Yisaipu

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.

Yisaipu has not been studied in children aged less than 2 years.

Paediatric plaque psoriasis

Treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.

Yisaipu treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of juvenile idiopathic arthritis or paediatric plaque psoriasis. Patients treated with Yisaipu should be given the Patient Alert Card.

Posology

Special populations

Renal and hepatic impairment

No dose adjustment is required.

Paediatric population

The 10 mg presentation is for paediatric patients prescribed a dose of 10 mg or less. Each vial of Yisaipu 10 mg should be used on a single occasion in a single patient, and the remainder of the vial should be discarded.

Juvenile idiopathic arthritis

The recommended dose is 0.4 mg/kg (up to a maximum of 25 mg per dose) given twice weekly as a subcutaneous injection with an interval of 3-4 days between doses or 0.8 mg/kg (up to a maximum of 50 mg per dose) given once weekly. Discontinuation of treatment should be considered in patients who show no response after 4 months.

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.

There is generally no applicable use of Yisaipu in children aged below 2 years in the indication juvenile idiopathic arthritis.

Paediatric plaque psoriasis (age 6 years and above)

The recommended dose is 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly for up to 24 weeks. Treatment should be discontinued in patients who show no response after 12 weeks.

If re-treatment with Yisaipu is indicated, the above guidance on treatment duration should be followed. The dose should be 0.8 mg/kg (up to a maximum of 50 mg per dose) once weekly.

There is generally no applicable use of Yisaipu in children aged below 6 years in the indication plaque psoriasis.

Method of administration

Yisaipu is administered by subcutaneous injection. Yisaipu powder for solution must be reconstituted in 1 ml of solvent before use.

Comprehensive instructions for the preparation and administration of the reconstituted Yisaipu vial are given in the package leaflet, section 7, "Instructions for preparation and giving an injection of Yisaipu."

Sepsis or risk of sepsis.

Treatment with Yisaipu should not be initiated in patients with active infections, including chronic or localised infections.

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 Yisaipu, 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, including invasive fungal infections, listeriosis and legionellosis, have been reported with the use of Yisaipu. These infections were due to bacteria, mycobacteria, fungi, viruses and parasites (including protozoa). In some cases, particular fungal and other opportunistic infections have not been recognised, resulting in delay of appropriate treatment and sometimes death. In evaluating patients for infections, the patient's risk for relevant opportunistic infections (e.g., exposure to endemic mycoses) should be considered.

Patients who develop a new infection while undergoing treatment with Yisaipu should be monitored closely. Administration of Yisaipu should be discontinued if a patient develops a serious infection. The safety and efficacy of Yisaipu in patients with chronic infections have not been evaluated. Physicians should exercise caution when considering the use of Yisaipu in patients with a history of recurring or chronic infections or with underlying conditions that may predispose patients to infections, such as advanced or poorly controlled diabetes.

Tuberculosis

Cases of active tuberculosis, including miliary tuberculosis and tuberculosis with extra-pulmonary location, have been reported in patients treated with Yisaipu.

Before starting treatment with Yisaipu, all patients must be evaluated for both active and inactive ('latent') tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible 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 risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

If active tuberculosis is diagnosed, Yisaipu 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 Yisaipu, and in accordance with local recommendations. In this situation, the benefit/risk balance of Yisaipu 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 Yisaipu 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 Yisaipu, 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 Yisaipu. 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 Yisaipu 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, Yisaipu should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.

Worsening of hepatitis C

There have been reports of worsening of hepatitis C in patients receiving Yisaipu. Yisaipu should be used with caution in patients with a history of hepatitis C.

Concurrent treatment with anakinra

Concurrent administration of Yisaipu and anakinra has been associated with an increased risk of serious infections and neutropenia compared to Yisaipu alone. This combination has not demonstrated increased clinical benefit. Thus, the combined use of Yisaipu and anakinra is not recommended.

Concurrent treatment with abatacept

In clinical studies, concurrent administration of abatacept and Yisaipu resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended.

Allergic reactions

Allergic reactions associated with Yisaipu administration have been reported commonly. Allergic reactions have included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, Yisaipu therapy should be discontinued immediately and appropriate therapy initiated.

Immunosuppression

The possibility exists for TNF-antagonists, including Yisaipu, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 adult patients with rheumatoid arthritis treated with Yisaipu, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of 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 virus should temporarily discontinue Yisaipu therapy and be considered for prophylactic treatment with Varicella Zoster Immune Globulin.

The safety and efficacy of Yisaipu in patients with immunosuppression have not been evaluated.

Malignancies 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.

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 Yisaipu, 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 Yisaipu. Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Yisaipu. 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 Yisaipu compared with control patients, particularly in patients with psoriasis.

Vaccinations

Live vaccines should not be given concurrently with Yisaipu. No data are available on the secondary transmission of infection by live vaccines in patients receiving Yisaipu. 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 Yisaipu 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 Yisaipu. The clinical significance of this is unknown.

Autoantibody formation

Treatment with Yisaipu may result in the formation of autoimmune antibodies.

Haematologic reactions

Rare cases of pancytopenia and very rare cases of aplastic anaemia, some with fatal outcome, have been reported in patients treated with Yisaipu. Caution should be exercised in patients being treated with Yisaipu 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 Yisaipu, they should seek immediate medical advice. Such patients should be investigated urgently, including full blood count; if blood dyscrasias are confirmed, Yisaipu should be discontinued.

Neurological disorders

There have been rare reports of CNS demyelinating disorders in patients treated with Yisaipu. Additionally, there have been rare reports of peripheral demyelinating polyneuropathies (including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy). Although no clinical trials have been performed evaluating Yisaipu 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 Yisaipu 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 adult rheumatoid arthritis patients, the combination of Yisaipu and methotrexate did not result in unexpected safety findings, and the safety profile of Yisaipu when given in combination with methotrexate was similar to the profiles reported in studies of Yisaipu and methotrexate alone. Long-term studies to assess the safety of the combination are ongoing. The long-term safety of Yisaipu in combination with other disease-modifying antirheumatic drugs (DMARD) has not been established.

The use of Yisaipu in combination with other systemic therapies or phototherapy for the treatment of psoriasis has not been studied.

Renal and hepatic impairment

Based on pharmacokinetic data , no dose adjustment is needed in patients with renal or hepatic impairment; clinical experience in such patients is limited.

Congestive heart failure (Cardiac failure congestive)

Physicians should use caution when using Yisaipu 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 Yisaipu. 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 Yisaipu in the treatment of CHF were terminated early due to lack of efficacy. Although not conclusive, data from one of these trials suggest a possible tendency toward worsening CHF in those patients assigned to Yisaipu treatment.

Alcoholic hepatitis

In a phase II randomised placebo-controlled study of 48 hospitalised patients treated with Yisaipu or placebo for moderate to severe alcoholic hepatitis, Yisaipu was not efficacious, and the mortality rate in patients treated with Yisaipu was significantly higher after 6 months. Consequently, Yisaipu should not be used in patients for the treatment of alcoholic hepatitis. Physicians should use caution when using Yisaipu in patients who also have moderate to severe alcoholic hepatitis.

Wegener's granulomatosis

A placebo-controlled trial, in which 89 adult patients were treated with Yisaipu in addition to standard therapy (including cyclophosphamide or methotrexate, and glucocorticoids) for a median duration of 25 months, has not shown Yisaipu 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 Yisaipu than in the control group. Yisaipu is not recommended for the treatment of Wegener's granulomatosis.

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of Yisaipu in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.

Special 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 Yisaipu 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 Yisaipu 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 Yisaipu.

No studies on the effects on the ability to drive and use machines have been performed.

Summary of the safety profile

Paediatric population

Undesirable effects in paediatric patients with juvenile idiopathic arthritis

In general, the adverse events in paediatric patients with juvenile idiopathic arthritis were similar in frequency and type to those seen in adult patients (see below, Undesirable effects in adults). Differences from adults and other special considerations are discussed in the following paragraphs.

The types of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years were generally mild to moderate and consistent with those commonly seen in outpatient paediatric populations.), 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 Yisaipu 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 open-label extension therapy. The types and proportion of adverse events in juvenile idiopathic arthritis patients were similar to those seen in trials of Yisaipu 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 Yisaipu 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 Yisaipu from post-marketing sources, including a very small number of cases indicating a positive rechallenge.

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 adverse events reported were similar to those seen in previous studies in adults with plaque psoriasis.

Adult population

Undesirable effects in adults

The most commonly reported adverse reactions are injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), infections (such as upper respiratory infections, bronchitis, bladder infections and skin infections), allergic reactions, development of autoantibodies, itching, and fever.

Serious adverse reactions have also been reported for Yisaipu. TNF-antagonists, such as Yisaipu, affect the immune system and their use may affect the body's defenses against infection and cancer. Serious infections affect fewer than 1 in 100 patients treated with Yisaipu. Reports have included fatal and life-threatening infections and sepsis. Various malignancies have also been reported with use of Yisaipu, 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 Yisaipu 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).

Description of selected adverse reactions

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 Yisaipu for up to approximately 6 years, including 231 patients treated with Yisaipu 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 Yisaipu-treated psoriatic arthritis patients. In clinical studies conducted for more than 2 years with 351 ankylosing spondylitis patients, 6 malignancies were reported in Yisaipu-treated patients. In a group of 2,711 plaque psoriasis patients treated with Yisaipu 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 of 7,416 patients treated with Yisaipu in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis clinical trials, 18 lymphomas were reported.

Reports of various malignancies (including breast and lung carcinoma and lymphoma) have also been received in the postmarketing period.

Injection site reactions

Compared to placebo, patients with rheumatic diseases treated with Yisaipu 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 Yisaipu 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 Yisaipu 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 Yisaipu 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 Yisaipu alone, methotrexate alone or Yisaipu in combination with methotrexate, the rates of serious infections were similar among the treatment groups. However, it cannot be excluded that the combination of Yisaipu 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 Yisaipu and those treated with placebo for plaque psoriasis in placebo-controlled trials of up to 24 weeks duration. Serious infections experienced by Yisaipu-treated patients included cellulitis, gastroenteritis, pneumonia, cholecystitis, osteomyelitis, gastritis, appendicitis, Streptococcal fasciitis, myositis, septic shock, diverticulitis and abscess. In the double-blind and open-label psoriatic arthritis trials, 1 patient reported a serious infection (pneumonia).

Serious and fatal infections have been reported during use of Yisaipu; reported pathogens include bacteria, mycobacteria (including tuberculosis), viruses and fungi. Some have occurred within a few weeks after initiating treatment with Yisaipu in patients who have underlying conditions (e.g., diabetes, congestive heart failure, history of active or chronic infections) in addition to their rheumatoid arthritis. Yisaipu treatment may increase mortality in patients with established sepsis.

Opportunistic infections have been reported in association with Yisaipu, 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 Yisaipu. 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.

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 new positive ANA (>1:40) was higher in patients treated with Yisaipu (11%) than in placebo-treated patients (5%). The percentage of patients who developed new positive anti-double-stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Yisaipu compared to 4% of placebo-treated patients) and by Crithidia luciliae assay (3% of patients treated with Yisaipu compared to none of placebo-treated patients). The proportion of patients treated with Yisaipu who developed anticardiolipin antibodies was similarly increased compared to placebo-treated patients. The impact of long-term treatment with Yisaipu 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.

Interstitial lung disease

In controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of interstitial lung disease in patients receiving etanercept without concomitant methotrexate was 0.06% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of interstitial lung disease was 0.47% (frequency uncommon). There have been postmarketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.

Concurrent treatment with anakinra

In studies when adult patients received concurrent treatment with Yisaipu plus anakinra, a higher rate of serious infections compared to Yisaipu 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.

Elevated liver enzymes

In the double-blind periods of controlled clinical trials of etanercept across all indications, the frequency (incidence proportion) of adverse events of elevated liver enzymes in patients receiving etanercept without concomitant methotrexate was 0.54% (frequency uncommon). In the double-blind periods of controlled clinical trials that allowed concomitant treatment 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 across all indications, the frequency (incidence proportion) of autoimmune hepatitis in patients receiving etanercept without concomitant methotrexate was 0.02% (frequency rare). In the controlled clinical trials that allowed concomitant treatment with etanercept and methotrexate, the frequency (incidence proportion) of autoimmune hepatitis was 0.24% (frequency uncommon).

Paediatric population

See Summary of the safety profile, above.

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.

United Kingdom

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Ireland

Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: [email protected].

No dose-limiting toxicities were observed during clinical trials of rheumatoid arthritis patients. The highest dose level evaluated has been an intravenous loading dose of 32 mg/m² followed by subcutaneous doses of 16 mg/m² administered twice weekly. One rheumatoid arthritis patient mistakenly self-administered 62 mg Yisaipu subcutaneously twice weekly for 3 weeks without experiencing undesirable effects. There is no known antidote to Yisaipu.

Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-α) inhibitors, ATC code: L04AB01

Tumour necrosis factor (TNF) is a dominant cytokine in the inflammatory process of rheumatoid arthritis. Elevated levels of TNF are also found in the synovium and psoriatic plaques of patients with psoriatic arthritis and in serum and synovial tissue of patients with ankylosing spondylitis. In plaque psoriasis, infiltration by inflammatory cells, including T-cells, leads to increased TNF levels in psoriatic lesions compared with levels in uninvolved skin. Etanercept is a competitive inhibitor of TNF binding to its cell surface receptors, and thereby inhibits the biological activity of TNF. TNF and lymphotoxin are pro-inflammatory cytokines that bind to two distinct cell surface receptors: the 55-kilodalton (p55) and 75-kilodalton (p75) tumour necrosis factor receptors (TNFRs). Both TNFRs exist naturally in membrane-bound and soluble forms. Soluble TNFRs are thought to regulate TNF biological activity.

TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on cross-linking of cell surface TNFRs. Dimeric soluble receptors, such as etanercept, possess a higher affinity for TNF than monomeric receptors and are considerably more potent competitive inhibitors of TNF binding to its cellular receptors. In addition, use of an immunoglobulin Fc region as a fusion element in the construction of a dimeric receptor imparts a longer serum half-life.

Mechanism of action

Much of the joint pathology in rheumatoid arthritis and ankylosing spondylitis and skin pathology in plaque psoriasis is mediated by pro-inflammatory molecules that are linked in a network controlled by TNF. The mechanism of action of etanercept is thought to be its competitive inhibition of TNF binding to cell surface TNFR, preventing TNF-mediated cellular responses by rendering TNF biologically inactive. Etanercept may also modulate biologic responses controlled by additional downstream molecules (e.g., cytokines, adhesion molecules, or proteinases) that are induced or regulated by TNF.

Clinical efficacy and safety

This section presents data from three studies in juvenile idiopathic arthritis, one study in paediatric patients with plaque psoriasis, four studies in adults with rheumatoid arthritis, and four studies in adults with plaque psoriasis.

Paediatric population

Paediatric patients with juvenile idiopathic arthritis

The safety and efficacy of Yisaipu were assessed in a two-part study in 69 children with polyarticular-course juvenile idiopathic arthritis who had a variety of juvenile idiopathic arthritis onset types (polyarthritis, pauciarthritis, systemic onset). Patients aged 4 to 17 years with moderately to severely active polyarticular-course juvenile idiopathic arthritis refractory to, or intolerant of, methotrexate were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug and/or prednisone (< 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) Yisaipu subcutaneously twice weekly. In part 2, patients with a clinical response at day 90 were randomised to remain on Yisaipu or receive placebo for four months and assessed for disease flare. Responses were measured using the ACR Pedi 30, defined as > 30% improvement in at least three of six and > 30% worsening in no more than one of six JRA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and erythrocyte sedimentation rate (ESR). Disease flare was defined as a > 30% worsening in three of six JRA core set criteria and > 30% improvement in not more than one of the six JRA core set criteria and a minimum of two active joints.

In part 1 of the study, 51 of 69 (74%) patients demonstrated a clinical response and entered part 2. In part 2, 6 of 25 (24%) patients remaining on Yisaipu experienced a disease flare compared to 20 of 26 (77%) patients receiving placebo (p=0.007). From the start of part 2, the median time to flare was > 116 days for patients who received Yisaipu and 28 days for patients who received placebo. Of patients who demonstrated a clinical response at 90 days and entered part 2 of the study, some of the patients remaining on Yisaipu continued to improve from month 3 through month 7, while those who received placebo did not improve.

In an open-label, safety extension study, 58 paediatric patients from the above study (from the age of 4 years at time of enrolment) continued to receive Yisaipu for up to 10 years. Rates of serious adverse events and serious infections did not increase with long-term exposure.

Long-term safety of Yisaipu monotherapy (n=103), Yisaipu plus methotrexate (n=294), or methotrexate monotherapy (n=197) were assessed for up to 3 years in a registry of 594 children aged 2 to 18 years with juvenile idiopathic arthritis, 39 of whom were 2 to 3 years of age. Overall, infections were more commonly reported in patients treated with etanercept compared to methotrexate alone (3.8 versus 2%), and the infections associated with etanercept use were of a more severe nature.

In another open-label single-arm study, 60 patients with extended oligoarthritis (15 patients aged 2 to 4, 23 patients aged 5 to 11 and 22 patients aged 12 to 17 years old), 38 patients with enthesitis-related arthritis (12 to 17 years old), and 29 patients with psoriatic arthritis (12 to 17 years old) were treated with Yisaipu at a dose of 0.8 mg/kg (up to a maximum of 50 mg per dose) administered weekly for 12 weeks. In each of the JIA subtypes, the majority of patients met ACR Pedi 30 criteria and demonstrated clinical improvement in secondary endpoints such as number of tender joints and physician global assessment. The safety profile was consistent with that observed in other JIA studies.

Studies have not been done in patients with juvenile idiopathic arthritis to assess the effects of continued Yisaipu therapy in patients who do not respond within 3 months of initiating Yisaipu therapy. Additionally, studies have not been conducted to assess the effects of discontinuing or reducing the recommended dose of Yisaipu following its long-term use in patients with JIA.

Paediatric patients with plaque psoriasis

The efficacy of Yisaipu was assessed in a randomised, double-blind, placebo-controlled study in 211 paediatric patients aged 4 to 17 years with moderate to severe plaque psoriasis (as defined by an sPGA score > 3, involving > 10% of the BSA, and PASI > 12). Eligible patients had a history of receiving phototherapy or systemic therapy, or were inadequately controlled on topical therapy.

Patients received Yisaipu 0.8 mg/kg (up to 50 mg) or placebo once weekly for 12 weeks. At week 12, more patients randomised to Yisaipu had positive efficacy responses (e.g., PASI 75) than those randomised to placebo.

After the 12-week double-blind treatment period, all patients received Yisaipu 0.8 mg/kg (up to 50 mg) once weekly for additional 24 weeks. Responses observed during the open-label period were similar to those observed in the double-blind period.

During a randomised withdrawal period, significantly more patients re-randomised to placebo experienced disease relapse (loss of PASI 75 response) compared with patients re-randomised to Yisaipu. With continued therapy, responses were maintained up to 48 weeks.

The long-term safety and effectiveness of Yisaipu 0.8 mg/kg (up to 50 mg) once weekly was assessed in an open-label extension study of 181 paediatric subjects with plaque psoriasis for up to 2 years beyond the 48 week study discussed above. Long-term experience with Yisaipu was generally comparable to the original 48-week study and did not reveal any new safety findings.

Adult patients with rheumatoid arthritis

The efficacy of Yisaipu was assessed in a randomised, double-blind, placebo-controlled study. The study evaluated 234 adult patients with active rheumatoid arthritis who had failed therapy with at least one but no more than four disease-modifying antirheumatic drugs (DMARDs). Doses of 10 mg or 25 mg Yisaipu or placebo were administered subcutaneously twice a week for 6 consecutive months. The results of this controlled trial were expressed in percentage improvement in rheumatoid arthritis using American College of Rheumatology (ACR) response criteria.

ACR 20 and 50 responses were higher in patients treated with Yisaipu at 3 and 6 months than in patients treated with placebo (ACR 20: Yisaipu 62% and 59%, placebo 23% and 11% at 3 and 6 months, respectively: ACR 50: Yisaipu 41% and 40%, placebo 8% and 5% at months 3 and 6, respectively; p<0.01 Yisaipu vs. placebo at all timepoints for both ACR 20 and ACR 50 responses).

Approximately 15% of subjects who received Yisaipu achieved an ACR 70 response at month 3 and month 6 compared to fewer than 5% of subjects in the placebo arm. Among patients receiving Yisaipu, the clinical responses generally appeared within 1 to 2 weeks after initiation of therapy and nearly always occurred by 3 months. A dose response was seen; results with 10 mg were intermediate between placebo and 25 mg. Yisaipu was significantly better than placebo in all components of the ACR criteria, as well as other measures of rheumatoid arthritis disease activity not included in the ACR response criteria, such as morning stiffness. A Health Assessment Questionnaire (HAQ), which included disability, vitality, mental health, general health status, and arthritis-associated health status subdomains, was administered every 3 months during the trial. All subdomains of the HAQ were improved in patients treated with Yisaipu compared to controls at 3 and 6 months.

After discontinuation of Yisaipu, symptoms of arthritis generally returned within a month. Re-introduction of treatment with Yisaipu after discontinuation of up to 24 months resulted in the same magnitudes of responses as patients who received Yisaipu without interruption of therapy based on results of open-label studies. Continued durable responses have been seen for up to 10 years in open-label extension treatment trials when patients received Yisaipu without interruption.

The efficacy of Yisaipu was compared to methotrexate in a randomised, active-controlled study with blinded radiographic evaluations as a primary endpoint in 632 adult patients with active rheumatoid arthritis (<3 years duration) who had never received treatment with methotrexate. Doses of 10 mg or 25 mg Yisaipu were administered subcutaneously (SC) twice a week for up to 24 months. Methotrexate doses were escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial and continued for up to 24 months. Clinical improvement, including onset of action within 2 weeks with Yisaipu 25 mg, was similar to that seen in the previous trials and was maintained for up to 24 months. At baseline, patients had a moderate degree of disability, with mean HAQ scores of 1.4 to 1.5. Treatment with Yisaipu 25 mg resulted in substantial improvement at 12 months, with about 44% of patients achieving a normal HAQ score (less than 0.5). This benefit was maintained in Year 2 of this study.

In this study, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and Joint Space Narrowing (JSN) score. Radiographs of hands/wrists and feet were read at baseline and 6, 12, and 24 months. The 10 mg Yisaipu dose had consistently less effect on structural damage than the 25 mg dose. Yisaipu 25 mg was significantly superior to methotrexate for erosion scores at both 12 and 24 months. The differences in TSS and JSN were not statistically significant between methotrexate and Yisaipu 25 mg. The results are shown in the figure below.

Radiographic Progression: Comparison of Yisaipu vs. Methotrexate in Patients with RA of <3 Years Duration

In another active-controlled, double-blind, randomised study, clinical efficacy, safety, and radiographic progression in RA patients treated with Yisaipu alone (25 mg twice weekly), methotrexate alone (7.5 to 20 mg weekly, median dose 20 mg), and the combination of Yisaipu and methotrexate initiated concurrently were compared in 682 adult patients with active rheumatoid arthritis of 6 months to 20 years duration (median 5 years) who had a less than satisfactory response to at least 1 disease-modifying antirheumatic drug (DMARD) other than methotrexate.

Patients in the Yisaipu in combination with methotrexate therapy group had significantly higher ACR 20, ACR 50, ACR 70 responses and improvement for DAS and HAQ scores at both 24 and 52 weeks than patients in either of the single therapy groups (results shown in table below). Significant advantages for Yisaipu in combination with methotrexate compared with Yisaipu monotherapy and methotrexate monotherapy were also observed after 24 months.

Radiographic progression at 12 months was significantly less in the Yisaipu 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 Yisaipu vs. Methotrexate vs. Yisaipu in Combination with Methotrexate in Patients with RA of 6 Months To 20 Years Duration (12 Month Results)

Pairwise comparison p-values: * = p < 0.05 for comparisons of Yisaipu vs. methotrexate, †= p < 0.05 for comparisons of Yisaipu + methotrexate vs. methotrexate and ϕ = p < 0.05 for comparisons of Yisaipu + methotrexate vs. Yisaipu.

Significant advantages for Yisaipu in combination with methotrexate compared with Yisaipu monotherapy and methotrexate monotherapy were also observed after 24 months. Similarly, the significant advantages for Yisaipu 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 Yisaipu in combination with methotrexate group compared with the Yisaipu alone and methotrexate alone groups (62%, 50%, and 36%, respectively; p<0.05). The difference between Yisaipu 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 Yisaipu (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 Yisaipu once weekly and 153 patients received 25 mg Yisaipu twice weekly. The safety and efficacy profiles of the two Yisaipu 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 plaque psoriasis

The efficacy of Yisaipu versus other systemic therapies in patients with moderate to severe psoriasis (responsive to other systemic therapies) has not been evaluated in studies directly comparing Yisaipu with other systemic therapies. Instead, the safety and efficacy of Yisaipu were assessed in four randomised, double-blind, placebo-controlled studies. The primary efficacy endpoint in all four studies was the proportion of patients in each treatment group who achieved the PASI 75 (i.e., at least a 75% improvement in the Psoriasis Area and Severity Index score from baseline) at 12 weeks.

Study 1 was a Phase 2 study in patients with active, but clinically stable, plaque psoriasis involving > 10% of the body surface area who were > 18 years old. One hundred and twelve (112) patients were randomised to receive a dose of 25 mg of Yisaipu (n=57) or placebo (n=55) twice a week for 24 weeks.

Study 2 evaluated 652 patients with chronic plaque psoriasis using the same inclusion criteria as study 1 with the addition of a minimum psoriasis area and severity index (PASI) of 10 at screening. Yisaipu was administered at doses of 25 mg once a week, 25 mg twice a week or 50 mg twice a week for 6 consecutive months. During the first 12 weeks of the double-blind treatment period, patients received placebo or one of the above three Yisaipu doses. After 12 weeks of treatment, patients in the placebo group began treatment with blinded Yisaipu (25 mg twice a week); patients in the active treatment groups continued to week 24 on the dose to which they were originally randomised.

Study 3 evaluated 583 patients and had the same inclusion criteria as study 2. Patients in this study received a dose of 25 mg or 50 mg Yisaipu, or placebo twice a week for 12 weeks and then all patients received open-label 25 mg Yisaipu twice weekly for an additional 24 weeks.

Study 4 evaluated 142 patients and had similar inclusion criteria to studies 2 and 3. Patients in this study received a dose of 50 mg Yisaipu or placebo once weekly for 12 weeks and then all patients received open-label 50 mg Yisaipu once weekly for an additional 12 weeks.

In study 1, the Yisaipu-treated group had a significantly higher proportion of patients with a PASI 75 response at week 12 (30%) compared to the placebo-treated group (2%) (p<0.0001). At 24 weeks, 56% of patients in the Yisaipu-treated group had achieved the PASI 75 compared to 5% of placebo-treated patients. Key results of studies 2, 3 and 4 are shown below.

Among patients with plaque psoriasis who received Yisaipu, significant responses relative to placebo were apparent at the time of the first visit (2 weeks) and were maintained through 24 weeks of therapy.

Study 2 also had a drug withdrawal period during which patients who achieved a PASI improvement of at least 50% at week 24 had treatment stopped. Patients were observed off treatment for the occurrence of rebound (PASI >150% of baseline) and for the time to relapse (defined as a loss of at least half of the improvement achieved between baseline and week 24). During the withdrawal period, symptoms of psoriasis gradually returned, with a median time to disease relapse of 3 months. No rebound flare of disease and no psoriasis-related serious adverse events were observed. There was some evidence to support a benefit of re-treatment with Yisaipu in patients initially responding to treatment.

In study 3, the majority of patients (77%) who were initially randomised to 50 mg twice weekly and had their Yisaipu dose decreased at week 12 to 25 mg twice weekly maintained their PASI 75 response through week 36. For patients who received 25 mg twice weekly throughout the study, the PASI 75 response continued to improve between weeks 12 and 36.

In study 4, the Yisaipu-treated group had a higher proportion of patients with PASI 75 at week 12 (38%) compared to the placebo-treated group (2%) (p<0.0001). For patients who received 50 mg once weekly throughout the study, the efficacy responses continued to improve with 71% achieving PASI 75 at week 24.

In long-term (up to 34 months) open-label studies where Yisaipu was given without interruption, clinical responses were sustained and safety was comparable to shorter-term studies.

An analysis of clinical trial data did not reveal any baseline disease characteristics that would assist clinicians in selecting the most appropriate dosing option (intermittent or continuous). Consequently, the choice of intermittent or continuous therapy should be based upon physician judgment and individual patient needs.

Antibodies to Yisaipu

Antibodies to etanercept have been detected in the sera of some subjects treated with etanercept. These antibodies have all been non-neutralising and are generally transient. There appears to be no correlation between antibody development and clinical response or adverse events.

In subjects treated with approved doses of etanercept in clinical trials for up to 12 months, cumulative rates of anti-etanercept antibodies were approximately 6% of subjects with rheumatoid arthritis, 7.5% of subjects with psoriatic arthritis, 2% of subjects with ankylosing spondylitis, 7% of subjects with psoriasis, 9.7% of subjects with paediatric psoriasis, and 4.8% of subjects with juvenile idiopathic arthritis.

The proportion of subjects who developed antibodies to etanercept in longer-term trials (of up to 3.5 years) increases over time, as expected. However, due to their transient nature, the incidence of antibodies detected at each assessment point was typically less than 7% in rheumatoid arthritis subjects and psoriasis subjects.

In a long-term psoriasis study in which patients received 50 mg twice weekly for 96 weeks, the incidence of antibodies observed at each assessment point was up to approximately 9%.

Etanercept serum values were determined by an Enzyme-Linked Immunosorbent Assay (ELISA) method, which may detect ELISA-reactive degradation products as well as the parent compound.

Special populations

Renal impairment

Although there is elimination of radioactivity in urine after administration of radiolabelled etanercept to patients and volunteers, increased etanercept concentrations were not observed in patients with acute renal failure. The presence of renal impairment should not require a change in dosage.

Hepatic impairment

Increased etanercept concentrations were not observed in patients with acute hepatic failure. The presence of hepatic impairment should not require a change in dosage.

Paediatric population

Paediatric patients with juvenile idiopathic arthritis

In a polyarticular-course juvenile idiopathic arthritis trial with Yisaipu, 69 patients (aged 4 to 17 years) were administered 0.4 mg Yisaipu/kg twice weekly for three months. Serum concentration profiles were similar to those seen in adult rheumatoid arthritis patients. The youngest children (4 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.

Adults

Absorption

Etanercept 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 Yisaipu, the average maximum serum concentration observed in healthy volunteers was 1.65 ± 0.66 μg/ml, and the area under the curve was 235 ± 96.6 μg-hr/ml. Mean serum concentration profiles at steady state in treated RA patients were C_max of 2.4 mg/l vs. 2.6 mg/l, C_min of 1.2 mg/l vs. 1.4 mg/l, and partial AUC of 297 mgh/l vs. 316 mgh/l for 50 mg Yisaipu once weekly (n=21) vs. 25 mg Yisaipu 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 state AUCs were 466 μg-hr/ml and 474 μg-hr/ml for 50 mg Yisaipu 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 central volume of distribution of etanercept is 7.6 l, while the volume of distribution at steady-state is 10.4 l.

Elimination

Etanercept is cleared slowly from the body. The half-life is long, approximately 70 hours. Clearance is approximately 0.066 l/hr in patients with rheumatoid arthritis, somewhat lower than the value of 0.11 l/hr observed in healthy volunteers. Additionally, the pharmacokinetics of Yisaipu in rheumatoid arthritis patients, ankylosing spondylitis and plaque psoriasis patients are similar.

There is no apparent pharmacokinetic difference between males and females.

Linearity

Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.

In the toxicological studies with Yisaipu, no dose-limiting or target organ toxicity was evident. Yisaipu 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 Yisaipu due to the development of neutralising antibodies in rodents.

Yisaipu 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. Yisaipu did not elicit dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneous administration for 4 or 26 consecutive weeks at a dose (15 mg/kg) that resulted in AUC-based serum drug concentrations that were over 27-fold higher than that obtained in humans at the recommended dose of 25 mg.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Instructions for use and handling

Yisaipu is reconstituted with 1 ml water for injections before use, and administered by subcutaneous injection. 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. Yisaipu should not be used if all the powder in the vial is not dissolved within 10 minutes. Start again with another vial.

Comprehensive instructions for the preparation and administration of the reconstituted Yisaipu vial are given in the package leaflet, section 7, "Instructions for preparation and giving an injection of Yisaipu"

Any unused product or waste material should be disposed of in accordance with local requirements.