 0.5
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Discontinue RoActemra
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• Low platelet count
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Laboratory Value
(cells x 103/ μl)
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Action
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50 to 100
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Interrupt RoActemra dosing
When platelet count > 100 x 103/ μl resume RoActemra at 4 mg/kg and increase to 8 mg/kg as clinically appropriate
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< 50
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Discontinue RoActemra
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Special populations
Paediatric patients:
sJIA Patients
The recommended posology in patients above 2 years of age is 8 mg/kg once every 2 weeks in patients weighing greater than or equal to 30 kg or 12 mg/kg once every 2 weeks in patients weighing less than 30 kg. The dose should be calculated based on the patient's body weight at each administration. A change in dose should only be based on a consistent change in the patient's body weight over time.
The safety and efficacy of 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 eva luated. 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
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Laboratory Value
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Action
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> 1 to 3 x ULN
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Modify the dose of the concomitant MTX if appropriate
For persistent increases in this range, interrupt RoActemra until ALT/AST have normalized.
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> 3 x ULN to 5x ULN
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Modify the dose of the concomitant MTX if appropriate
Interrupt RoActemra dosing until < 3x ULN and follow recommendations above for >1 to 3x ULN
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> 5x ULN
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Discontinue RoActemra.
The decision to discontinue RoActemra in sJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.
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• Low absolute neutrophil count (ANC)
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Laboratory Value
(cells x 109/ l )
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Action
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ANC > 1
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Maintain dose
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ANC 0.5 to 1
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Interrupt RoActemra dosing
When ANC increases to > 1 x 109/ l resume RoActemra
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ANC < 0.5
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Discontinue RoActemra
The decision to discontinue RoActemra in sJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.
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• Low platelet count
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Laboratory Value
(cells x 103/ μl)
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Action
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50 to 100
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Modify the dose of the concomitant MTX if appropriate
Interrupt RoActemra dosing
When platelet count is > 100 x 103/μl resume RoActemra
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< 50
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Discontinue RoActemra.
The decision to discontinue RoActemra in sJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.
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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 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 eva luated. 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
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Laboratory Value
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Action
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> 1 to 3 x ULN
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Modify the dose of the concomitant MTX if appropriate
For persistent increases in this range, interrupt RoActemra until ALT/AST have normalized.
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> 3 x ULN to 5x ULN
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Modify the dose of the concomitant MTX if appropriate
Interrupt RoActemra dosing until < 3x ULN and follow recommendations above for >1 to 3x ULN
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> 5x ULN
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Discontinue RoActemra.
The decision to discontinue RoActemra in pJIA for a laboratory abnormality should be based on the medical assessment of the individual patient
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• Low absolute neutrophil count (ANC)
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Laboratory Value
(cells x 109/ l )
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Action
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ANC > 1
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Maintain dose
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ANC 0.5 to 1
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Interrupt RoActemra dosing
When ANC increases to > 1 x 109/ l resume RoActemra
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ANC < 0.5
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Discontinue RoActemra
The decision to discontinue RoActemra in pJIA for a laboratory abnormality should be based on the medical assessment of the individual patient
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• Low platelet count
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Laboratory Value
(cells x 103/ μl)
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Action
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50 to 100
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Modify the dose of the concomitant MTX if appropriate
Interrupt RoActemra dosing
When platelet count is > 100 x 103/μl resume RoActemra
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< 50
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Discontinue RoActemra.
The decision to discontinue RoActemra in pJIA for a laboratory abnormality should be based on the medical assessment of the individual patient.
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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.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active, severe infections (see section 4.4).
4.4 Special warnings and precautions for use
Infections
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including RoActemra (see section 4.8, undesirable effects). RoActemra treatment 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 eva luating a patient for a potential infection. Patients (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients, should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid eva luation 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 eva luated 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. 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.
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 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 (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential must use effective contraception during and up to 3 months after treatment.
Pregnancy
There are no adequate data from the use of tocilizumab in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3). The potential risk for humans is unknown.
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
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.
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 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 1. Summary of ADRs occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the double-bl
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System Organ Class
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Very Common
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Common
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Uncommon
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Infections and infestations
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Upper respiratory tract infections
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Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster
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Diverticulitis
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Gastrointestinal disorders
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Abdominal pain, Mouth ulceration, Gastritis
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Stomatitis, Gastric ulcer
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Skin and subcutaneous tissue disorders
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Rash, Pruritus, Urticaria
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Nervous system disorders
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Headache, Dizziness
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Investigations
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Hepatic transaminases increased, Weight increased, Total bilirubin increased*
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Vascular disorders
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Hypertension
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Blood and lymphatic system disorders
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Leukopenia, Neutropenia
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Metabolism and nutrition disorders
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Hypercholesterolaemia*
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Hypertriglyceridaemia
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General disorders and administration site conditions
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Peripheral oedema, Hypersensitivity reactions
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Eye disorders
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Conjunctivitis
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Respiratory, thoracic and mediastinal disorders
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Cough, Dyspnoea
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Renal disorders
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Nephrolithiasis
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Endocrine disorders
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Hypothyroidism
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ind 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 eva luations are ongoing.
Paediatric population
The safety of toclizumab in the pediatric population in the sections on pJIA and sJIA below. In general, the ADRs in pJIA and sJIA patients were similar i |
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