Etveza

Etanercept.

Each vial contains: Recombinant Human Tumor Necrosis Factor-α Receptor II: IgG Fc Fusion Protein (rh TNFR:Fc) 25mg.
Etanercept the INN for Recombinant Human Tumor Necrosis Factor-α Receptor II: IgG Fc (rhTNFR: Fc) Fusion Protein for Injection is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system.
The Molecular Weight of the monomer is 63-77kDa and Dimer is 450kDa.
The Sequence of 15 Amino Acids at N-terminal is Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly.
Etanercept is a colorless or slightly yellow and transparent liquid when dissolved in water.
Excipients/Inactive Ingredients: Mannitol, Sucrose, Tromethamine.

Pharmacotherapeutic Group: Immunosuppressants. Tumour Necrosis Factor alpha (TNF-α) inhibitors.
Pharmacology: Pharmacodynamics: 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.
Pharmacokinetics: The clinical study results indicated rh TNFR: FC was absorbed slowly at injection site after subcutaneous injection. The peak blood concentration achieved at 48 hours after single administration, the absolute bioavailability was 76%. After administered twice weekly, the blood concentration at steady state was two times of the peak concentration of single dose.
11 active RA patients were injected with Yisaipu 25mg subcutaneously twice a week for consecutive 6 weeks, the time to steady state for rhTNFR:FC was 480±20h, Cmax(ss) was 3.0±0.2μg/ml, Cmin(ss) was 2.6±0.2μg/ml, the mean Css was 2.8±0.3μg/ml, the fluctuation index (FI) was 12.8±3.3%. After the last administration of rhTNFR:Fc, T1/2 was 74±4h, Tmax was 53±6h and CL was 102.8±10.4 ml/h.
No significant difference in blood concentration was observed among healthy persons, patients with acute renal failure and patients with abnormal liver functions, therefore, the dose does not need to be adjusted for the patients with renal function impairment. The influence of MTX on the pharmacokinetics of rhTNFR:Fc was not observed in the previously mentioned studies.

Rheumatoid Arthritis: Etanercept is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA). Etanercept can be initiated in combination with methotrexate (MTX) or used alone.
Psoriatic Arthritis: Etanercept is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). Etanercept can be used in combination with methotrexate (MTX) in patients who do not respond adequately to MTX alone.
Ankylosing Spondylitis: Etanercept is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis (AS).
Plaque Psoriasis: Etanercept is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

Posology: Rheumatoid arthritis: 25 mg Etanercept administered twice weekly is the recommended dose. Alternatively, 50 mg administered once weekly has been shown to be safe and effective.
Psoriatic arthritis and ankylosing spondylitis: The recommended dose is 25 mg Etanercept administered twice weekly, or 50 mg administered once weekly.
Plaque psoriasis: The recommended dose of Etanercept 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 Etanercept should continue until remission is achieved, for up to 24 weeks. Continuous therapy beyond 24 weeks may be appropriate for some adult patients. Treatment should be discontinued in patients who show no response after 12 weeks. If re-treatment with Etanercept is indicated, the same guidance on treatment duration should be followed. The dose should be 25 mg twice weekly or 50 mg once weekly.
SPECIAL POPULATIONS: Renal and hepatic impairment: No dose adjustment is required.
Older people (>65 years): No dose adjustment is required. Posology and administration are the same as for adults 18-64 years of age.
Paediatric population: 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 Etanercept 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 Etanercept is indicated, the previously mentioned 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 Etanercept in children aged below 6 years in the indication plaque psoriasis.
METHOD OF ADMINISTRATION: Etanercept is administered by subcutaneous injection. The injection sites could be thighs, abdomen and upper arms.
Etanercept is reconstituted with 1ml WFI before use. The reconstituted solution could be stored at 2-8°C in confined environment for 72 hours.

The maximum tolerated dose has not been established in humans. It was reported Single IV doses up to 60 mg/m² have been administered to healthy volunteers in an endotoxemia study without evidence of dose-limiting toxicities. In a clinical study conducted in RA patients, a patient wrongly received rhTNFR:Fc 62mg/m² twice weekly for consecutive 3 weeks and no adverse reactions were observed.

Hypersensitivity to the active substance or to any of the excipients listed.
Sepsis or risk of sepsis.
Treatment with Etanercept should not be initiated in patients with active infections, including chronic or localised infections.

Serious infections (sepsis, lethal and life threatening infections) occurred in the patients who received the like product abroad, therefore the administration of Etanercept should be cautious to the patients with history of repeated infectious diseases or latent diseases easily leading to infection.
When repeated upper respiratory tract infection or obvious tendency of infection occurs during administration of Etanercept, consultation of a doctor is recommended.
When serious infection occurs such as infection secondary to diabetes, tuberculosis infection etc, the administration of Etanercept should be discontinued temporarily.
During the using of Etanercept, allergic reactions including angio-edema, urticaria and other reactions should be concerned. Once the allergic reaction occurs, Etanercept therapy should be discontinued immediately and appropriate medical treatment should be given.
Since Etanercept can regulate inflammatory and cell immune reactions, its influence on anti-infection and anti-tumor therapy should be considered when using Etanercept.
No data are available on the secondary transmission of infection by live vaccines in patients receiving Etanercept. The concurrent vaccination of live vaccines is not recommended when receiving Etanercept.
It was reported overseas that Etanercept may lead to the exacerbation of patients with congestive heart failure, so administration of Etanercept in patients with heart failure should be extremely cautious.
Women of childbearing potential: Women of childbearing potential should be advised to use appropriate contraception to avoid becoming pregnant during Etanercept therapy and for three weeks after discontinuation of therapy.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
Use in Pregnancy & Lactation: Etanercept is not recommended for use in pregnant and lactating women.
Use in Children: There are no drug application data in children of 2 years and under. It is reported in foreign literatures that the dose for children (4 to 17 years old) is 0.8mg/kg, given twice weekly by 3-4 days apart.
Use in the Elderly: It was reported in a foreign literature that it is demonstrated in a clinical trial conducted in 197 elderly patients above 65 years that there were no significant differences in efficacy and safety between young and elderly patients. Because elder patients are susceptible to infections, attention should be paid to the elder patients during their treatment with Etanercept.

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 (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Infections and infestations: Very common: Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections).
Uncommon: Serious infections (including pneumonia, cellulitis, septic arthritis, sepsis and parasitic infection).
Rare: Tuberculosis, opportunistic infections (including invasive fungal, protozoal, bacterial and atypical mycobacterial infections and Legionella).
Not known: Listeria, hepatitis B reactivation.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Uncommon: Non-melanoma skin cancers.
Rare: Lymphoma, melanoma.
Not known: Leukaemia, Merkel cell carcinoma.
Blood and lymphatic system disorders: Uncommon: Thrombocytopenia.
Rare: Anaemia, leukopenia, neutropenia, pancytopenia.
Very rare: Aplastic anaemia.
Immune system disorders: Common: Allergic reactions, autoantibody formation*.
Uncommon: Systemic vasculitis (including anti-neutrophilic cytoplasmic antibody positive vasculitis).
Rare: Serious allergic/anaphylaxis reactions (including angioedema, bronchospasm), sarcoidosis.
Not known: Macrophage activation.
Nervous system disorders: Rare: Seizures.
CNS demyelinating events suggestive of multiple sclerosis or localised demyelinating conditions, such as optic neuritis and transverse myelitis.
Very rare: Peripheral demyelinating events, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, demyelinating polyneuropathy, and multifocal motor neuropathy.
Eye disorders: Uncommon: Uveitis, scleritis.
Cardiac disorders: Rare: Worsening of congestive heart failure.
Respiratory, thoracic and mediastinal disorders: Uncommon: Interstitial lung disease (including pneumonitis and pulmonary fibrosis)*.
Hepatobiliary disorders: Rare: Elevated liver enzymes, autoimmune hepatitis.
Skin and subcutaneous tissue disorders: Common: Pruritus.
Uncommon: Angioedema, urticaria, rash, psoriasiform rash, psoriasis (including new onset or worsening and pustular, primarily palms and soles).
Rare: Cutaneous vasculitis (including leukocytoclastic vasculitis), Stevens-Johnson syndrome, erythema multiforme.
Very rare: Toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: Rare: Subacute cutaneous lupus erythematosus, discoid lupus erythematosus, lupus-like syndrome.
General disorders and administration site conditions: Very common: Injection site reactions (including bleeding, bruising, erythema, itching, pain, swelling).
Common: Fever.
The common adverse reactions are the local reactions of the injection site, including erythema, itching, pain and swelling. The injection site reactions were generally occurred in the first month of treatment and subsequently decreased in frequency. The mean duration of injection site reactions is 3 to 5 days. Other adverse reactions are headache, vertigo, rash, cough, abdominal pain, upper respiratory tract infection, elevated blood pressure, increase of the percentage of peripheral lymphocytes, rhinitis, fever, arthralgia, myalgia, sleepy, facial swelling, elevated transaminase and so on. Most of previously mentioned adverse reactions do not need to be treated.
The adverse reactions of its similar product reported in foreign literatures are: Infections: The most common infection is upper respiratory tract infections. In a placebo controlled clinical study, the incidence of serious infection was not significantly increased. The incidence of serious infections of study drug group is also similar to that of control group in an open labeled study. The RA patients who experienced a serious adverse reaction(s) were often accompanied with other diseases (such as diabetes mellitus, congestive heart failure, active or chronic infections). No serious infections occurred in domestic clinical studies.
Autoantibodies: In foreign clinical studies, ANA and Anti-double strand DNA antibody were reported to be generated in the patients treated with Etanercept. Compared to the patients received MTX, there was no significant difference in newly generated autoantibodies between two groups. However, the long term influences of Etanercept on human autoimmune diseases are not clear.
Malignant Tumors: It has been observed very rare cases of lymphoma occurred in foreign patients who received Etanercept and the incidence is related positively to the severity of rheumatoid arthritis. Other observed tumors include colon, breast, lung and prostate cancers and the incidence rates are similar to those of normal people.

Concurrent Treatment with Anakinra: Adult patients treated with Etanercept and anakinra were observed to have a higher rate of serious infection when compared with patients treated with either Etanercept or anakinra alone (historical data).
In addition, in a double-blind, placebo-controlled trial in adult patients receiving background methotrexate, patients treated with Etanercept and anakinra were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with Etanercept. The combination Etanercept and anakinra has not demonstrated increased clinical benefit, and is therefore not recommended.
Concurrent treatment with abatacept: In clinical studies, concurrent administration of abatacept and Etanercept resulted in increased incidences of serious adverse events. This combination has not demonstrated increased clinical benefit; such use is not recommended.
Concurrent treatment with sulfasalazine: In a clinical study of adult patients who were receiving established doses of sulfasalazine, to which Etanercept was added, patients in the combination group experienced a statistically significant decrease in mean white blood cell counts in comparison to groups treated with Etanercept 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 interactions have been observed when Etanercept was administered with glucocorticoids, salicylates (except sulfasalazine), nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or methotrexate. No clinically significant pharmacokinetic drug-drug interactions were observed in studies with methotrexate, digoxin or warfarin.

Protect from light and moisture. Store between 2°-8°C. Do not freeze.
Shelf-Life: 36 months.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

L04AB01 - etanercept ; Belongs to the class of tumor necrosis factor alpha (TNF-alpha) inhibitors. Used as immunosuppressants.

POM

Powd for inj (vial) 25 mg (white, lyophilized powder) x 1's.