Summary of medicine characteristics - Lifmior
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 25 mg of etanercept.
Etanercept is a human tumour necrosis factor receptor p75 Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression system. Etanercept is a dimer of a chimeric protein genetically engineered by fusing the extracellular ligand binding domain of human tumour necrosis factor receptor-2 (TNFR2/p75) to the Fc domain of human IgG1. This Fc component contains the hinge, CH2 and CH3 regions, but not the CH1 region of IgG1. Etanercept contains 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. The specific activity of etanercept is 1.7 × 106 units/mg.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder and solvent for solution for injection (powder for injection).
The powder is white. The solvent is a clear, colourless liquid.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Rheumatoid arthritis
LIFMIOR in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate.
LIFMIOR an be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate.
LIFMIOR is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate.
LIFMIOR, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.
Juvenile idiopathic arthritis
Treatment of polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis in children and adolescents from the age of 2 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.
Treatment of psoriatic arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, methotrexate.
Treatment of enthesitis-related arthritis in adolescents from the age of 12 years who have had an inadequate response to, or who have proved intolerant of, conventional therapy.
LIFMIOR has not been studied in children aged less than 2 years.
Psoriatic arthritis
Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate. LIFMIOR has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression o peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical su the disease.
Axial spondyloarthritis
Ankylosing spondylitis (AS)
Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Non-radiographic axial spondyloarthritis
Treatment of adults with severe non-radiographic axial spondyloarthritis w bjective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence, who have had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).
Plaque psoriasis
Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy, including ciclosporin, methotrexate or psoralen and ultraviolet-A light (PUVA) (see section 5.1).
Paediatric plaque psoriasis
Treatment of chronic severe plaque psoria hildren and adolescents from the age of 6 years who
are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.
4.2 Posology and method of
ration
LIFMIOR treatment s diagnosis and treatme ankylosing spondyli psoriasis. Patients treat
e initiated and supervised by specialist physicians experienced in the eumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, -radiographic axial spondyloarthritis, plaque psoriasis or paediatric plaque with LIFMIOR should be given the Patient Alert Card.
LIFMI
le in strengths of 10, 25 and 50 mg.
Poso]
weekly.
atoid arthritis
LIFMIOR administered twice weekly is the recommended dose. Alternatively, 50 mg istered once weekly has been shown to be safe and effective (see section 5.1).
Psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis
The recommended dose is 25 mg LIFMIOR administered twice weekly, or 50 mg administered once
For all of the above indications, available data suggest that a clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.
Plaque psoriasis
The recommended dose of LIFMIOR is 25 mg administered twice weekly or 50 mg administered once weekly. Alternatively, 50 mg given twice weekly may be used for up to 12 weeks followed, if necessary, by a dose of 25 mg twice weekly or 50 mg once weekly. Treatment with LIFMIOR should continue until remission is achieved, for up to 24 weeks. Continuous therapy beyond 24 weeks may be appropriate for some adult patients (see section 5.1). Treatment should be discontinued in patients who show no response after 12 weeks. If re-treatment with LIFMIOR is indicated, the same guidance on treatment duration should be followed. The dose should be 25 mg twice weekly or 50 mg once weekly.
ears of
), given twice weekly as a g/kg (up to a maximum of
Special populations
Renal and hepatic impairment No dose adjustment is required.
Elderly
No dose adjustment is required. Posology and administration are the same as for ad age.
Paediatric population
Juvenile idiopathic arthritis
The recommended dose is 0.4 mg/kg (up to a maximum of 25 mg p subcutaneous injection with an interval of 3–4 days between doses o
hould be considered in patients
50 mg per dose) given once weekly. Discontinuation of trea who show no response after 4 months.
inistration to children with JIA below the
The 10 mg vial strength may be more appropriate f weight of 25 kg.
No formal clinical trials have been conducted in children aged 2 to 3 years. However, limited safety data from a patient registry suggest that the safety profile in children from 2 to 3 years of age is similar to that seen in adults and children aged 4 years and older, when dosed every week with 0.8 mg/kg subcutaneously (see section 5.1).
There is generally no applic juvenile idiopathic arthritis.
f LIFMIOR in children aged below 2 years in the indication
Paediatric plaque psoriasis (age 6 years and above)
The recommen e is 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly for up to
24 weeks. Trea hould be discontinued in patients who show no response after 12 weeks.
If re-tre follo
ith LIFMIOR is indicated, the above guidance on treatment duration should be dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.
generally no applicable use of LIFMIOR in children aged below 6 years in the indication e psoriasis.
ethod of administration
LIFMIOR is administered by subcutaneous injection. LIFMIOR powder for solution must be reconstituted in 1 ml of solvent before use (see section 6.6).
Comprehensive instructions for the preparation and administration of the reconstituted LIFMIOR vial are given in the package leaflet, section 7, „Instructions for preparation and giving an injection of LIFMIOR.“
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Sepsis or risk of sepsis.
Treatment with LIFMIOR should not be initiated in patients with active infections, including chronic or localised infections.
4.4 Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the trademark and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Infections
Patients should be evaluated for infections before, during, and after treatment with LIFMIOR, taking into consideration that the mean elimination half-life of etanercept is approximately 70 hours (range 7 to 300 hours).
Serious infections, sepsis, tuberculosis, and opportunistic infections, inclu infections, listeriosis and legionellosis, have been reported with the use These infections were due to bacteria, mycobacteria, fungi, viruses and In some cases, particular fungal and other opportunistic infections have
g invasive fungal
MIOR (see section 4.8). tes (including protozoa). been recognised, resulting
in delay of appropriate treatment and sometimes death. In eval patient’s risk for relevant opportunistic infections (e.g., exp considered.
ndemic mycoses) should be
ts for infections, the
Patients who develop a new infection while undergoing treatment with LIFMIOR should be monitored closely. Administration of LIFMIOR should be discontinued if a patient develops a serious infection. The safety and efficacy of LIFMIOR in patients with chronic infections have not been evaluated.
Physicians should exercise caution when considering the use of LIFMIOR in patients with a history of recurring or chronic infections or with u ing conditions that may predispose patients to infections, such as advanced or poorly c led diabetes.
Tuberculosis
Cases of active tuberculosis i location, have been repor
ing miliary tuberculosis and tuberculosis with extra-pulmonary tients treated with LIFMIOR.
Before starting trea (‘latent’) tuberc of tuberculosis sible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e., tuberculin skin test and chest X-ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient’s alert card. Prescribers are reminded of the risfalse negative tuberculin skin test results, especially in patients who are severely ill or mpromised.
LIFMIOR, all patients must be evaluated for both active and inactive s evaluation should include a detailed medical history with personal history
active tuberculosis is diagnosed, LIFMIOR therapy must not be initiated. If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before the initiation of LIFMIOR, and in accordance with local recommendations. In this situation, the benefit/risk balance of LIFMIOR therapy should be very carefully considered. All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g., persistent cough, wasting/weight loss, low-grade fever) appear during or after LIFMIOR treatment.
Hepatitis B reactivation
Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant TNF-antagonists, including LIFMIOR, has been reported. This includes reports of reactivation of hepatitis B in patients who were anti-HBc positive but HBsAg negative. Patients should be tested for HBV infection before initiating treatment with LIFMIOR. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when administering LIFMIOR in patients previously infected with HBV. These patients should be monitored for signs and symptoms of active HBV infection throughout therapy and for several weeks following termination of therapy. Adequate data from treating patients infected with HBV with anti-viral therapy in conjunction with TNF-antagonist therapy are not available. In patients who develop HBV infection, LIFMIOR sho be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiat
Worsening of hepatitis C
There have been reports of worsening of hepatitis C in patients receiving LIFMIOR. L be used with caution in patients with a history of hepatitis C.
Concurrent treatment with anakinra
Concurrent administration of LIFMIOR and anakinra has been associated with an increased risk of serious infections and neutropenia compared to LIFMIOR alone. This combination has not demonstrated increased clinical benefit. Thus, the combined use of LIF and anakinra is not recommended (see sections 4.5 and 4.8).
Concurrent treatment with abatacept
In clinical studies, concurrent administration of abatacept and LIFMIOR resulted in increased incidences of serious adverse events. This combination t demonstrated increased clinical benefit; such use is not recommended (see section 4.5).
Allergic reactions
Allergic reactions associated with LIFMIOR administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, LIFMIOR therapy should be discontinued immediately and appropriate therapy initiated.
Immunosuppression
The possibility exists for T infections and malignanci responses. In a study o no evidence of depression
change in enumeration
nists, including LIFMIOR, to affect host defences against
TNF mediates inflammation and modulates cellular immune dult patients with rheumatoid arthritis treated with LIFMIOR, there was delayed-type hypersensitivity, depression of immunoglobulin levels, or
effector cell populations.
Two juvenile idiopathic arthritis patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. Patients with a significant exposure to varicella d temporarily discontinue LIFMIOR therapy and be considered for prophylactic treatment lla Zoster Immune Globulin.
and efficacy of LIFMIOR in patients with immunosuppression have not been evaluated.
alignancies and lymphoproliferative disorders
Solid and haematopoietic malignancies (excluding skin cancers)
Reports of various malignancies (including breast and lung carcinoma and lymphoma) have been received in the postmarketing period (see section 4.8).
In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. However, the occurrence was rare, and the follow-up period of placebo patients was shorter than for patients
receiving TNF-antagonist therapy. In the postmarketing setting, cases of leukaemia have been reported in patients treated with TNF-antagonists. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.
Based on current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded. Caution should be exercised when considering TNF-antagonist therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy.
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-antagonists (initiation of therapy < 18 years of age), including LIFMIOR, in the postmarketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies typically associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-antagonists cannot be excluded.
Skin cancers
Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with
TNF-antagonists, including LIFMIOR. Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with LIFMIOR. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Combining the results of controlled clinical trials, more cases of NMSC were observed in patients receiving LIFMIOR compared with control patients, particularly in patients with psoriasis.
Vaccinations
IOR. No data are available on the
Live vaccines should not be given concurrently wit secondary transmission of infection by live vaccines in patients receiving LIFMIOR. In a double-blind, placebo-controlled, randomised clinical study in adult patients with psoriatic arthritis, 184 patients also received a multivalent pneumococcal polysaccharide vaccine at week 4. In this study, most psoriatic arthritis patients receiving LIFMIOR were able to mount effective B-cell immune response to pneumococcal polysaccharide vaccine, but titres in aggregate were moderately lower, and few patients had two-fold rises in titres compared to patients not receiving LIFMIOR. The clinical significance of this is unknown.
Autoantibody formation ikJ..... .. .. ........
Treatment with LIFMIOR may result in the formation of autoimmune antibodies (see section 4.8).
Haematologic rcOction^ ^
Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome, have been reported in patients treated with LIFMIOR. Caution should be exercised in patients being treated with LIFMIOR who have a previous history of blood dyscrasias. All patients and parents/caregivers should be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias or infections (e.g., persistent fever, sore throat, bruising, bleeding, paleness) whilst on LIFMIOR, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, LIFMIOR should be discontinued.
Neurological disorders
There have been rare reports of CNS demyelinating disorders in patients treated with LIFMIOR (see section 4.8). Additionally, there have been rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have been performed evaluating LIFMIOR therapy in patients with multiple sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have shown increases in disease activity. A careful risk/benefit evaluation, including a neurologic assessment, is recommended when prescribing
LIFMIOR to patients with pre-existing or recent onset of demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.
Combination therapy
In a controlled clinical trial of two years duration in rheumatoid arthritis patients, the combination of LIFMIOR and methotrexate did not result in unexpected safety findings, and the safety profile of
LIFMIOR when given in combination with methotrexate was similar to the profiles reported in studies of LIFMIOR and methotrexate alone. Long-term studies to assess the safety of the combination are ongoing. The long-term safety of LIFMIOR in combination with other disease-modifying antirheumatic drugs (DMARD) has not been established.
renal
The use of LIFMIOR in combination with other systemic therapies or phototherapy for the trea of psoriasis has not been studied.
Renal and hepatic impairment
Based on pharmacokinetic data (see section 5.2), no dose adjustment is needed in pati or hepatic impairment; clinical experience in such patients is limited.
Congestive heart failure (Cardiac failure congestive)
Physicians should use caution when using LIFMIOR in patients who have congestive heart failure (CHF). There have been postmarketing reports of worsening of CHF, with and without identifiable precipitating factors, in patients taking LIFMIOR. There have also been rare (< 0.1%) reports of new onset CHF, including CHF in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. Two large clinical trials evaluating the use of
ck of efficacy. Although not cy toward worsening CHF in those
LIFMIOR in the treatment of CHF were terminated early d conclusive, data from one of these trials suggest a possi patients assigned to LIFMIOR treatment.
Alcoholic hepatitis
In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with LIFMIOR or placebo for moderate to severe alcoholic hepatitis, LIFMIOR was not efficacious, and the mortality rate in patients treated with LIFMIOR was significantly higher after 6 months. Consequently, LIFMIOR should not be used in patients for the treatment of alcoholic hepatitis. Physicians should use
caution when using LIFMIOR i
nts who also have moderate to severe alcoholic hepatitis.
Wegener's granulomatosis
A placebo-controlled trial, in which 89 adult patients were treated with LIFMIOR in addition to standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median duration of 25 months, has not shown LIFMIOR to be an effective treatment for Wegener’s granulomatosis. The incidence of non-cutaneous malignancies of various types was significantly higher in patients treated with LIFMIOR than in the control group. LIFMIOR is not recommended for the treatment of Wegener’s granulomatosis.
Hyp
emia in patients treated for diabetes
been reports of hypoglycaemia following initiation of LIFMIOR in patients receiving for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.
pecial populations
Elderly
In the Phase 3 studies in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, no overall differences in adverse events, serious adverse events, and serious infections in patients age 65 or older who received LIFMIOR were observed compared with younger patients. However, caution should be exercised when treating the elderly and particular attention paid with respect to occurrence of infections.
Paediatric population
Vaccinations
It is recommended that paediatric patients, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating LIFMIOR therapy (see Vaccinations, above).
Inflammatory bowel disease (IBD) and uveitis in patients with juvenile idiopathic arthritis (JIA) There have been reports of IBD and uveitis in JIA patients being treated with LIFMIOR (see section 4.8).
4.5 Interaction with other medicinal products and other forms of interaction
Concurrent treatment with anakinra
Adult patients treated with LIFMIOR and anakinra were observed to have a higher rat infection when compared with patients treated with either LIFMIOR or anakinra alon data).
In addition, in a double-blind, placebo-controlled trial in adult patients receivin methotrexate, patients treated with LIFMIOR and anakinra were observed ve a higher rate of
serious infections (7%) and neutropenia than patients treated with LIFMIO e sections 4.4 and 4.8). The combination LIFMIOR and anakinra has not demonstrated increased clinical benefit, and is therefore not recommended.
Concurrent treatment with abatacept
OR resulted in increased nstrated increased clinical
In clinical studies, concurrent administration of abatace incidences of serious adverse events. This combination benefit; such use is not recommended (see section 4.4).
Concurrent treatment with sulfasalazine
In a clinical study of adult patients who were receiving established doses of sulfasalazine, to which LIFMIOR was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with LIFMIOR or sulfasalazine alone. The clinical significance of this interaction is unknown. Physicians should use caution when considering combination therapy with sulfasalazine.
Non-interactions
In clinical trials, no i glucocorticoids, salic analgesics, or methot
ons have been observed when LIFMIOR was administered with (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), See section 4.4 for vaccination advice.
No clinic methotrex
cant pharmacokinetic drug-drug interactions were observed in studies with in or warfarin.
regnancy and lactation
en of childbearing potential
en of childbearing potential should consider the use of appropriate contraception to avoid ecoming pregnant during LIFMIOR therapy and for three weeks after discontinuation of therapy.
Pregnancy
Developmental toxicity studies performed in rats and rabbits have revealed no evidence of harm to the foetus or neonatal rat due to etanercept. The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. A higher rate of major birth defects was observed in one observational study comparing pregnancies exposed to etanercept (n=370) during the first trimester with pregnancies not exposed to etanercept or other TNF-antagonists (n=164) (adjusted odds ratio 2.4, 95% CI: 1.0–5.5). The types of major birth defects were consistent with those most
commonly reported in the general population and no particular pattern of abnormalities was identified. No change in the rate of spontaneous abortion, stillbirth, or minor malformations was observed. In another observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept during the first 90 days of pregnancy (n=425) to those exposed to non-biologic drugs (n=3497), there was no observed increased risk of major birth defects (crude odds ratio [OR]= 1.22, 95% CI: 0.79–1.90; adjusted OR = 0.96, 95% CI: 0.58–1.60 after adjusting for country, maternal disease, parity, maternal age and smoking in early pregnancy). This study also showed no increased risks of minor birth defects, preterm birth, stillbirth, or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. LIFMIOR should only be used during pregnancy if clearly needed.
Etanercept crosses the placenta and has been detected in the serum of infants born to female patie treated with LIFMIOR during pregnancy. The clinical impact of this is unknown, however, infant may be at increased risk of infection. Administration of live vaccines to infants for 16 weeks after mother’s last dose of LIFMIOR is generally not recommended.
Breast-feeding
Etanercept has been reported to be excreted in human milk following subcutaneous administration. In lactating rats following subcutaneous administration, etanercept was excreted in the milk and detected in the serum of pups. Because immunoglobulins, in common with many m nal products, can be
excreted in human milk, a decision must be made whether to discontinue b -feeding or to discontinue LIFMIOR therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
f effects of etanercept on fertility
Preclinical data about peri- and postnatal toxicity of eta and general reproductive performance are not available.
4.7 Effects on ability to drive and use machi
No studies on the effects on the ability to drive and use machines have been performed.
Summary of the safety profile The most commonly reporte itching, reddening and bl bronchitis, bladder infe itching, and fever
4.8 Undesirable effects
reactions are injection site reactions (such as pain, swelling, the puncture site), infections (such as upper respiratory infections, s and skin infections), allergic reactions, development of autoantibodies,
Serious adver
M
affect the i Serious i fatal of
ave also been reported for LIFMIOR. TNF-antagonists, such as LIFMIOR, stem and their use may affect the body’s defenses against infection and cancer. s affect fewer than 1 in 100 patients treated with LIFMIOR. Reports have included threatening infections and sepsis. Various malignancies have also been reported with use , including cancers of the breast, lung, skin and lymph glands (lymphoma).
Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia and very rare reports of aplastic anaemia. Central and peripheral demyelinating events have been seen rarely and very rarely, respectively, with LIFMIOR use. There have been rare reports of lupus, lupus-related conditions, and vasculitis.
Tabulated list of adverse reactions
The following list of adverse reactions is based on experience from clinical trials in adults and on postmarketing experience.
Within the organ system classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (>1/10);
common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
| System Organ Class | Very Common > 1/10 | Common > 1/100 to < 1/10 | Uncommon > 1/1,000 to < 1/100 | Rare > 1/10,000 to < 1/1,000 | Very Rare < 1/10,000 | Frequency Not Known (Cannot be Estimated from Available Data) |
| Infections and infestations | Infection (including upper respiratory tract infection, bronchitis, cystitis, skin infection) | Serious infections (including pneumonia, cellulitis, arthritis bacterial, sepsis and parasitic infection) | Tuberculosis, opportunistic infection (including invasive fungal, protozoal, bacterial, atypical mycobacterial, viral infections, and Legionella) | Hepatitis B reactivation, 1 listeria | ||
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Non-melanoma skin cancers* (see section 4.4) | Malignant melanoma (see section 4.4), lymphoma, leukaemia | ^Merkel cell carcinoma (see section 4.4) | |||
| Blood and lymphatic system disorders | Thrombocytopenia, anaemia, leukopenia, neutropenia | Pancytopenia*^^ J | Aplastic anaemia* | Histiocytosis haematophagic (macrophage activation syndrome) | ||
| Immune system disorders | Allergic reactions (see Skin and subcutaneous tissue disorders), autoantibody formation | Vasculitis (including anti-neutrophilic cytoplasmic antibody.y | Serioj s WTcrgic anaphylactic reactions (including angioedema, bronchospasm), sarcoidosis | Worsening of symptoms of dermatomyositis | ||
| Nervous system disorders | Y | Xj | CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating conditions, such as optic neuritis and transverse myelitis (see section 4.4), peripheral demyelinating events, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy (see section 4.4), seizure | |||
| Eye disorders | Uveitis, scleritis | |||||
| Cardiac disorders | Worsening of cardiac failure congestive (see section 4.4) | New onset cardiac failure congestive (see section 4.4) | ||||
| Respiratory, thoracic, and mediastinal disorders | Interstitial lung disease (including pneumonitis and pulmonary fibrosis) |
| System Organ Class | Very Common > 1/10 |
| Hepatobiliary disorders | |
| Skin and subcutaneous tissue disorders | |
| Musculoskeletal and connective tissue disorders | |
| General disorders and administration site conditions | Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling) |
Pruritus, rash
Pyrexia
Common > 1/100 to < 1/10
Uncommon
> 1/1,000 to < 1/100
Rare
> 1/10,000 to
< 1/1,000
Very Rare < 1/10,000
Frequency Not Known (Cannot be Estimated from Available Data) _________
*see Description of selected adverse reactions, below.
epidermal necrolysis
Cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, lupus-like syndrome
Autoimmune hepatitis* _____________
Stevens-Johnson syndrome, cutaneous vasculitis (including hypersensitivity vasculitis), erythema multiforme, lichenoid reactions
Elevated liver enzymes* ________
Angioedema, psoriasis (including new onset or worsening and pustular, primarily palms and soles), urticaria, psoriasiform rash
Malignancies and lymphoproliferative disorders
One hundred and twenty-nine (129) new malignancies of various types were observed in
4,114 rheumatoid arthritis patients treated in clinical trials with LIFMIOR for up to approximately 6 years, including 231 patients treated with LIFMIOR in combination with methotrexate in the 2-year active-controlled study. The observed rates and incidences in these clinical trials were similar to those expected for the population studied. A total of 2 malignancies were reported in clinical studies of approximately 2 years duration involving 240 LIFMIOR-treated psoriatic arthritis patients. In clinical studies conducted for m an 2 years with 351 ankylosing spondylitis patients, 6 malignancies were
reported in LIFMIOR-tr patients. In a group of 2,711 plaque psoriasis patients treated with
LIFMIOR in double-blind and open-label studies of up to 2.5 years, 30 malignancies and 43 nonmelanoma skin cancers were reported.
In a group ankylosing
16 patients treated with LIFMIOR in rheumatoid arthritis, psoriatic arthritis, dylitis and psoriasis clinical trials, 18 lymphomas were reported.
f various malignancies (including breast and lung carcinoma and lymphoma) have also been n the postmarketing period (see section 4.4).
Injection site reactions
Compared to placebo, patients with rheumatic diseases treated with LIFMIOR had a significantly higher incidence of injection site reactions (36% vs. 9%). Injection site reactions usually occurred in the first month. Mean duration was approximately 3 to 5 days. No treatment was given for the majority of injection site reactions in the LIFMIOR treatment groups, and the majority of patients who were given treatment received topical preparations, such as corticosteroids, or oral antihistamines. Additionally, some patients developed recall injection site reactions characterised by a skin reaction at the most recent site of injection, along with the simultaneous appearance of injection site reactions at previous injection sites. These reactions were generally transient and did not recur with treatment.
In controlled trials in patients with plaque psoriasis, approximately 13.6% of patients treated with LIFMIOR developed injection site reactions compared with 3.4% of placebo-treated patients during the first 12 weeks of treatment.
Serious infections
In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, or requiring hospitalisation or intravenous antibiotics) was observed. Serious infections occurred in 6.3% of rheumatoid arthritis patients treated with LIFMIOR for up to 48 months. These included abscess (at various sites), bacteraemia, bronchitis, bursitis, cellulitis, cholecystitis, diarrhoea, diverticulitis, endocarditis (suspected), gastroenteritis, hepatitis B, herpes zoster, leg ulcer, mouth infection, osteomyelitis, otitis, peritonitis, pneumonia, pyelonephritis, sepsis, septic arthritis, sinusitis, skin infection, skin ulcer, urinary tract infection, vasculitis, and wound infection. In the 2-year active-controlled study where patients were treated with either LIFMIOR alone, methotrexate alone LIFMIOR in combination with methotrexate, the rates of serious infections were similar among the treatment groups. However, it cannot be excluded that the combination of LIFMIOR with methotrexate could be associated with an increase in the rate of infections.
There were no differences in rates of infection among patients treated with LIF treated with placebo for plaque psoriasis in placebo-controlled trials of up to 24
those duration.
Serious infections experienced by LIFMIOR-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis, gastritis, appendicitis, Streptococcal fasciitis, myositis, septic shock, diverticulitis and abscess. In the double-blind and open-labe ic arthritis trials, 1 patient
reported a serious infection (pneumonia).
Serious and fatal infections have been reported during use o bacteria, mycobacteria (including tuberculosis), viruses weeks after initiating treatment with LIFMIOR in patients diabetes, congestive heart failure, history of active rheumatoid arthritis (see section 4.4). LIFMIOR tr established sepsis.
IOR; reported pathogens include i. Some have occurred within a few ave underlying conditions (e.g., ections) in addition to their ncrease mortality in patients with
Opportunistic infections have been reporte ssociation with LIFMIOR, including invasive fungal, parasitic (including protozoal), viral (including herpes zoster), bacterial (including Listeria and Legionella ), and atypical mycobacterial infections. In a pooled data set of clinical trials, the overall incidence of opportunistic infections was 0.09% for the 15,402 subjects who received LIFMIOR. The exposure-adjusted rate was 0.06 events per 100 patient-years. In postmarketing experience, approximately half of all of the case reports of opportunistic infections worldwide were invasive fungal infections. The most commonly reported invasive fungal infections included Candida, Pneumocystis, Aspergillus, and Histoplasma. Invasive fungal infections accounted for more than half of the fatalities amongst patients who developed opportunistic infections. The majority of the reports with a fatal outcome were in patients with Pneumocystis pneumonia, unspecified systemic fungal infections, and aspergillosis (see section 4.4).
Autoantibodies
Adult patients had serum samples tested for autoantibodies at multiple timepoints. Of the rheumatoid arthritis patients evaluated for antinuclear antibodies (ANA), the percentage of patients who developed nW positive ANA (>1:40) was higher in patients treated with LIFMIOR (11%) than in placebo-treated patients (5%). The percentage of patients who developed newpositive anti-double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with LIFMIOR compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with LIFMIOR compared to none of placebo-treated patients). The proportion of patients treated with LIFMIOR who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with LIFMIOR on the development of autoimmune diseases is unknown.
There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a lupus-like syndrome or rashes that are compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.
Pancytopenia and aplastic anaemia
There have been postmarketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes (see section 4.4).
Interstitial lung disease
In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion interstitial lung disease in patients receiving etanercept without concomitant methotrexate was 0.0 (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanerce and methotrexate, the frequency (incidence proportion) of interstitial lung disease was 0.47% (frequency uncommon). There have been postmarketing reports of interstitial lung disease (in pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
Concurrent treatment with anakinra
In studies when adult patients received concurrent treatment with LIFMIOR plus anakinra, a higher rate of serious infections compared to LIFMIOR alone was observed and 2% of patients (3/139) developed neutropenia (absolute neutrophil count < 1000/mm3). While neutropenic, one patient developed cellulitis that resolved after hospitalisation (see sections 4.4
Elevated liver enzymes
In the double-blind periods of controlled clinical trials of etanerce
frequency (incidence proportion) of adverse events of eleva etanercept without concomitant methotrexate was 0.54% (fr periods of controlled clinical trials that allowed concomitan
all indications, the er enzymes in patients receiving cy uncommon). In the double-blind
eatment with etanercept and
methotrexate, the frequency (incidence proportion) of adverse events of elevated liver enzymes was 4.18% (frequency common).
Autoimmune hepatitis
In controlled clinical trials of etanercept autoimmune hepatitis in patients receivi
(frequency rare). In the controlle and methotrexate, the frequency (frequency uncommon).
Paediatric population
ll indications, the frequency (incidence proportion) of nercept without concomitant methotrexate was 0.02% trials that allowed concomitant treatment with etanercept
nce proportion) of autoimmune hepatitis was 0.24%
Undesirable effects in paediatric patients with juvenile idiopathic arthritis
In general, th se events in paediatric patients with juvenile idiopathic arthritis were similar in frequency to those seen in adult patients. Differences from adults and other special consider re discussed in the following paragraphs.
pes of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years enerally mild to moderate and consistent with those commonly seen in outpatient paediatric populations. Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae (see also section 4.4), appendicitis, gastroenteritis, depression/personality disorder, cutaneous ulcer, oesophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection.
In one study in children with juvenile idiopathic arthritis aged 4 to 17 years, 43 of 69 (62%) children experienced an infection while receiving LIFMIOR during 3 months of the study (part 1, open-label), and the frequency and severity of infections was similar in 58 patients completing 12 months of openlabel extension therapy. The types and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of LIFMIOR in adult patients with rheumatoid arthritis, and the majority were mild. Several adverse events were reported more commonly in 69 juvenile
idiopathic arthritis patients receiving 3 months of LIFMIOR compared to the 349 adult rheumatoid arthritis patients. These included headache (19% of patients, 1.7 events per patient year), nausea (9%, 1.0 event per patient year), abdominal pain (19%, 0.74 events per patient year), and vomiting (13%, 0.74 events per patient year).
There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.
There have been reports of inflammatory bowel disease and uveitis in JIA patients being treated with LIFMIOR from post-marketing sources, including a very small number of cases indicating a positive rechallenge (see section 4.4).
Undesirable effects in paediatric patients with plaque psoriasis
In a 48-week study in 211 children aged 4 to 17 years with paediatric plaque psoriasis, the adv events reported were similar to those seen in previous studies in adults with plaque psor
Reporting of suspected adverse reactions <
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product^Healtihcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
0.8
0.9
0.4* 0.4 0.4
TSS Erosions JSN
p < 0.05
dy, clinical efficacy, safety, and MIOR alone (25 mg twice weekly),
In another active-controlled, double-blind, randomised
radiographic progression in RA patients treate methotrexate alone (7.5 to 20 mg weekly, med
methotrexate initiated concurrently were arthritis of 6 months to 20 years duration at least 1 disease-modifying anti
ose 20 mg), and the combination of LIFMIOR and in 682 adult patients with active rheumatoid
Patients in the LIFMIOR in c
sp
median 5 years) who had a less than satisfactory response to drug (DMARD) other than methotrexate.
ACR 20, ACR 50, ACR 7 52 weeks than patients i Significant advantag monotherapy a
nation with methotrexate therapy group had significantly higher ses and improvement for DAS and HAQ scores at both 24 and f the single therapy groups (results shown in table below).
FMIOR in combination with methotrexate compared with LIFMIOR xate monotherapy were also observed after 24 months.
Clinical Efficacy Results at 12 Months: Comparison of LIFMIOR vs. Methotrexate vs.
LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration
LIFMIOR +
| Endpoint | Methotrexate (n = 228) | LIFMIOR (n = 223) | Methotrexat (n = 231) |
| ACR Responses a | |||
| ACR 20 | 58.8% | 65.5% | 74.5% ™ |
| ACR 50 | 36.4% | 43.0% | 63.2% W |
| ACR 70 | 16.7% | 22.0% | 39.8% ™ |
| DAS | |||
| Baseline scoreb | 5.5 | 5.7 | 5.5 |
| Week 52 scoreb | 3.0 | 3.0 | 2.3fÎ |
| Remissionc | 14% | 18% | 37%^jS |
| HAQ | |||
| Baseline | 1.7 | 1.7 | 1.8 |
| Week 52 | 1.1 | 1.0 | 0.8™ |
a: Patients who did not complete 12 months in the study were consi
on-responders.
-
b: Values for Disease Activity Score (DAS) are means.
-
c: Remission is defined as DAS <1.6.
Pairwise comparison p-values: f = p < 0.05 for comparisons of LFMIOR^ methotrexate vs. methotrexate and 0 = p < 0.05 for comparisons of LIFM thotrexate vs. LIFMIOR.
Radiographic progression at 12 months was significantl in the LIFMIOR group than in the methotrexate group, while the combination was significantly better than either monotherapy at slowing radiographic progression (see figure below).
Radiographic Progression: Comparison of LIFMIOR vs. Methotrexate vs. LIFMIOR in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration
Month Results)
-0.23
-0.30
-0.54**
—JSN —
— TSS— —Erosions—
Methotrexate
LIFMIOR
LI FMI OR + Methotrexate
Pairwise comparison p-values: * = p < 0.05 for comparisons of LIFMIOR vs.
methotrexate, f = p < 0.05 for comparisons of LIFMIOR + methotrexate vs.
methotrexate and 0 = p < 0.05 for comparisons of LIFMIOR + methotrexate vs. LIFMIOR.
Significant advantages for LIFMIOR in combination with methotrexate compared with LIFMIOR monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for LIFMIOR monotherapy compared with methotrexate monotherapy were also observed after 24 months.
In an analysis in which all patients who dropped out of the study for any reason were considered to have progressed, the percentage of patients without progression (TSS change < 0.5) at 24 months was higher in the LIFMIOR in combination with methotrexate group compared with the LIFMIOR alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p<0.05). The difference between LIFMIOR alone and methotrexate alone was also significant (p<0.05). Among patients who completed a full 24 months of therapy in the study, the non-progression rates were 78%, 70%, and 61%, respectively.
The safety and efficacy of 50 mg LIFMIOR (two 25 mg SC injections) administered once weekly were evaluated in a double-blind, placebo-controlled study of 420 patients with active RA. In this study, 53 patients received placebo, 214 patients received 50 mg LIFMIOR once weekly and 153 patients received 25 mg LIFMIOR twice weekly. The safety and efficacy profiles of the two LIFMIOR treatment regimens were comparable at week 8 in their effect on signs and symptoms of RA; data at week 16 did not show comparability (non-inferiority) between the two regimens.
Adult patients with psoriatic arthritis
The efficacy of LIFMIOR was assessed in a randomised, double-blind, placebo-controlled study in 205 patients with psoriatic arthritis. Patients were between 18 and 70 years of age and had active psoriatic arthritis (> 3 swollen joints and > 3 tender joints) in atJeOstWe^lf the following forms: (1) distal interphalangeal (DIP) involvement; (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); (3) arthritis mutilans; (4) asymmetric psoriatic arthritis; or
(5) spondylitis-like ankylosis. Patients also had plaque psoriasis with a qualifying target lesion > 2 cm in diameter. Patients had previously been treated with NSAIDs (86%), DMARDs (80%), and corticosteroids (24%). Patients currently on methotrexate therapy (stable for > 2 months) could continue at a stable dose of < 25 mg/week methotrcXate. Doses of 25 mg of LIFMIOR (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months. At the end of the double-blind study, patients could enter a long-term open-label extension study for a total duration of up to 2 years.
Clinical responses were expressed as percentages of patients achieving the ACR 20, 50, and 70 response and percentages w are summarised in the table
ement in Psoriatic Arthritis Response Criteria (PsARC). Results
Responses of Patients with Psoriatic Arthritis in a Placebo-Controlled Trial
| Percent of Patients | ||
| Placebo | LIFMIORa | |
| Psoriatic Arthritis Response | n = 104 | n = 101 |
| ACR 20 | ||
| Month 3 | 15 | 59b |
| Month 6 | 13 | 50b |
| ACR 50 | ||
| Month 3 | 4 | 38b |
| Month 6 | 4 | 37b |
| ACR 70 | ||
| Month 3 | 0 | 11b |
| Month 6 | 1 | 9c |
| PsARC | ||
| Month 3 | 31 | 72b |
| Month 6 | 23 | z^0V |
a: 25 mg LIFMIOR SC twice weekly b: p < 0.001, LIFMIOR vs. placebo
c: p < 0.01, LIFMIOR vs. placebo
Among patients with psoriatic arthritis who received LIF at the time of the first visit (4 weeks) and were maintain
the clinical responses were apparent gh 6 months of therapy. LIFMIOR
was significantly better than placebo in all measures of disease activity (p < 0.001), and responses were similar with and without concomitant methotrexate therapy. Quality of life in psoriatic arthritis patients was assessed at every timepoint using the disability index of the HAQ. The disability index score was significantly improved at all timepoints in psoriatic arthritis patients treated with LIFMIOR, relative to placebo (p < 0.001).
Radiographic changes were assessed in the psoriatic arthritis study. Radiographs of hands and wrists
were obtained at baseline and the table below. In an analysis
considered to have progr 12 months was higher i respectively, p <0.0 patients who continued
nths 6, 12, and 24. The modified TSS at 12 months is presented in which all patients who dropped out of the study for any reason were !e percentage of patients without progression (TSS change < 0.5) at
LIFMIOR group compared with the placebo group (73% vs. 47%, e effect of LIFMIOR on radiographic progression was maintained in treatment during the second year. The slowing of peripheral joint damage
was observed
Time
Month 12
SE = standard error. a. p = 0.0001.
nts with polyarticular symmetrical joint involvement.
Placebo
(n = 104)
1.00 (0.29)
Etanercept (n = 101) –0.03 (0.09)a
LIFMIOR treatment resulted in improvement in physical function during the double-blind period, and this benefit was maintained during the longer-term exposure of up to 2 years.
There is insufficient evidence of the efficacy of LIFMIOR in patients with ankylosing spondylitis-like and arthritis mutilans psoriatic arthropathies due to the small number of patients studied.
No study has been performed in patients with psoriatic arthritis using the 50 mg once-weekly dosing regimen. Evidence of efficacy for the once-weekly dosing regimen in this patient population has been based on data from the study in patients with ankylosing spondylitis.
Adult patients with ankylosing spondylitis
The efficacy of LIFMIOR in ankylosing spondylitis was assessed in 3 randomised, double-blind studies comparing twice-weekly administration of 25 mg LIFMIOR with placebo. A total of 401 patients were enrolled, from which 203 were treated with LIFMIOR. The largest of these trials (n= 277) enrolled patients who were between 18 and 70 years of age and had active ankylosing spondylitis defined as visual analog scale (VAS) scores of > 30 for average of duration and intensity of morning stiffness plus VAS scores of > 30 for at least 2 of the following 3 parameters: patient ♦ global assessment; average of VAS values for nocturnal back pain and total back pain; average o 10 questions on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients receivin DMARDs, NSAIDS, or corticosteroids could continue them on stable doses. Patients wi ankylosis of the spine were not included in the study. Doses of 25 mg of LIFMIOR (b dose-finding studies in patients with rheumatoid arthritis) or placebo were administere subcutaneously twice a week for 6 months in 138 patients.
the
The primary measure of efficacy (ASAS 20) was a >20% improvement in at lea
4 Assessment in Ankylosing Spondylitis (ASAS) domains (patient global assessments, back pain, BASFI, and inflammation) and absence of deterioration in the remaining domain. ASAS 50 and 70 responses used the same criteria with a 50% improvement or a 7 rovement, respectively.
Compared to placebo, treatment with LIFMIOR resulted in signific rovements in the ASAS 20,
ASAS 50 and ASAS 70 as early as 2 weeks after the initiation of therapy.
5.2 Pharmacokinetic properties
sorption
tanercept is slowly absorbed from the site of subcutaneous injection, reaching maximum concentration approximately 48 hours after a single dose. The absolute bioavailability is 76%. With twice-weekly doses, it is anticipated that steady-state concentrations are approximately twice as high as those observed after single doses. After a single subcutaneous dose of 25 mg LIFMIOR, the average maximum serum concentration observed in healthy volunteers was 1.65 ± 0.66 ^g/ml. and the area under the curve was 235 ± 96.6 p.g^hr/ml.
Mean serum concentration profiles at steady state in treated RA patients were Cmax of 2.4 mg/l vs.
2.6 mg/l, Cmin of 1.2 mg/l vs. 1.4 mg/l, and partial AUC of 297 mgh/l vs. 316 mgh/l for 50 mg
LIFMIOR once weekly (n=21) vs. 25 mg LIFMIOR twice weekly (n=16), respectively. In an open-label, single-dose, two-treatment, crossover study in healthy volunteers, etanercept administered as a single 50 mg/ml injection was found to be bioequivalent to two simultaneous injections of 25 mg/ml.
In a population pharmacokinetics analysis in ankylosing spondylitis patients, the etanercept steady
nce is
state AUCs were 466 |Jg^hr/ml and 474 ^g^hr/ml for 50 mg LIFMIOR once weekly (N= 154) and 25 mg twice weekly (N = 148), respectively.
Distribution
A biexponential curve is required to describe the concentration time curve of etanercept. The cent volume of distribution of etanercept is 7.6 l, while the volume of distribution at steady-state is 10.
Elimination
Etanercept is cleared slowly from the body. The half-life is long, approximately 70 ho approximately 0.066 l/hr in patients with rheumatoid arthritis, somewhat lower than th 0.11 l/hr observed in healthy volunteers. Additionally, the pharmacokinetics of LIFMI rheumatoid arthritis patients, ankylosing spondylitis and plaque psoriasis patients are similar.
There is no apparent pharmacokinetic difference between males and femal
Linearity
Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.
Special populations
Renal impairment
r administration of radiolabelled etanercept trations were not observed in patients with ment should not require a change in dosage.
Although there is elimination of radioactivity in uri to patients and volunteers, increased etanercept acute renal failure. The presence of renal i
Hepatic impairment
Increased etanercept concentrati presence of hepatic impairment
ot observed in patients with acute hepatic failure. The require a change in dosage.
Elderly
The impact of advanced age was studied in the population pharmacokinetic analysis of etanercept serum concentrations. Clearance and volume estimates in patients aged 65 to 87 years were similar to estimates in patients less than 65 years of age.
Paediatric
Paedi n
tients with juvenile idiopathic arthritis
lyarticular-course juvenile idiopathic arthritis trial with LIFMIOR, 69 patients (aged 4 to rs) were administered 0.4 mg LIFMIOR/kg twice weekly for three months. Serum concentration es were similar to those seen in adult rheumatoid arthritis patients. The youngest children years of age) had reduced clearance (increased clearance when normalised by weight) compared with older children (12 years of age) and adults. Simulation of dosing suggests that while older children (10–17 years of age) will have serum levels close to those seen in adults, younger children will have appreciably lower levels.
Paediatric patients with plaque psoriasis
Patients with paediatric plaque psoriasis (aged 4 to 17 years) were administered 0.8 mg/kg (up to a maximum dose of 50 mg per week) of etanercept once weekly for up to 48 weeks. The mean serum steady-state trough concentrations ranged from 1.6 to 2.1 mcg/ml at weeks 12, 24, and 48. These mean concentrations in patients with paediatric plaque psoriasis were similar to the concentrations observed in patients with juvenile idiopathic arthritis (treated with 0.4 mg/kg etanercept twice weekly, up to maximum dose of 50 mg per week). These mean concentrations were similar to those seen in adult patients with plaque psoriasis treated with 25 mg etanercept twice-weekly.
5.3 Preclinical safety data
In the toxicological studies with LIFMIOR, no dose-limiting or target organ toxicity was evident. LIFMIOR was considered to be non-genotoxic from a battery of in vitro and in vivo studies. Carcinogenicity studies, and standard assessments of fertility and postnatal toxicity, were not performed with LIFMIOR due to the development of neutralising antibodies in rodents.
LIFMIOR did not induce lethality or notable signs of toxicity in mice or rats following a single subcutaneous dose of 2000 mg/kg or a single intravenous dose of 1000 mg/kg. LIFMIOR did not dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneo administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AU drug concentrations that were over 27-fold higher than that obtained in humans at the dose of 25 mg.
serum nded
s medicinal product must not be mixed with other medicinal
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Powder
Mannitol (E421)
Sucrose
Trometamol
Solvent
Water for injections
6.2 Incompatibilities
In the absence of compatibility products.
6.3 Shelf life
4 years.
Chemical and p l in-use stability has been demonstrated for 6 hours at temperatures of up to 25°C after reconstitution. From a microbiological point of view, the reconstituted medicinal product should be used immediately. If not used immediately, storage times and conditions prior to use are the e user and would normally not be longer than 6 hours at temperatures of up to stitution has taken place in controlled and validated aseptic conditions.
resp
Store in a refrigerator (2°C – 8°C). Do not freeze.
LIFMIOR may be stored at temperatures up to a maximum of 25°C for a single period of up to four weeks; after which, it should not be refrigerated again. LIFMIOR should be discarded if not used within four weeks of removal from refrigeration.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Clear glass vial (4 ml, type I glass) with rubber stoppers, aluminium seals, and flip-off plastic caps. LIFMIOR is supplied with pre-filled syringes containing water for injection. The syringes are type I glass. Cartons contain 4, 8 or 24 vials of LIFMIOR with 4, 8 or 24 pre-filled solvent syringes, 4, 8 or 24 needles, 4, 8 or 24 vial adaptors and 8, 16 or 48 alcohol swabs. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Instructions for use and handling
LIFMIOR is reconstituted with 1 ml water for injections before use, and administered by subcutaneo injection. LIFMIOR contains no antibacterial preservative, and therefore solutions prepared with wat for injections should be administered as soon as possible and within 6 hours following reconstitution The solution should be clear and colourless to pale yellow or pale brown, with no lumps, flakes or particles. Some white foam may remain in the vial – this is normal. LIFMIOR should notbeusedTf all the powder in the vial is not dissolved within 10 minutes. If this is the case, start again with another vial.
Comprehensive instructions for the preparation and administration of the reconstituted LIFMIOR vial are given in the package leaflet, section 7, “INSTRUCTIONS FOR PREP TION AND GIVING AN INJECTION OF LIFMIOR”.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDERPfizer Europe MA EEIG Boulevard de la Plaine 17 1050 BruxellesBelgium8. MARKETING AUTHON NUMBER(S)
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.