Etarfion

Etanercept.

Etarfion containing Etanercept 25 mg as active ingredient which is available in white lyophilized powder for injection in vial.
Etanercept, a tumor necrosis factor (TNF)-blocker, is a fusion protein consisting of the extracellular ligand-binding portion of the human p75 TNF-receptor (recombinant human factor necrosis factor = rhTNFR) produced by recombinant DNA technology in a Chinese hamster Ovary (CHO) mammalian expression system.
Each vial Etarfion contains: Etanercept 25 mg, Mannitol, Sucrose, Tromethamine.

Pharmacology: Etarfion binds specifically to the TNF and blocks its interaction with cell surface TNFRs. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of rheumatoid arthritis (RA) and the resulting joint pathology. Elevated levels of TNF are found in the involved tissue and fluids of patients with RA.
Etanercept inhibits binding of both TNF-α and TNF-β (lymphotoxin-α [LT-α]) to cell surface TNFRs, rendering TNF biologically inactive. Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (ie, E-selectin and, to a lesser extent, intracellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (e.g. IL-6), and serum levels of matrix metalloproteinase-3 [MMP-3] or stromelysin.
In a randomized, double-blind, Methotrexate controlled multicenter clinical trial conducted in 238 patients with severe active rheumatoid arthritis, the patients in the study drug group received 25 mg Etarfion by subcutaneous injection twice weekly for 24 weeks and the patients in the control group received MTX orally for 24 weeks. ACR 20/50/70 criteria were used for efficacy assessment. The study results demonstrated the rate of patients achieving ACR 20 in Etarfion group was 35.59% at 2 weeks after the treatment and significantly higher than that in the MTX control group (P<0.05). At 12 weeks after the treatment, the rate of patients achieving ACR 20 in the Etarfion group was 66.10% and also significantly superior to MTX control group (P<0.05). At 24 weeks after treatment, the rate of achieving ACR 20 in Etarfion group was 80.39% and ACR70 also superior to MTX control group (P<0.05). The main observed adverse reactions were injection site reactions, rash, elevated transaminases, and infections. There was no significant difference between the two groups in incidence of infections.

Rheumatoid Arthritis: Etarfion 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).
Etarfion can be initiated in combination with Methotrexate (MTX) or used alone.

The recommended dose is 25 mg twice weekly (50 mg/week), 3 or 4 days apart. Methotrexate (MTX), corticosteroids, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics may be continued during treatment with Etarfion.
Administration: Etarfion powder for injection is reconstituted with 1 mL Water for Injection (WFI) before use, and administered by subcutaneous injection. Sites for injection (thighs, abdomen or upper arms) should be rotated. Never inject into areas where the skin is tender, bruised, red or hard.

The maximum tolerated dose has not been established in humans. Toxicology studies have been performed in monkeys at doses up to 30 times the human dose with no evidence of dose-limiting toxicities. No dose-limiting toxicities have been observed during clinical trials of Etarfion. Single intravenous doses up to 60 mg/m² (approximately twice the recommended dose) have been administered to healthy volunteers in an endotoxaemia study without evidence of dose-limiting toxicities.

Etarfion should not be administered to patients with sepsis or with a known hypersensitivity to Etanercept or any of its components.

Serious infections: Patients treated with Etarfion are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens, including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with Etarfion should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or Methotrexate), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: Who have chronic or recurrent infection; Who have been exposed to tuberculosis; With a history of opportunistic infection; Who have resided or travelled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or with underlying conditions that may predispose them to infection such as advanced or poorly controlled diabetes.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Etarfion. Etarfion should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with Etarfion should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
Tuberculosis: Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving Etanercept, including patients who have previously received treatment for latent or active tuberculosis.
Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating Etarfion and periodically during therapy. Tests for latent tuberculosis infection may be falsely negative while on therapy with Etarfion.
Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. In duration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating Etarfion, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Anti-tuberculosis therapy should also be considered prior to initiation of Etarfion in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Tuberculosis should be strongly considered in patients who develop a new infection during Etarfion treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Invasive fungal infections: Cases of serious and sometimes fatal fungal infections, including histoplasmosis, have been reported with TNF blockers, including Etarfion. For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric anti-fungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric anti-fungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of anti-fungal therapy.
Neurologic events: Treatment with TNF-blocking agents, including Etarfion, has been associated with rare (<0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Prescribers should exercise caution in considering the use of Etarfion in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.
Malignancies: Lymphomas: In the controlled portions of clinical trials of TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared to control patients.
Leukemia: Cases of acute and chronic leukemia have been reported in association with postmarketing TNF-blocker use in rheumatoid arthritis patients. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at higher risk (approximately 2-fold) than the general population for the development of leukemia.
Melanoma and non-melanoma skin cancer (NMSC): Melanoma and non-melanoma skin cancer have been reported in patients treated with TNF antagonists including Etanercept.
Other malignancies: For malignancies other than lymphoma and non-melanoma skin cancer, there was no difference in exposure-adjusted rates between Etanercept and control arms in the controlled portions of clinical studies for all indications.
Patients with heart failure: Physicians should exercise caution when using Etarfion in patients who also have heart failure, and monitor patients carefully.
Hematologic events: All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (eg, persistent fever, bruising, bleeding, or pallor) while on Etarfion. Discontinuation of Etarfion therapy should be considered in patients with confirmed significant hematologic abnormalities.
Hepatitis B Virus (HBV) reactivation: In some instances, hepatitis B reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to hepatitis B reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. Physicians should exercise caution in prescribing TNF blockers in patients previously infected with HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. Patients previously infected with HBV and require treatment with Etarfion should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, consideration should be given to stopping Etarfion and initiating anti-viral therapy with appropriate supportive treatment. The safety of resuming Etarfion therapy after HBV reactivation is controlled is not known. Therefore, physicians should weigh the risks and benefits when considering resumption of therapy in this situation.
Allergic Reactions: If an anaphylactic reaction or other serious allergic reaction occurs, administration of Etarfion should be discontinued immediately and appropriate therapy initiated.
Immunizations: Live vaccines should not be given concurrently with Etarfion.
Autoimmunity: If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with Etarfion, treatment should be discontinued and the patient should be carefully evaluated.
Immunosuppression: TNF mediates inflammation and modulates cellular immune responses. TNF-blocking agents including Etarfion affect host defenses against infections. The effect of TNF inhibition on the development and course of malignancies is not fully understood.
Use with Anakinra or Abatacept: Use of Etarfion with Anakinra or Abatacept is not recommended.
Use in patients with moderate or severe alcoholic hepatitis: Physicians should use caution when using Etarfion in patients with moderate to severe alcoholic hepatitis.

Pregnancy (Pregnancy Category B): Developmental toxicity studies have been performed in rats and rabbits at doses ranging from 60- to 100-fold higher than the human dose and have revealed no evidence of harm to the fetus due to Etarfion. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Lactation: It is not known whether Etarfion is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Etarfion, a decision should be made whether to discontinue nursing or to discontinue the drug.

Infections: viral, bacterial, and fungal infections, upper respiratory tract infection, sinusitis, and influenza.
Injection site reactions: erythema, itching, pain, swelling, bleeding, bruising (mild to moderate).
Immunogenicity: antibodies to the TNF-receptor portion or other protein components.
Patients with RA were tested at multiple time points for antibodies to Etanercept. Antibodies to the TNF-receptor portion or other protein components of Etanercept drug product were detected at least once in the sera of approximately 6% of RA patients. These antibodies were all non-neutralizing.
The percentage of patients tested positive increased with an increase in the duration of the study; however, the clinical significance of this finding is unknown.
No apparent correlation of antibody development to clinical response or adverse events was observed.
The long-term immunogenicity data of Etanercept beyond 120 weeks of exposure are unknown.
The data reflect the percentage of patients whose test results were considered positive for antibodies to Etanercept in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of any antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Etanercept with the incidence of antibodies to other products may be misleading.
Autoantibodies: antinuclear antibodies (ANA), anti-double-stranded DNA.
Other adverse reactions: diarrhea, rash, pruritus, pyrexia, urticaria, hypersensitivity.
Blood and lymphatic system disorders: pancytopenia, anemia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, aplastic anemia.
Cardiac disorders: congestive heart failure.
Gastrointestinal disorders: inflammatory bowel disease (IBD).
General disorders: angioedema, chest pain.
Hepatobiliary disorders: autoimmune hepatitis, elevated transaminases, hepatitis B reactivation.
Immune disorders: macrophage activation syndrome, systemic vasculitis, sarcoidosis.
Musculoskeletal and connective tissue disorders: Lupus-like syndrome.
Neoplasms benign, malignant, and unspecified: melanoma and non-melanoma skin cancers, Merkel cell carcinoma.
Nervous system disorders: convulsions, multiple sclerosis, demyelination, optic neuritis, transverse myelitis, paresthesias.
Ocular disorders: uveitis, scleritis.
Respiratory, thoracic, and mediastinal disorders: interstitial lung disease.
Skin and subcutaneous tissue disorders: cutaneous lupus erythematosus, cutaneous vasculitis (including leukocytoclastic vasculitis), erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, subcutaneous nodule, new or worsening psoriasis (all sub-types including pustular and palmoplantar).
Opportunistic infections, including atypical mycobacterial infection, herpes zoster, aspergillosis and Pneumocystis jiroveci pneumonia, and protozoal infections.

Vaccines: Patients receiving Etarfion may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving Etarfion.
Patients with significant exposure to the varicella virus should temporarily discontinue Etarfion therapy and be considered for prophylactic treatment with varicella zoster immunoglobulin.
Immune-modulating biologic products: Concurrent Etanercept and Anakinra therapy, a 7% rate of serious infections was observed, and did not result in higher ACR response rates. The most common infections consisted of bacterial pneumonia, cellulitis, pulmonary fibrosis and pneumonia died due to respiratory failure, neutropenia (ANC <1x10⁹/L).
Concurrent administration of Abatacept and Etanercept resulted in increased incidences of serious adverse events, including infections, and did not demonstrate increased clinical benefit.
Cyclophosphamide: The use of Etarfion in patients receiving concurrent Cyclophosphamide therapy is not recommended.
Sulfasalazine: Patients in a clinical study who were on established therapy with Sulfasalazine, to which Etanercept was added, were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either Etanercept or Sulfasalazine alone. The clinical significance of this observation is unknown.

Store at temperature between 2°C to 8°C.
Keep in dry place, protect from light and do not freeze.
Use the reconstituted solution within 72 hours.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

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

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