Summary Basis of Decision for Actemra ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
ActemraTM
Tocilizumab, 20 mg/mL, Solution, Intravenous
Hoffmann-La Roche Ltd.
Submission control no: 121089
Date issued: 2010-10-04
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02350092 - 80 mg/4.0 mL
- 02350106 - 200 mg/10.0 mL
- 02350014 - 400 mg/20.0 mL
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On April 30, 2010, Health Canada issued a Notice of Compliance to Hoffmann-La Roche Limited for the drug product Actemra.
Actemra contains the medicinal ingredient tocilizumab which is an interleukin receptor inhibitor.
Actemra is indicated for reducing the signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis (RA) who have inadequate response to one or more disease modifying anti-rheumatic drugs (DMARDs) and/or tumour necrosis factor (TNF) antagonists.
General use of Actemra in DMARD-inadequate responder (IR) patients is not recommended at this time. Physicians may consider the use of Actemra in the DMARD-IR population on a case by case basis dependent on disease and patient characteristics, experience with the drug, and the benefits and risks of Actemra as compared to other therapeutic options available.
Rheumatoid arthritis is an autoimmune disorder of unknown etiology; however, evidence suggests that excessive production of interleukin-6 (IL-6) may play a role in the pathogenesis of this disease. Interleukin-6 is a cytokine that influences the regulation of immune response, inflammation, and haematopoiesis. Actemra is a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody that blocks the binding of IL-6 to its receptors, thereby producing an immunosuppressant effect. Actemra is the first-in-class IL-6 inhibitor for the treatment of RA.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Actemra were assessed in five pivotal Phase III, randomized, double-blind, controlled, multicentre studies in patients >18 years of age with active RA diagnosed according to the American College of Rheumatology (ACR) criteria. A total of 4211 patients took part in the five studies all of which had the same primary endpoint (an ACR 20 response at Week 24 following treatment) but differed in target population and dosing strategies. An ACR 20 response requires a patient to have a 20% reduction in the number of swollen and tender joints, and a 20% reduction in three of the following five parameters: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), and degree of disability in Health Assessment Questionnaire (HAQ) score. The primary endpoint was met in all five pivotal studies.
Actemra (20.0 mg/mL, tocilizumab) is presented as a solution for intravenous (IV) infusion. Actemra should be given in combination with methotrexate (MTX) or other DMARDs. Actemra may also be given as monotherapy in cases of intolerance to MTX or where treatment with MTX is not appropriate. The recommended dose of Actemra for adult patients with RA is a starting dose of 4 mg/kg as an intravenous infusion over 1 hour every 4 weeks followed by an increase to 8 mg/kg based on clinical response. Dosing guidelines are available in the Product Monograph.
Actemra is contraindicated for patients with a known hypersensitivity to tocilizumab or any of its components. Concurrent therapy with Actemra and another biologic agent is not recommended. When transitioning from another biologic therapy to Actemra, patients should be monitored for signs of infection. In the clinical studies, a higher incidence of infections was observed in patients previously exposed to a TNF inhibitor. Actemra should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Actemra are described in the Product Monograph.
A Black Box Warning in the Product Monograph outlines safety concerns with the use of Actemra including the risk of serious infections such as sepsis, tuberculosis (TB), invasive fungal, and other opportunistic infections. Before starting treatment with Actemra, all patients should be evaluated for both active and latent TB. Treatment with Actemra should not be initiated in patients with active infections including chronic or localized infections. If a serious infection develops, treatment with Actemra should be interrupted until the infection is controlled. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Actemra, including possible development of TB in patients who tested negative for latent TB prior to initiating therapy.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Actemra is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
On April 1, 2008, Hoffmann-La Roche Limited submitted a New Drug Submission for Actemra. A Notice of Deficiency (NOD) was issued on April 3, 2009 for this New Drug Submission based on the identification of deficiencies during the clinical assessment.
Hoffmann-La Roche Limited requested an extension to provide the NOD response. Due to the nature of the NOD comments, Health Canada granted an extension. The NOD response was received on July 29, 2009. The submission entered the review stream and was issued a Notice of Compliance (NOC) on April 30, 2010. A timeline of these events is documented in section 4 Submission Milestones.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Interleukin-6 is produced by synovial and endothelial cells in joints affected by inflammatory processes such as RA.
Tocilizumab, the medicinal ingredient of Actemra is a recombinant humanized anti-IL-6 receptor monoclonal antibody that binds specifically to both soluble and membrane-bound IL-6 receptors. Consequently, the signalling pathways generated by the activation of these receptors are inhibited, reducing the signs and symptoms of RA.
Manufacturing Process and Process Controls
The drug substance is generated by recombinant technology.
Tocilizumab is manufactured using a 10,000-L scale, fed-batch mammalian cell culture process. The purification process consists of a combination of chromatography and viral inactivation/removal steps. Process validation data demonstrated that the manufacturing process operates in a consistent manner, yielding product of acceptable quality.
The drug substance manufacturing process has been scaled-up and optimized during development. The process changes introduced at each generation of the process were adequately described and comparatively assessed. Lot release, stability, and characterization data have also been used to support the comparability assessment.
In-process controls performed during the manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that tocilizumab consistently exhibits the desired characteristic structure and biological activity.
Comparability of tocilizumab lots produced by different processes was performed and comparable physicochemical characteristics and immunoreactivity were demonstrated.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of tocilizumab are considered acceptable.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, accelerated, stress, and photostability data submitted, the proposed shelf-life and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Actemra is supplied as a sterile, colourless to pale yellow, preservative-free 20 mg/mL solution for IV infusion in either 10-mL (80 mg) or 20-mL (200 mg and 400 mg) single-use Type-I glass vials. The vials are capped with a fluoro-resin laminated stopper made from butyl rubber. There are three dosage strengths: 80 mg, 200 mg, and 400 mg. The drug product strengths are identical in their qualitative and quantitative composition; they only differ with respect to their fill volume.
In addition to the medicinal ingredient tocilizumab, each vial of Actemra contains the following non-medicinal ingredients: disodium phosphate dodecahydrate, polysorbate 80, sodium dihydrogen phosphate dihydrate, sucrose, and water for injection.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of tocilizumab with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Actemra, a rationale for the choice of formulation, the manufacturing process including packaging, information on batches used in in vitro studies for characterization, and a discussion on the effect of formulation change on the safety and/or efficacy of Actemra. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Parameters relevant to the performance of the drug product were not affected by the changes described.
Data pertaining to the physicochemical characteristics and biological activity demonstrated biocomparability between the development and commercial batches.
Manufacturing Process and Process Controls
The Actemra drug product manufacturing process essentially consists of thawing the drug substance, formulation, sterile filtration, and aseptic filling into vials. The manufacturing process has been adequately validated.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Actemra is tested to verify that its identity, assay, pH, particulates, sterility, protein content, osmolality, colour, clarity, levels of degradation products, drug-related impurities, foreign particulate matter, bacterial endotoxins, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all of the batches were within the proposed specification limits.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
Stability
Based on the long-term, accelerated, and stress-test stability data submitted, the proposed 24-month shelf-life at 2 to 8°C, protected from light, is considered acceptable for Actemra.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The facility involved the manufacture of the drug substance and drug product was inspected by a qualified team of inspectors from the Biologics and Genetic Therapies Directorate, Health Canada. The on-site evaluation and the review of the responses to the Exit Notice observations were found to be satisfactory.
The design, operations, and controls of the facility and equipment that are involved in the production of Actemra are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Actemra has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
In vitro pharmacodynamic (PD) studies demonstrated that tocilizumab binds specifically to interleukin-6 receptors (IL-6R) on the cell surface and has nearly equal binding affinities for both soluble IL-6R (sIL-6R) and membrane bound IL-6R (mIL-6R). Therefore, tocilizumab has the capability to block IL-6 binding to cells, thus blocking the agonistic activities of IL-6.
Tocilizumab is also able to neutralize trans-signalling active IL-6/sIL-6R complexes at pharmacologically achievable concentrations. This is accomplished by either blocking the formation of IL-6/IL-6R complexes and/or dissociating pre-existing IL-6/sIL-6R complexes by displacing IL-6 from the complex. Tocilizumab had no effect on signal transmission in members of the human gp130 cytokine family other than IL-6R, demonstrating its specificity and selectivity to IL-6R. Tocilizumab did not transmit the proliferation signal to BAF-h130 cells, even at 1000-fold the concentration of IL-6 required for cell proliferation, indicating that the tocilizumab/sIL-6R complex does not have signal transduction capacity. In addition, it was shown that tocilizumab had no signal transduction effect on TNF-α, IL-1, IL-15 or IL-2. It was noted, however, that this absence of a direct effect does not exclude the possibility that blocking IL-6 activity in vivo could have an indirect downstream impact on levels of these cytokines.
Effective blockade of receptor signalling requires the continuous presence of tocilizumab, since the continuous cellular reactions mediated by IL-6 signalling require persistent stimulation.
Tocilizumab also appeared to have cytostatic and cytotoxic functions, such as (i.e.) arrest of the G1 phase of the cell cycle and apoptosis, respectively, and expressed anti-tumour activity through a combination of these functions.
In vitro tissue binding studies utilizing human, rat and monkey tissues indicated that tocilizumab does not bind to tissues known to express mIL-6R, and like other IgG molecules, can non-specifically associate with tissues.
In vivo studies conducted using cynomolgus monkeys demonstrated that tocilizumab was well-tolerated and elicited a therapeutic effect with a reduction of the clinical signs of collagen-induced arthritis (CIA), as well as a reduction in CRP (a marker of systemic inflammation). There were no observed adverse events (AEs) including changes in liver function tests and serum lipids. In addition, other surrogate markers of disease, i.e., ESR and inflamed joints, were significantly inhibited, and exhibited a return towards normal.
In vivo studies also demonstrated that tocilizumab does not affect the primary antibody response to a T-cell dependent antigen, nor does it show any effect on the secondary antibody response to T-cell antigen. Findings also suggested that tocilizumab does not affect the development of T-cell memory and T-cell helper cell activity.
Safety Pharmacology
A battery of safety pharmacology studies was conducted. Studies utilizing isolated guinea pig ileum indicated that tocilizumab did not interfere with smooth muscle tonus. Studies in male mice revealed that tocilizumab did not elicit a change in general activity or behaviour, spontaneous motor activity, body temperature, gastrointestinal propulsion or hexobarbital-induced sleeping time, and did not affect induction of convulsions or pain sensation. There was no treatment-related effect on acute water metabolism in rats, nor any effect on respiratory rate and cardiovascular parameters in dogs and cynomolgus monkeys. Gastrointestinal propulsion in cynomolgus monkeys was unaffected.
3.2.2 Pharmacokinetics
Pharmacokinetic (PK) studies were conducted in rats and cynomolgus monkeys. In both species, the PK properties were consistent with those of other IgG molecules, and were characterized by a low plasma clearance and a small volume of distribution. Differences in the PKs between species could be explained by the interaction between tocilizumab and the IL-6 receptor in cynomolgus monkeys, which does not occur in rats. The PK profile of tocilizumab in cynomolgus monkeys was similar to humans supporting their use as a model. Trans-placental transfer of tocilizumab was detected in cynomolgus monkeys.
3.2.3 Toxicology
Single-Dose Toxicity
The acute non-lethal dose of tocilizumab when administered by intravenous (IV) injection to Sprague-Dawley rats or cynomolgus monkeys was determined to be >150 mg/kg bodyweight (bw) and >100 mg/kg bw, respectively (the highest dose levels tested). All animals survived the duration of the study period and no signs of toxicity were observed in either species. The safety margin compared to the proposed clinical dose is 150-fold for rats, and 10- to 100-fold for monkeys.
Repeat-Dose Toxicity
As tocilizumab is intended for IV infusion for RA patients, toxicity studies compliant with good laboratory practices (GLP) were conducted following IV administration of tocilizumab to the test species.
Sub-chronic testing in Sprague Dawley rats was carried out for 2 and 4 weeks at dose levels of 0, 2, 10 or 50 mg/kg bw/day. Dose levels were well-tolerated and there were no adverse, treatment-related findings observed at any dose level tested.
Sub-chronic testing in cynomolgus monkeys was carried out for 2 weeks (0.4, 2, 10, and 50 mg/kg bw/day), 1 month (2, 10, and 50 mg/kg bw/day), and 6 months (1, 10, and 100 mg/kg bw/week). Measurements of electrocardiograms (ECGs) and body temperatures were incorporated into the 6-month study. Dose levels were well-tolerated and findings were consistent after 2 weeks, 1, and 6 months of treatment. There were no treatment-related AEs after treatment for up to 6 months for any of the measured parameters at any dose level tested.
Genotoxicity
Genotoxicity testing was comprised of an in vitro reverse mutation assay and an an in vitro chromosomal aberration assay, both of which yielded negative results. In vivo genotoxicity studies were not performed since the International Conference on Harmonisation S6 guidance, Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, states that: "The range and type of genotoxicity studies routinely conducted for pharmaceuticals are not applicable to biotechnology-derived pharmaceuticals and therefore are not needed."
Carcinogenicity
Tocilizumab has not been tested in carcinogenicity studies. As tocilizumab does not bind to rodent IL-6R, conventional long-term cancer studies in rats or mice are inappropriate to assess a function-related carcinogenic potential of tocilizumab and are not requested by international guidelines.
However, non-clinical studies conducted with tocilizumab or MR16-1 demonstrated anti-proliferative effects. Tocilizumab inhibited the proliferation of IL-6 dependent cell lines such as human myeloma cell line in vitro and in vivo. In addition, proliferative lesions have not been observed in a chronic 6-month toxicity study in monkeys, nor were they described in knock-out mice under chronic IL-6 depletion.
Reproductive and Developmental Toxicity
Embryofoetal developmental and fertility toxicity testing were conducted in Sprague-Dawley rats at dose levels of 5, 16, and 50 mg/kg bw. In these studies, no AEs were noted for reproductive function/fertility, maternal toxicity, embryo/foetal toxicity and developmental toxicity
Embryofoetal developmental toxicity testing was conducted in Japanese white rabbits at dose levels of 0.5, 5, and 50 mg/kg bw. The only findings observed were in the 5 mg/kg bw group. These included decreased food intake for dams, a decrease in foetal bodyweight, and an increase in foetal mortality. The foetal effects were not considered to be a primary treatment-related effect, but rather secondary to the decrease in maternal food consumption. This is supported by the observation that there were no treatment-related findings observed in the 50 mg/kg bw group.
Embryofoetal testing was conducted in cynomolgus monkeys at dose levels of 2, 10, and 50 mg/kg bw. The only finding in this study was a dose-related increase in the incidence of abortions/embryo-foetal death, which were considered to be treatment-related at 10 and 50 mg/kg bw (10%, 10%, 20% and 30%, respectively, for the 0, 2, 10, and 50 mg/kg bw/day groups).
Supportive reproductive/developmental studies were conducted in mice at dose levels of 15 and 50 mg/kg bw. There were no treatment-related effects on male and female fertility, embryo-foetal development, pre- and post-natal development (including the development of the foetal immune system), nor on maternal function. The primary finding observed in these studies was an increase in mortality at the low dose of 15 mg/kg bw, which was considered to be associated with an immunoreaction towards the rat protein sequences in MR16-1, the rat anti-mouse IL-6R monoclonal antibody used in this study. This immunoreaction was not observed at the higher dose of 50 mg/kg bw, and was not considered to have any impact on the study objectives. There was a high transfer of MR16-1 from the dam to the foetus via the placenta. In addition, MR16-1 was excreted in the milk of lactating mice, with concentrations of approximately 25% that found in the maternal plasma.
Local Tolerance
Local tolerance of tocilizumab was demonstrated after single 100 mg IV/perivenous, subcutaneous or intramuscular injections of tocilizumab.
In PD studies, it was demonstrated that administration of tocilizumab at a dose of 133.4 mg/kg bw, did not affect the respiratory system, cardiovascular system or gastrointestinal motility in cynomolgus monkeys.
3.2.4 Summary and Conclusion
In conclusion, the above studies have characterized the pharmacological properties of tocilizumab, demonstrating its activity via inhibition of the IL-6R signalling system. Safety pharmacology studies indicated that tocilizumab was well-tolerated under the conditions of the studies conducted.
In the toxicology studies, tocilizumab was generally well tolerated in the repeat-dose toxicity studies and local tolerance studies at doses up to 100 mg/kg bw (safety margin of up to 117-fold). Similarly, there was no evidence of treatment-related maternal toxicity or teratogenicity at doses up to 50 mg/kg bw. However, there was an increased incidence of abortions observed in cynomolgus monkeys at dose levels of 10 mg/kg bw and higher, which cannot be ruled out as unrelated to treatment. In addition, studies in mice revealed that tocilizumab was transferred from the dam to the foetus via the placenta, and was excreted in the milk of lactating dams.
In conclusion, the non-clinical toxicology data base was considered adequate to assess the safety profile of tocilizumab and support its use for RA in humans, provided adequate safety precautions are taken, as described in section 3.3.4 Clinical Safety.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
C-reactive protein is synthesized by hepatocytes as a direct effect of IL-6 stimulation. Elevated CRP levels are an indication of the intensity of inflammation in RA patients and are included in the assessment of a patient's response to therapy using the ACR criteria.
A dose-dependent decrease in CRP was observed in RA patients who received tocilizumab doses of 4 mg/kg and 8 mg/kg. For patients who received 8 mg/kg tocilizumab every 4 weeks, CRP levels were markedly suppressed as early as Week 2 and were sustained close to the normal range during the entire dosing interval, indicating persistent and consistent suppression of the joint-degrading inflammation associated with RA synovitis. Only slight fluctuations in CRP were observed in a few patients following this dose. For patients administered 4 mg/kg tocilizumab every 4 weeks, saw-tooth fluctuations in CRP levels were observed in most patients, with the lowest CRP levels exhibited at 2 weeks post-dose with return to near baseline levels before the next 4-weekly dose. Therefore, a sustained decrease in CRP throughout treatment duration was achieved only in patients administered 8 mg/kg every 4 weeks.
Following administration of tocilizumab, IL-6 levels temporarily increase. This increase may be caused by a displacement of IL-6 from the receptor, or by a temporary change in IL-6 formation or elimination. There was a trend for decreasing IL-6 peak levels over 24 weeks for patients who received 8 mg/kg tocilizumab, suggestive of an adaptation of IL-6 regulation with amelioration of the disease or inflammatory status. A sustained increase in sIL-6R levels was observed for the 8 mg/kg dose, suggestive of persistent binding of tocilizumab to sIL-6R. At the 4 mg/kg dose, the saw-tooth pattern in sIL-6R levels suggests intermittent binding of tocilizumab to sIL-6R.
Anaemia, in particular anaemia of inflammation, is a very common manifestation in RA. Inflammation leads to macrophage elaboration of IL-6, which acts on hepatocytes to induce hepcidin production. Hepcidin inhibits macrophage iron release and intestinal iron absorption, leading to hypoferraemia that subsequently limits erythropoiesis. Following administration of tocilizumab, an initial increase of urinary excretion of hepcidin occurred which was immediately followed by decreased excretion of hepcidin. Thereafter, the mean urinary hepcidin levels remained slightly below baseline values for several weeks. The inter-patient variability of the levels of urinary excretion of hepcidin was extremely high in this study; therefore these results should be interpreted with caution.
Serum levels of ferritin and iron rapidly increased following administration of tocilizumab. These concentrations returned to pre-dose values within 2 weeks for ferritin and more slowly for iron (approximately 8 weeks). These findings appear to agree with the blockade of the IL-6 signaling by tocilizumab, which decreases hepcidin production and consequently the inhibition of both intestinal absorption and macrophage release of iron, thereby increasing serum iron. This mechanism may partially explain the increase in haemoglobin that has been observed in arthritis patients treated with tocilizumab in Phase III studies.
These parameters suggest a rapid but temporary blockade of IL-6 signalling by tocilizumab.
3.3.2 Pharmacokinetics
The PKs of tocilizumab are best described by a two-compartment disposition model with parallel first-order (linear or concentration-independent clearance) and Michaelis-Menten elimination (non-linear or concentration-dependent clearance) kinetics. Therefore, the total clearance of tocilizumab is the sum of the non-linear and linear clearances.
The PK characteristics and clearance of tocilizumab are concentration- and dose-dependent at low exposures. At low tocilizumab concentrations, the clearance is primarily non-linear; once the non-linear clearance pathway is saturated at higher tocilizumab concentrations, clearance is primarily linear.
The volume of distribution of the central compartment of tocilizumab was 3.5 L, which approximates the serum volume and is in the range of what has been previously described for IgGs and other monoclonal antibodies. The volume of distribution at steady-state (Vss) (6.4 L) tends to indicate a limited distribution into the body; however, it is known that for most antibodies, distribution into tissues is often part of the elimination process and not part of the distribution process and hence contributes to the small apparent distribution volumes. Therefore, a small Vss should not necessarily be interpreted as low tissue penetration, and adequate concentrations may be reached in a single-target organ due to receptor-mediated uptake.
The PK parameters of tocilizumab did not change with time. Accumulation ratios for the area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were low, while the highest ratios were observed for trough concentration (Cmin): 1.96 and 2.35 for 4 and 8 mg/kg tocilizumab, respectively. This is expected based on the contribution of non-linear clearance at low tocilizumab concentrations. Following the first administration of the 4 mg/kg and 8 mg/kg doses, steady-state was achieved for Cmax, AUC, and Cmin after 4 to 8 weeks, and after 16 to 20 weeks, respectively. The inter-subject variability for tocilizumab was moderate (44%, 47%, and 107% for AUC, Cmax and Cmin, respectively), at steady-state for 8 mg/kg tocilizumab every 4 weeks).
Special Populations
Age, gender, race, and ethnicity had no impact on the PKs of tocilizumab. Body size [body surface area, body weight, body mass index (BMI)] had an effect on clearance; this was accounted for by body weight-adjusted dosing, although this adjustment results in slightly higher exposures to tocilizumab with higher bodyweight.
Mild renal impairment did not alter the PKs of tocilizumab.
Drug Interaction Studies
A single dose of 10 mg/kg of tocilizumab in addition to MTX once weekly, with or without single doses of simvastatin, was well tolerated with no unexpected safety findings. In RA patients, administration of tocilizumab significantly reduced the exposure to simvastatin to levels close to those found in non-RA patients. The effect persisted for 5 weeks after tocilizumab administration. In addition, tocilizumab had no relevant effect on MTX exposure.
Tocilizumab is a protein and is not metabolized via the cytochrome P450 (CYP450) or the P-glycoprotein (Pgp) pathway as it is a protein product. A direct interaction of tocilizumab with other medicinal products which are substrates, inhibitors or inducers of CYP450 and/or Pgp is not expected and therefore no formal studies were conducted. Population PK analysis revealed that concomitant use of medicinal products for RA did not affect the PKs of tocilizumab.
A recognized effect of inflammation is suppression of CYP450 enzyme levels. Treatment with tocilizumab, which reduces inflammation, may normalize CYP450 levels. An in vitro mechanistic study with human hepatocytes demonstrated that high IL-6 concentrations down-regulate the messenger ribonucleic acid (mRNA) expression of various CYP450 enzymes. Co-incubation with tocilizumab inhibited the IL-6-mediated down-regulation of CYP450 enzyme mRNA.
Data from a supportive clinical study in RA patients indicated that the systemic exposure of concomitantly administered CYP450 substrates can decrease with the inhibition of IL-6 signaling to exposures observed in patients without inflammatory disease. This may be clinically relevant for CYP450 substrates (for example, warfarin) with a narrow therapeutic index, where the dose is individually adjusted by means of therapeutic monitoring.
3.3.3 Clinical Efficacy
The efficacy of Actemra for the proposed indication was evaluated in five pivotal, Phase III, randomized, double-blind, controlled, multicentre studies. All 4211 patients enrolled in these studies were >18 years of age with moderately to severely active RA diagnosed according to ACR criteria. Patients had at least eight tender and six swollen joints at baseline.
Each of the five pivotal studies had the same primary endpoint (the proportion of patients who achieved an ACR 20 response at Week 24 following treatment) but differed in target patient populations and dosing regimens. Actemra was administered as monotherapy (Study I); in combination with MTX (Studies II and III); or in combination with other DMARDs (Study IV) in patients who had an inadequate response to these drugs. Actemra was also given intravenously every 4 weeks in combination with MTX in patients who had an inadequate response to therapy with TNF antagonists (Study V).
The majority of patients in the pivotal studies were Caucasian females with a mean age of 52 years. Most patients (~80% in all studies) completed 24 weeks of study. Drop-outs due to lack of efficacy were more common in the control arm than with Actemra treatment.
Actemra Monotherapy
Study I (AMBITION) enrolled 673 patients with active RA who had not been treated with MTX within 6 months prior to randomization and who had not discontinued previous MTX treatment as a result of clinically important toxic effects or lack of response. Patients in this study had the shortest median duration of RA (3 years) and over 40% of the enrolled patients had RA for less than 2 years. This study compared 8 mg/kg Actemra as monotherapy versus (vs.) MTX (in MTX-naïve patients) vs. placebo. Patients who received Actemra [sample size (n) = 286] received 8 mg/kg Actemra intravenously every 4 weeks as monotherapy. The comparator group (n = 284) received MTX as a titrated dose from 7.5 mg to 20 mg weekly over an 8-week period.
Actemra Combination Therapy with Methotrexate or other Disease-Modifying Anti-Rheumatic Drugs (DMARDs) in DMARD Inadequate-Responder (IR) Patients
Study II (LITHE), Study III (OPTION) and Study IV (TOWARD) enrolled 3039 patients with active RA who had an inadequate response to non-biologic DMARDs. Patients in Study II and III were administered 4 mg/kg or 8 mg/kg of Actemra intravenously every 4 weeks in combination with MTX or placebo in combination with MTX. For Study IV, patients were administered 8 mg/kg of Actemra in combination with a DMARD or placebo in combination with a DMARD.
Actemra Combination Therapy with Methotrexate in Tumour Necrosis Factor Antagonist Inadequate-Response Patients
Study V (RADIATE) evaluated the efficacy and safety of the administration of 4 mg/kg or 8 mg/kg Actemra in combination with MTX (10 - 25 mg weekly) as compared to placebo in combination with MTX (10 - 25 mg weekly). A total of 499 patients with moderately to severely active RA and a history of inadequate clinical response or who were intolerant to one or more TNF-antagonist therapies were enrolled in the study. The TNF-antagonist therapy was discontinued prior to randomization.
Efficacy Results
For all five clinical studies, the efficacy results demonstrate a treatment benefit in favour of Actemra at either dose (4 mg/kg or 8 mg/kg) with respect to ACR response as compared to the control group (either placebo + MTX/DMARD or MTX monotherapy).
An ACR 20 response requires a patient to have a 20% reduction in the number of swollen ageand tender joints, and a 20% reduction in three of the following five parameters: physician global assessment of disease, patient global assessment of disease, patient assessment of pain, CRP or erythrocyte sedimentation rate, and degree of disability in HAQ score. The percentage of patients achieving an ACR 20, ACR 50, and ACR 70 response in Studies I to V is shown in the table below.
| Study | American College of Rheumatology (ACR) 20 | ACR 50 | ACR 70 | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Control * | 4 mg/kg | 8 mg/kg | Control * | 4 mg/kg | 8 mg/kg | Control * | 4 mg/kg | 8 mg/kg | |
| *Control group varies across the studies as follows: Study I: MTX; Study II, III, and IV: placebo + MTX or DMARD; Study V: placebo + MTX | |||||||||
| I | 53% | - | 70% | 34% | - | 44% | 15% | - | 28% |
| II | 27% | 51% | 56% | 10% | 25% | 32% | 2% | 11% | 13% |
| III | 27% | 48% | 59% | 11% | 32% | 44% | 2% | 12% | 22% |
| IV | 25% | - | 61% | 9% | - | 38% | 3% | - | 21% |
| V | 10% | 30% | 50% | 4% | 17% | 29% | 1% | 5% | 12% |
In all studies, patients treated with 8 mg/kg Actemra had a statistically superior ACR 20, ACR 50, and ACR 70 response rate vs. MTX- or placebo-treated patients (p <0.01) at Week 24.
In patients treated with Actemra after an inadequate response to DMARDs or TNF-antagonist therapy, the response rates were lower in the 4 mg/kg Actemra treatment group compared to the 8 mg/kg group.
Although pooled efficacy data indicates a greater ACR response in the 8 mg/kg Actemra treatment group, the recommended starting dose should be 4 mg/kg due to dose-related safety concerns (see section 3.3.4 Clinical Safety for details).
Although Actemra monotherapy was studied in early RA patients with the majority of these patients being MTX-naïve, Actemra should not be used as a first-line therapy in RA patients due to the significant risks associated with Actemra treatment.
Patients with inadequate response to DMARDs or TNF therapy (DMARD-IR or TNF-IR RA) were excluded from the Actemra monotherapy Study I (AMBITION).
Actemra monotherapy is therefore limited to RA patients who are intolerant of MTX treatment or for whom MTX is not appropriate.
3.3.4 Clinical Safety
The safety of Actemra was evaluated based on data from the controlled pivotal studies described in section 3.3.3 Clinical Efficacy and data from the safety update of the All Exposure population. The primary safety population presented in the safety update includes a total of 4009 patients (8580 patient-years of exposure) up to the clinical cut-off date of February 6, 2009. The All Exposure population was composed of all patients who received at least one dose of Actemra in the following studies: Study I (including the transition phase), Study II, Study III (including the extension phase), Study IV, Study V, Study WP18663 (an ongoing drug interaction study), and the open-label long-term extension (LTE) studies WA18695 and WA18696. Of note, patients in the open-label LTE studies all received Actemra at a dose of 8 mg/kg. A total of 3577 patients from the All Exposure population received Actemra for at least 6 months and 3296 patients have received it for at least 1 year. Most patients received Actemra 8 mg/kg (n = 3863, 7760 patient years), and 1397 patients received Actemra 4 mg/kg (817 patient years).
The All Control population was composed of 774 patients randomized to receive Actemra 4 mg/kg + DMARD, 1870 patients randomized to receive Actemra 8 mg/kg + DMARD, and 1555 patients randomized to receive the control [placebo + MTX or placebo + DMARD(s)]. The exposure time for the All Control, Actemra 4 mg/kg, and Actemra 8 mg/kg was 824.6, 564.6, and 1194.1 patient-years, respectively.
The most commonly reported AEs in the 6-month controlled studies (occurring in ≥5% of patients treated with monotherapy or in combination with traditional DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension, and increased alanine aminotransferase (ALT).
In the All Exposure population, the rate of AEs was 332.2 per 100 patient-years for patients who had received at least one dose of Actemra. This was lower than the rate reported in the 6-month controlled studies (468.44 per 100 patient-years). There was no clear evidence in the long-term safety updates of an increase in the frequency or severity of the most common AEs with increased duration of exposure to Actemra from the long-term safety updates.
In the All Control population, a dose-dependent increase in the overall rate of AEs was observed in the Actemra 8 mg/kg treatment group (381.6 per 100 patients-years) compared to the Actemra 4 mg/kg treatment group (358.0 per 100 patient-years). Infections were the most frequently reported AEs.
The most frequently reported AEs in patients from the All Exposure population were infections and infestations (74.4 per 100 patient-years; most commonly upper respiratory tract infections and urinary tract infections; opportunistic infections including herpes simplex/herpes zoster were also reported), gastrointestinal disorders (36.4 per 100 patient-years; most commonly diarrhoea and nausea), and musculoskeletal tissue disorders (28.9 per 100 patient-years; most commonly back pain and RA flare). Other common AEs included: nervous system disorders (most commonly headache and dizziness) and dermatologic disorders (most commonly rash, pruritis, and alopecia).
Overall, there was a higher risk associated with the Actemra 8 mg/kg treatment group compared to the Actemra 4 mg/kg treatment group, with exposure-adjusted increased rates of AEs, laboratory abnormalities, serious adverse events (SAEs), and death. As a result, the recommended starting dose for Actemra is 4 mg/kg.
Serious Safety Concerns
Serious Infections
In the All Control population, the rate of serious infections reported was 3.4 per 100 patient-years for the control group, 3.5 per 100 patient-years for the Actemra 4 mg/kg group, and 4.9 per 100 patient-years for the Actemra 8 mg/kg group, with an increased risk of serious infection with the higher dose of Actemra. Serious infections, some of which were fatal, included: pneumonia, cellulitis, urinary tract infection, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. Opportunistic infections were also reported.
In the All Exposure population, the rate of serious infections was 4.66 per 100 patient-years. The rate of serious infections in the All Exposure population was 2.8 per 100 patient-years for patients <50 years of age, 4.9 per 100 patient-years for patients ≥50 to ≤64 years of age, and 7.7 per 100 patient-years for patients >65 years of age, indicating an age-related risk of serious infections with Actemra treatment. Other factors included corticosteroid use, previous anti-TNF therapy use, chronic pulmonary disease and diabetes.
A Black Box Warning in the Product Monograph outlines safety concerns with the use of Actemra including the risk of serious infections such as sepsis, TB, invasive fungal, and other opportunistic infections. Before starting treatment with Actemra, all patients should be evaluated for both active and latent TB. Treatment with Actemra should not be initiated in patients with active infections including chronic or localized infections. If a serious infection develops, treatment with Actemra should be interrupted until the infection is controlled. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Actemra, including possible development of TB in patients who tested negative for latent TB prior to initiating therapy.
Gastrointestinal Perforations
In the clinical trial with Actemra a total of 26 gastrointestinal perforations were reported in the All Exposure population vs. 5 in the All Control population. The calculated exposure-adjusted incidence rate is 0.28/100 patient-years, which is higher than the reported incidence for TNF inhibitors (0.12/100 patient-years).
Infusion Reactions
In the 6-month controlled clinical studies, AEs associated with infusion (occurring during or within 24 hours of infusion) were reported in 8% and 7% of patients in the 4 mg/kg and 8 mg/kg Actemra plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported AE on the 4 mg/kg and 8 mg/kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported AEs occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses) including rash, pruritus, and urticaria.
Immunogenicity
In 6-month controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (1.6%) developed positive anti-tocilizumab antibodies of which five had an associated medically significant hypersensitivity reaction leading to withdrawal. Thirty patients (1.1%) developed neutralizing antibodies. The clinical significance of this is not known.
Malignancies
In the All Control population, malignancy was reported in 17 patients in the Actemra treatment group and 6 patients in the control group. The solid cancers reported in the All Control population included: two cases of colon cancer and one case of prostate cancer in the control group, two cases of prostate cancer, one case of cervical cancer (stage III), and one case of lung cancer (stage III) in the Actemra 4 mg/kg group, and one case each of dermatofibrosarcoma, endometrial cancer, gastric cancer, and rectal cancer in the Actemra 8 mg/kg group.
In the All Exposure population, the overall rate of malignancy was 1.19 and 0.4 per 100 patient-years for malignancies and other neoplasms, respectively. The incidence of malignancy did not exceed the expected rate as calculated from the Surveillance Epidemiology End Results (SEER) for the general population. Although data on long-term exposure through 42 months showed that the rate of malignancies remained stable, the possibility of increased risk in malignancies following long-term exposure to Actemra cannot be ruled out.
Laboratory Abnormalities
Low-Density Lipoprotein (LDL) Cholesterol
Actemra treatment has been associated with an increase in all lipid parameters, including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. In the All Exposure population, 37% of patients (954/2546) had an increase in LDL from <130 mg/dL (<3.4 mmol/L) at baseline to ≥130 mg/dL (≥3.4 mmol/L) at the last observation following continued dosing with Actemra for up to 176 weeks. The rates of myocardial infarction and cerebrovascular accidents have remained within the known range for RA patients; therefore, based on the current data, there have been no strong safety signals for lipid elevations resulting in cardiovascular AEs.
Haematology
In both Actemra monotherapy and combination therapy groups, decreases in mean values were observed for white blood cell counts (predominantly in mean neutrophil counts) and platelet counts. These decreases were not observed in the respective control groups. Of the patients treated with Actemra, 20% and 14% experienced neutropaenia (Grade 1 or 2) or thrombocytopaenia (Grade 1 or 2), respectively, but few cases were severe (Grade 4). Absolute neutrophil count (ANC) decreases were dose related: <1 x 109/L occurred in 1.8% and 3.4% of patients in the 4 mg/kg and 8 mg/kg Actemra + DMARD group, respectively, compared to 0.1% of patients in the placebo + DMARD group. Approximately half occurred within 8 weeks of starting therapy. These haematology abnormalities were reversible with discontinuation of Actemra treatment.
Recommendations for the management of dose-related neutropaenia and thrombocytopaenia are provided in the Product Monograph.
Liver Enzyme Elevation
Actemra treatment was associated with a reversible elevation in hepatobiliary parameters, which is consistent with its mechanism of action (i.e. IL-6 receptor inhibition). Approximately 50% of the All Exposure population treated with Actemra experienced elevations in aspartate aminotransferase (AST) or ALT up to three times the upper limit of normal (≤3x ULN). For all patients in RA trials who received Actemra (n = 4009), 56 patients reported 57 hepatotoxicity events, including 42 cases of steatosis.
Elevations of ALT/AST >5x ULN were observed in 0.7% of Actemra monotherapy patients and 1.4% of Actemra plus traditional DMARD patients, the majority of whom were discontinued from Actemra treatment. No clinical events of hepatitis or hepatic failure have been reported; patients who screened positive for hepatitis were excluded from the studies.
Recommendations for the management of dose-related liver enzyme elevations are provided in the Product Monograph.
Cardiovascular Events
The rate of cardiac disorder events that occurred in the All Control population was 3.5, 2.7, and 4.0 per 100 patient-years in the control, Actemra 4 mg/kg, and Actemra 8 mg/kg groups, respectively. The most frequently reported events were arrhythmias, ischaemic events, ventricular dysfunction, and conduction disorders.
The rate of myocardial infarction in patients taking Actemra during the Phase III studies was 0.35 per 100 patient-years. This is within the rates reported from the reported safety databases in RA (0.35 to 1.8 per 100 patient-years). A total of 8 cerebrovascular accidents occurred during the Phase III studies in patients treated with Actemra at a rate of 0.26 per 100 patient-years. This is also within the rates reported from RA databases (0.11 to 0.52 per 100 patient-years).
In the All Control population, hypertension was reported more often in patients treated with Actemra (4.4%) than those receiving DMARDs alone (2.7%). Most events were isolated and mild to moderate in intensity. Four patients treated with Actemra (0.3%) and two patients treated with DMARDs (0.2%) had severe elevations in blood pressure. No patients were withdrawn due to hypertension.
Demyelinating Events
Nine patients with potential demyelinating disease were identified in the safety update report. The estimated background incidence of demyelinating disorders in RA patients has not been reported. Uncommon cases of demyelinating disorders have been reported for other biologic immunosuppressives, for example, TNF inhibitors. A clear association of Actemra treatment with the development of demyelinating disorders cannot be established based on currently available data; this potential issue has been labelled in the Product Monograph and careful monitoring should be employed in the clinical use of Actemra.
Deaths
A total of 50 deaths (1.2% of total) have been reported in patients who received at least one dose of Actemra in the All Exposure population. The main causes of death were cardiac events, serious infections, and malignancies. The calculated exposure-adjusted rate of death is 0.53 per 100 patient-years of exposure, which is well below the published background rate of death in RA populations (estimated at 2.4 to 2.5 per 100 patient-years).
3.3.5 Additional Issues
As part of the marketing authorization for Actemra, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to):
- Providing a final Canadian Risk Management Plan (RMP).
- Including Canadian patients receiving Actemra in a patient registry program, either in the international registry program or in a Canadian registry program.
- Submit to the Health Canada any reports or correspondence regarding the registry program as well as the ongoing clinical trials or other sources to assess the long-term risk of cardiovascular events, potential hepatotoxicity, gastrointestinal tract perforation, demyelinating disorders, as well as long-ter
m risk of serious infections and malignancies that are known to be associated with immunosuppressant therapy.
- Notifying Health Canada, in accordance with Canadian Regulations, of all SAEs including malignancies, autoimmune diseases, serious infections, and other SAEs that occurred in clinical trials with Actemra.
Special Populations
Pediatric
The safety and efficacy of Actemra in children have not been established.
Geriatric
As with all biologics, there is a higher incidence of infections in the elderly population in general, therefore, caution should be used when treating the elderly.
Renal impairment
Actemra has not been studied in patients with moderate to severe renal impairment.
Hepatic impairment
The safety and efficacy of Actemra has not been studied in patients with hepatic impairment.
Pregnancy and Lactation
Actemra should not be used in pregnancy. To monitor the outcomes of pregnant women exposed to Actemra, a patient registry has been established.
Breastfeeding should be discouraged in lactating women treated with Actemra.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The sponsor has provided sufficient information to address the concerns outlined in the NOD letter. There is substantial evidence to demonstrate a favourable benefit/risk to support clinical use of Actemra, either used alone or in combination with MTX or other DMARDs, for treatment of RA patients with moderately to severely active disease. Despite the favourable benefit/risk, in addition to the underlying risks of serious infection and malignancy (known to be associated with immunosuppressants), Actemra has specific safety concerns for liver enzyme elevation (evidence for possible hepatotoxicity), lipid abnormalities (which may result in cardiovascular toxicity), gastrointestinal perforations, hypertension, and possible neurotoxicity. These safety concerns are significant and appear to be dose-related. Other therapeutic options are currently available; therefore, Actemra should be administered only to RA patients who have failed other treatments (i.e. one or more DMARDs and/or TNF-antagonists). Due to the risks associated with higher doses, treatment with Actemra should be initiated with the 4 mg/kg dose.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Actemra is favourable for reducing the signs and symptoms in adult patients with moderately to severely active RA who have inadequate response to one or more DMARDs and/or TNF antagonists. The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: ActemraTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-12-11 |
| Submission filed: | 2008-04-09 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2008-05-20 |
| Review 1 | |
| On-Site Evaluation: | 2008-11-10 - 2008-11-14 |
| Biostatistics Evaluation complete: | 2009-04-03 |
| Notice of Deficiency (NOD) issued by Director General (safety, efficacy, and quality issues): | 2009-04-03 |
| Response filed: | 2009-07-27 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2009-08-09 |
| Review 2 | |
| Quality Evaluation complete: | 2010-04-30 |
| Clinical Evaluation complete: | 2010-04-30 |
| Biostatistics Evaluation complete: | 2010-04-30 |
| Labelling Review complete: | 2010-04-29 |
| Notice of Compliance issued by Director General | 2010-04-30 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ACTEMRA | 02350106 | HOFFMANN-LA ROCHE LIMITED | TOCILIZUMAB 200 MG / 10 ML |
| ACTEMRA | 02350092 | HOFFMANN-LA ROCHE LIMITED | TOCILIZUMAB 80 MG / 4 ML |