These highlights do not include all the information needed to use ACTEMRA safely and effectively. See full prescribing information for ACTEMRA. ACTEMRA (tocilizumab) Injection, for intravenous infusionInitial U.S. Approval: 2010
Patients treated with ACTEMRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
If a serious infection develops, interrupt ACTEMRA until the infection is controlled.
Reported infections include:
The risks and benefits of treatment with ACTEMRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ACTEMRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].
ACTEMRA (tocilizumab) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.
ACTEMRA may be used as monotherapy or concomitantly with methotrexate or other DMARDs. The recommended dose of ACTEMRA for adult patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:
Recommended Adult Dosage Every 4 Weeks |
Patients who have had an inadequate response to one or more TNF antagonists |
When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg/kg followed by an increase to 8 mg/kg based on clinical response. |
ACTEMRA for intravenous infusion should be diluted to 100 mL by a healthcare professional using aseptic technique as follows:
ACTEMRA treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
Liver Enzyme Abnormalities [see Warnings and Precautions (5.3)]: |
Lab Value |
Recommendation |
> 1 to 3x ULN |
Dose modify concomitant DMARDs if appropriate |
|
For persistent increases in this range, reduce ACTEMRA dose to 4 mg/kg or interrupt ACTEMRA until ALT/AST have normalized |
> 3 to 5x ULN |
Interrupt ACTEMRA dosing until < 3x ULN and follow recommendations above for > 1 to 3x ULN |
(confirmed by repeat testing) |
For persistent increases > 3x ULN, discontinue ACTEMRA |
> 5x ULN |
Discontinue ACTEMRA |
Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.3)]: |
Lab Value
(cells/mm3) |
Recommendation |
ANC > 1000 |
Maintain dose |
ANC 500 to 1000 |
Interrupt ACTEMRA dosing
When ANC > 1000 cells/mm3 resume ACTEMRA at 4 mg/kg and increase to 8 mg/kg as clinically appropriate |
ANC < 500 |
Discontinue ACTEMRA |
Low Platelet Count [see Warnings and Precautions (5.3)]: |
Lab Value
(cells/mm3) |
Recommendation |
50,000 to 100,000 |
Interrupt ACTEMRA dosing
When platelet count is > 100,000 cells/mm3 resume ACTEMRA at 4 mg/kg and increase to 8 mg/kg as clinically appropriate |
< 50,000 |
Discontinue ACTEMRA |
Single-use vials of ACTEMRA (20 mg/mL):
None
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including ACTEMRA for rheumatoid arthritis. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with ACTEMRA. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections.
ACTEMRA should not be administered in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating ACTEMRA in patients:
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ACTEMRA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.3), Adverse Reactions (6.1), and Patient Counseling Information (17.1)].
ACTEMRA should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with ACTEMRA should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
Tuberculosis
Patients should be eva luated for tuberculosis risk factors and tested for latent infection prior to initiating ACTEMRA.
Anti-tuberculosis therapy should also be considered prior to initiation of ACTEMRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
It is recommended that patients be screened for latent tuberculosis infection prior to starting ACTEMRA. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating ACTEMRA.
Viral Reactivation
Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with ACTEMRA. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.
Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis. ACTEMRA should be used with caution in patients who may be at increased risk for gastrointestinal perforation. Patients presenting with new onset abdominal symptoms should be eva luated promptly for early identification of gastrointestinal perforation [see Adverse Reactions (6.1)].
Neutrophils
Treatment with ACTEMRA was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.
Platelets
Treatment with ACTEMRA was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see Adverse Reactions (6.1)].
Liver Function Tests
Treatment with ACTEMRA was associated with a higher incidence of transaminase elevations. These elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials [see Adverse Reactions (6.1)]. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with ACTEMRA.
In one case, a patient who had received ACTEMRA 8 mg/kg monotherapy without elevations in transaminases experienced elevation in AST to above 10x ULN and elevation in ALT to above 16x ULN when MTX was initiated in combination with ACTEMRA. Transaminases normalized when both treatments were held, but elevations recurred when MTX and ACTEMRA were restarted at lower doses. Elevations resolved when MTX and ACTEMRA were discontinued.
Lipids
Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse Reactions (6.1)].
The impact of treatment with ACTEMRA on the development of malignancies is not known but malignancies were observed in clinical studies [see Adverse Reactions (6.1)]. ACTEMRA is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.
Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with infusion of ACTEMRA [see Adverse Reactions (6.1)]. Appropriate medical treatment should be available for immediate use in the event of an anaphylactic reaction during administration of ACTEMRA.
The impact of treatment with ACTEMRA on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies. Patients should be closely monitored for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of ACTEMRA in patients with preexisting or recent onset demyelinating disorders.
Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment [see Adverse Reactions (6.1), Use in Specific Populations (8.6)].
Live vaccines should not be given concurrently with ACTEMRA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ACTEMRA. No data are available on the effectiveness of vaccination in patients receiving ACTEMRA. Because IL-6 inhibition may interfere with the normal immune response to new antigens, patients should be brought up to date on all recommended vaccinations, except for live vaccines, prior to initiation of therapy with ACTEMRA.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
The ACTEMRA data described below includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of ACTEMRA 8 mg/kg monotherapy (288 patients), ACTEMRA 8 mg/kg in combination with DMARDs (including methotrexate) (1582 patients), or ACTEMRA 4 mg/kg in combination with methotrexate (774 patients).
The all exposure population includes all patients in registration studies who received at least one dose of ACTEMRA. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.
All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.
The most common serious adverse reactions were serious infections [see Warnings and Precautions (5.1)]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in ≥ 5% of patients treated with ACTEMRA monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking ACTEMRA and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of ACTEMRA were increased hepatic transaminase values (per protocol requirement) and serious infections.
Overall Infections
In the 24 week, controlled clinical studies, the rate of infections in the ACTEMRA monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg/kg and 8 mg/kg ACTEMRA plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.
The overall rate of infections with ACTEMRA in the all exposure population remained consistent with rates in the controlled periods of the studies.
Serious Infections
In the 24 week, controlled clinical studies, the rate of serious infections in the ACTEMRA monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg/kg and 8 mg/kg ACTEMRA plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.
In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and Precautions (5.1)].
Gastrointestinal Perforations
During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with ACTEMRA therapy.
In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate [see Warnings and Precautions (5.2)]. The relative contribution of these concomitant medications versus ACTEMRA to the development of GI perforations is not known.
Infusion Reactions
In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start 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 event on the 4 mg/kg and 8 mg/kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event 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. These events were not treatment limiting.
Anaphylactoid and anaphylactic reactions associated with ACTEMRA and requiring treatment discontinuation were reported in 0.1% (3/2644) in the 24 week, controlled trials and in 0.2% (8/4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of ACTEMRA. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction [see Warnings and Precautions (5.5)].
Laboratory Tests
Neutrophils
In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000/mm occurred in 1.8% and 3.4% of patients in the 4 mg/kg and 8 mg/kg ACTEMRA plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000/mmoccurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500/mm occurred in 0.4% and 0.3% of patients in the 4 mg/kg and 8 mg/kg ACTEMRA plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000/mm and the occurrence of serious infections.
In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.3)].
Platelets
In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000/mm occurred in 1.3% and 1.7% of patients on 4 mg/kg and 8 mg/kg ACTEMRA plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.
In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings and Precautions (5.3)].
Liver Function Tests
Liver enzyme abnormalities are summarized in Table 1 . In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of ACTEMRA, or reduction in ACTEMRA dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration (2.3)]. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings and Precautions (5.3)].
In the all-exposure population, the elevations in ALT/AST remained consistent with what was seen in the 24 week, controlled clinical trials
Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to VFor a description of these studies, see Section 14, Clinical Studies.
|
ACTEMRA
8 mg/kg MONOTHERAPY |
Methotrexate |
ACTEMRA
4 mg/kg + DMARDs |
ACTEMRA
8 mg/kg + DMARDs |
Placebo + DMARDs |
|
N = 288
(%) |
N = 284
(%) |
N = 774
(%) |
N = 1582
(%) |
N = 1170
(%) |
ULN = Upper Limit of Normal |
AST (U/L) |
|
|
|
|
|
> ULN to 3x ULN |
22 |
26 |
34 |
41 |
17 |
> 3x ULN to 5x ULN |
0.3 |
2 |
1 |
2 |
0.3 |
> 5x ULN |
0.7 |
0.4 |
0.1 |
0.2 |
< 0.1 |
ALT (U/L) |
|
|
|
|
|
> ULN to 3x ULN |
36 |
33 |
45 |
48 |
23 |
> 3x ULN to 5x ULN |
1 |
4 |
5 |
5 |
1 |
> 5x ULN |
0.7 |
1 |
1.3 |
1.5 |
0.3 |
Lipids
Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of ACTEMRA in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg/dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were eva luated and are summarized below:
Elevated lipids responded to lipid lowering agents.
In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.
Immunogenicity
In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.
The data reflect the percentage of patients whose test results were positive for antibodies to tocilizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab with the incidence of antibodies to other products may be misleading.
Malignancies
During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving ACTEMRA, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the ACTEMRA groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).
In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period [ see Warnings and Precautions (5.4)].
Other Adverse Reactions
Adverse reactions occurring in 2% or more of patients on 4 or 8 mg/kg ACTEMRA plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.
Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with ACTEMRA in controlled trials were:
Infections and Infestations: oral herpes simplex
Gastrointestinal disorders: stomatitis, gastric ulcer
Investigations: weight increased, total bilirubin increased
Blood and lymphatic system disorders: leukopenia
General disorders and administration site conditions: edema peripheral
Respiratory, thoracic, and mediastinal disorders: dyspnea, cough
Eye disorders: conjunctivitis
Renal disorders: nephrolithiasis
Endocrine disorders: hypothyroidism
Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg/kg ACTEMRA plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD
24 Week Phase 3 Controlled Study Population |
|
ACTEMRA
8 mg/kg MONOTHERAPY |
Methotrexate |
ACTEMRA
4 mg/kg + DMARDs |
ACTEMRA
8 mg/kg + DMARDs |
Placebo + DMARDs |
Preferred Term |
N = 288
(%) |
N = 284
(%) |
N = 774
(%) |
N = 1582
(%) |
N = 1170
(%) |
Upper Respiratory Tract Infection |
7 |
5 |
6 |
8 |
6 |
Nasopharyngitis |
7 |
6 |
4 |
6 |
4 |
Headache |
7 |
2 |
6 |
5 |
3 |
Hypertension |
6 |
2 |
4 |
4 |
3 |
ALT increased |
6 |
4 |
3 |
3 |
1 |
Dizziness |
3 |
1 |
2 |
3 |
2 |
Bronchitis |
3 |
2 |
4 |
3 |
3 |
Rash |
2 |
1 |
4 |
3 |
1 |
Mouth Ulceration |
2 |
2 |
1 |
2 |
1 |
Abdominal Pain Upper |
2 |
2 |
3 |
3 |
2 |
Gastritis |
1 |
2 |
1 |
2 |
1 |
Transaminase increased |
1 |
5 |
2 |
2 |
1 |
Population pharmacokinetic analyses did not detect any effect of methotrexate, non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.
Concomitant administration of a single dose of 10 mg/kg ACTEMRA with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.
ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.1)].
Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effects on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of ACTEMRA, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Prescribers should exercise caution when ACTEMRA is coadministered with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)].
Live vaccines should not be given concurrently with ACTEMRA [see Warnings and Precautions (5.8)].
Teratogenic Effects. Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. ACTEMRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
An embryo-fetal developmental toxicity study was performed in which pregnant cynomolgus monkeys were treated intravenously with tocilizumab (daily doses of 2, 10, or 50 mg/kg from gestation day 20-50) during organogenesis. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at 10 mg/kg and 50 mg/kg doses (1.25 and 6.25 times the human dose of 8 mg/kg every 4 weeks based on a mg/kg comparison).
Nonteratogenic Effects. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation until day 21 after delivery (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.
Pregnancy Registry: To monitor the outcomes of pregnant women exposed to ACTEMRA, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
It is not known whether tocilizumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ACTEMRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of ACTEMRA in pediatric patients have not been established.
Of the 2644 patients who received ACTEMRA in Studies I to V [see Clinical Studies (14)], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. The frequency of serious infection among ACTEMRA treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
The safety and efficacy of ACTEMRA have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see Warnings and Precautions (5.7)].
No dose adjustment is required in patients with mild renal impairment. ACTEMRA has not been studied in patients with moderate to severe renal impairment [see Clinical Pharmacology (12.3)].
No studies on the potential for ACTEMRA to cause dependence have been performed. However, there is no evidence from the available data that ACTEMRA treatment results in dependence.
There are limited data available on overdoses with ACTEMRA. One case of accidental overdose was reported in which a patient with multiple myeloma received a dose of 40 mg/kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg/kg, although all 5 patients at the highest dose of 28 mg/kg developed dose-limiting neutropenia.
In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.
ACTEMRA (tocilizumab) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical HL polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. ACTEMRA has a molecular weight of approximately 148 kDa.
ACTEMRA is supplied as a sterile, preservative-free solution for intravenous (IV) infusion at a concentration of 20 mg/mL. ACTEMRA is a colorless to pale yellow liquid, with a pH of about 6.5. Single-use vials are available containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of ACTEMRA. Injectable solutions of ACTEMRA are formulated in an aqueous solution containing disodium phosphate dodecahydrate and sodium dihydrogen phosphate dehydrate (as a 15 mmol/L phosphate buffer), polysorbate 80 (0.5 mg/mL), and sucrose (50 mg/mL).
Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.
In clinical studies with the 4 mg/kg and 8 mg/kg doses of ACTEMRA, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate, serum amyloid A and increases in hemoglobin) with both doses, however the greatest improvements were observed with 8 mg/kg ACTEMRA.
In healthy subjects administered ACTEMRA in doses from 2 to 28 mg/kg, absolute neutrophil counts decreased to the nadir 3 to 5 days following ACTEMRA administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following ACTEMRA administration [see Warnings and Precautions (5.3)].
The pharmacokinetics characterized in healthy subjects and RA patients suggested that PK is similar between the two populations. The clearance (CL) of tocilizumab decreased with increased doses. At the 10 mg/kg single dose in RA patients, mean CL was 0.29 ± 0.10 mL/hr/kg and mean apparent terminal t was 151 ± 59 hours (6.3 days).
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis of 1793 rheumatoid arthritis patients treated with ACTEMRA 4 and 8 mg/kg every 4 weeks for 24 weeks.
The pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in area under the curve (AUC) and trough concentration (C) was observed for doses of 4 and 8 mg/kg every 4 weeks. Maximum concentration (C) increased dose-proportionally. At steady-state, predicted AUC and C were 2.7 and 6.5-fold higher at 8 mg/kg as compared to 4 mg/kg, respectively. In a long-term study with dosing for 104 weeks, observed C was sustained over time.
For doses of ACTEMRA 4 mg/kg given every 4 weeks, the predicted mean (± SD) steady-state AUC, C and C of tocilizumab were 13000 ± 5800 mcg∙h/mL, 1.49 ± 2.13 mcg/mL, and 88.3 ± 41.4 mcg/mL, respectively. The accumulation ratios for AUC and C were 1.11 and 1.02, respectively. The accumulation ratio was higher for C (1.96). Steady-state was reached following the first administration for C and AUC, respectively, and after 16 weeks C.
For doses of ACTEMRA 8 mg/kg given every 4 weeks, the predicted mean (± SD) steady-state AUC, C and C of tocilizumab were 35000 ± 15500 mcg∙h/mL, 9.74 ± 10.5 mcg/mL, and 183 ± 85.6 mcg/mL, respectively. The accumulation ratios for AUC and C were 1.22 and 1.06, respectively. The accumulation ratio was higher for C (2.35). Steady-state was reached following the first administration and after 8 and 20 weeks for C, AUC, and C, respectively. Tocilizumab AUC, C and C increased with increase of body weight. At body weight ≥ 100 kg, the predicted mean (± SD) steady-state AUC, C and C of tocilizumab were 55500 ± 14100 mcg∙h/mL, 19.0 ± 12.0 mcg/mL, and 269 ± 57 mcg/mL, respectively, which are higher than mean exposure values for the patient population. Therefore, ACTEMRA doses exceeding 800 mg per infusion are not recommended [see Dosage and Administration (2.1)].
Distribution
Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.
Elimination
The total clearance of tocilizumab is concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance was estimated to be 12.5 mL/h in the population pharmacokinetic analysis. The concentration-dependent nonlinear clearance plays a major role at low tocilizumab concentrations. Once the nonlinear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.
The t of tocilizumab is concentration-dependent. The concentration-dependent apparent t is up to 11 days for 4 mg/kg and up to 13 days for 8 mg/kg every 4 weeks at steady-state.
Pharmacokinetics in Special Populations
Population pharmacokinetic analyses in adult rheumatoid arthritis patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. The body weight-based dose (8 mg/kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg.
Hepatic Impairment
No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.
Renal Impairment
No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.
Most patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance < 80 mL/min and ≥ 50 mL/min based on Cockcroft-Gault) did not impact the pharmacokinetics of tocilizumab. No dose adjustment is required in patients with mild renal impairment.
Drug Interactions
In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when ACTEMRA is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates) [see Drug Interactions (7.2)].
Simvastatin
Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with ACTEMRA, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (10 mg/kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of ACTEMRA in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of ACTEMRA (due to normalization of CYP3A4) or higher exposures after discontinuation of ACTEMRA.
Omeprazole
Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after ACTEMRA infusion (8 mg/kg), the omeprazole AUC decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.
Dextromethorphan
Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (8 mg/kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after ACTEMRA infusion.
Carcinogenesis. No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.
Mutagenesis. Tocilizumab was negative in the in vitro Ames bacterial reverse mutation assay and the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes.
Impairment of Fertility. Fertility studies conducted in male and female mice using a murine analogue of tocilizumab showed no impairment of fertility.
The efficacy and safety of ACTEMRA was assessed in five randomized, double-blind, multicenter studies in patients > 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. ACTEMRA was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).
Study I eva luated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-naïve, and over 40% of patients had rheumatoid arthritis < 2 years. Patients received ACTEMRA 8 mg/kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of ACTEMRA patients who achieved an ACR20 response at Week 24.
Study II was a 104-week study with an ongoing optional 156-week extension phase that eva luated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received ACTEMRA 8 mg/kg, ACTEMRA 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with ACTEMRA 8 mg/kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a >70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score.
Study III eva luated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received ACTEMRA 8 mg/kg, ACTEMRA 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.
Study IV eva luated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received ACTEMRA 8 mg/kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.
Study V eva luated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received ACTEMRA 8 mg/kg, ACTEMRA 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.
Clinical Response
The percentages of ACTEMRA-treated patients achieving ACR20, 50 and 70 responses are shown in Table 3. In all studies, patients treated with 8 mg/kg ACTEMRA had higher ACR20, ACR50, and ACR70 response rates versus MTX- or placebo-treated patients at week 24.
During the 24 week controlled portions of Studies I to V, patients treated with ACTEMRA at a dose of 4 mg/kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to
Manufacturer
Genentech, Inc.
Active Ingredients
Source
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U.S. National Library of Medicine
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DailyMed
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Last Updated: 2nd of March 2011