Etanercept (Enbrel) inhibits Tumor Necrosis Factor (TNF). It is used in the treatment of various autoimmune diseases such as Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

Etanercept (Enbrel) Uses:

• Ankylosing spondylitis:

  • Used for reducing signs and symptoms in patients with active ankylosing spondylitis.

• Plaque psoriasis (Enbrel):

  • Used for the treatment of patients of 4 years or more than 4 years of age with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

• Polyarticular juvenile idiopathic arthritis:

  • Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients of 2 years or more than 2 years of age.

• Psoriatic arthritis (Enbrel):

  • Reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis. Etanercept can be used with or without methotrexate.

• Rheumatoid arthritis:

  • Reducing signs and symptoms, inhibiting the progression of structural damage, inducing major clinical response, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA).
  • Etanercept can be initiated in combination with methotrexate or used alone.

• Off Label Use of Etanercept in Adults:

  • Pyoderma gangrenosum;
  • Treatment of Graft-versus-host disease

Read: Biologics for Psoriasis

Read: TNF-Inhibitors - an overview

Etanercept (Enbrel) Dose in Adults

Note: Erelzi is approved as biosimilar to Enbrel.

Etanercept (Enbrel) Dose in the treatment of Ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis: SubQ:

Note: May continue methotrexate, salicylates, NSAIDs, glucocorticoid, or analgesics during etanercept therapy.

• Once-weekly dosing:

  • 50 mg once in a weak;
  • maximum dose (rheumatoid arthritis): 50 mg per week.

• Twice-weekly dosing (off-label dose):

  • 25 mg twice in a week.

Etanercept (Enbrel) Dose in the treatment of Plaque psoriasis: SubQ:

• Initial:
  • 50 mg twice in a weak  for 3 months (starting doses of 25 or 50 mg once in a weak have also been used successfully)

• Maintenance dose:

  • 50 mg once in a weak.

Etanercept (Enbrel) Dose in the treatment of Acute graft-versus-host disease (GVHD), (off-label):

• SubQ: 0.4 mg/kg (maximum: 25 mg/dose) twice in a weak for 8 weeks (in combination with methylprednisolone).

Etanercept (Enbrel) Dose in Childrens

Note: Erelzi (etanercept) is approved as a biosimilar to Enbrel. Approved uses for biosimilar agents may vary (consult product labeling).

Etanercept (Enbrel) Dose in the treatment of Juvenile idiopathic arthritis:

• Children ≥2 years and Adolescents:

  • Once a week dosing:

    • Weight <63 kg: Enbrel: SubQ:
      • 0.8 mg/kg/dose once in a weak;
      • maximum dose: 50 mg per dose.
      • Note: Although FDA approved in patients of 2 years or more than 2 years of age, Erelzi does not have a dosage form that would allow for dosing in patients less than 63 kg of weight.
    • Weight ≥63 kg: Enbrel, Erelzi: SubQ:
      • 50 mg once in a weak.

  • Twice-weekly dosing:

    • SubQ: 0.4 mg/kg/dose twice in a weak, given 72 to 96 hours apart;
    • maximum dose: 25 mg per dose;
    • Note: Trials performed with Enbrel product.

Etanercept (Enbrel) Dose as adjunctive therapy in the treatment of acute Kawasaki disease:

• Infants ≥6 months and Children <6 years:

  • SubQ: 0.8 mg/kg/dose for 3 doses;
  • administer the first dose within 24 hours after completion of IV immunoglobulin (day 0), the second dose at day 7, and the third dose at day 14;
  • maximum dose: 50 mg per dose.

Etanercept (Enbrel) Dose in the treatment of Familial Mediterranean fever (FMF) (intolerance or resistance to colchicine):

• Children ≥11 years and Adolescents:

  • SubQ: 0.8 mg/kg once in a weak;
  • maximum dose: 50 mg per dose;

Etanercept (Enbrel) Dose in the treatment of Plaque psoriasis:

• Children and Adolescents 4 to 17 years Enbrel:

  • SubQ: 0.8 mg/kg/dose once in a weak;
  • maximum dose: 50 mg per dose;
  • results of a long-term study (264 weeks) showed efficacy maintained and therapy generally well-tolerated.
  • Note: Studies performed with Enbrel product.

• Adolescents ≥18 years:

  • Enbrel: SubQ: Initial:
    • 50 mg two times in a week administered 72 to 96 hours apart for 3 months;
  • Note: Initial doses of 25 mg or 50 mg/week were also shown to be efficacious;
  • maintenance dose:
    • 50 mg once in weak.

Etanercept (Enbrel) Dose in the treatment of Psoriatic arthritis:

• Adolescents ≥18 years: Enbrel:

  • Once-weekly dosing:
    • SubQ: 50 mg once in weak.
  • Twice-weekly dosing:
    • SubQ: 25 mg two times in a  week (individual doses should be separated by 72 to 96 hours).

Etanercept (Enbrel) Dose in the treatment of Rheumatoid arthritis and ankylosing spondylitis:

• Adolescents ≥18 years: Enbrel, Erelzi:

  • Once-weekly dosing:
    • SubQ: 50 mg once in weak.
  • Twice-weekly dosing:
    • SubQ: 25 mg two times in a  week(individual doses should be separated by 72 to 96 hours).

Etanercept (Enbrel) Pregnancy Risk Category: Not assigned

• Animal reproduction studies have not shown any adverse events.
• The placenta is cross-exposed to Etanercept. The newborn serum concentrations at delivery after in utero exposure are between 3% and 32% of the maternal serum concentration.

Etanercept use during breastfeeding:

• Breast milk contains Etanercept in low amounts. It is not absorbed by breastfeeding infants (limited data).
• According to the manufacturer of the product, when deciding whether to continue or stop breastfeeding during therapy, it should consider the risks to infant exposure, the benefits to the infant and the benefits to the mother.

Etanercept (Enbrel) Dose in Kidney Disease:

The manufacturer's labeling doesn't provide any dosage adjustments (has not been studied).

Etanercept (Enbrel) Dose in Liver disease:

The manufacturer's labeling doesn't provide any dosage adjustments (has not been studied).

Common Side Effects of etanercept (Enbrel):

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Diarrhea

• Infection:

  • Infection

• Local:

  • Injection Site Reaction

• Respiratory:

  • Upper Respiratory Tract Infection
  • Respiratory Tract Infection

• Miscellaneous:

  • Antibody Development
  • Positive ANA Titer

Less Common Side Effects Of etanercept (Enbrel):

• Dermatologic:

  • Pruritus
  • Urticaria

• Hypersensitivity:

  • Hypersensitivity Reaction

• Miscellaneous:

  • Fever

Rare Side effects of etanercept (Enbrel):

• Dermatologic:

  • Cellulitis

• Gastrointestinal:

  • Gastroenteritis

• Infection:

  • Abscess
  • Influenza
  • Sepsis

• Neuromuscular & Skeletal:

  • Osteomyelitis
  • Septic Arthritis

• Renal:

  • Pyelonephritis

• Respiratory:

  • Bronchitis
  • Pneumonia
  • Sinusitis

Contraindications to etanercept (Enbrel):

• Sepsis

Canadian labeling: Additional contraindications not in US labeling

• Hypersensitivity to etanercept and any component of the formulation
• Patients at high risk for sepsis syndrome (eg HIV positive, immunocompromised)

Warnings and precautions

• Anaphylaxis/hypersensitivity reactions:

  • Allergies can occur. If anaphylactic reactions or other severe allergic reactions occur, stop administering the medication immediately and seek appropriate treatment.

• Autoimmune disorder:

  • Patients with negative baselines have shown positive antinuclear antibody levels.
  • Rare cases of autoimmune disorders, such as lupus-like or autoimmune liver disease, have been reported. If symptoms persist, discontinue treatment.

• Demyelinating CNS Disease:

  • Rare cases of CNS demyelinating disorders that have been exacerbated or new-onset have been reported.
  • Some may present with mental status changes, while others may cause permanent disability.
  • Optic neuritis and multiple sclerosis have all been reported.
  • Patients with CNS demyelinating disorders, whether pre-existing or new-onset, should be cautious.

• Heart failure:

  • Patients with reduced left ventricular function or heart failure should be cautious.
  • Patients without any known cardiovascular disease have been affected by worsening or new-onset heart problems.
  • According to the American Heart Association's scientific statement, TNF-blockers are agents that can either cause myocardial damage or worsen existing myocardial dysfunction.

• Hematologic disorders

  • Patients with a history if significant hematologic abnormalities should be cautious
  • Rare cases of pancytopenia or aplastic anemia (some fatal) have been reported.
  • Patients should seek medical attention immediately if they experience signs or symptoms that suggest blood dyscrasias. If significant hematologic abnormalities are found, discontinue treatment.

• Hepatitis B:

  • Rare cases of hepatitis B (HBV), have been reported in chronic carriers, often in patients who are taking immunosuppressants. This has led to death.
  • If therapy must be resumed, you should exercise caution and closely monitor your patient.
  • HBV carriers should be monitored for at least three months after stopping treatment. If reactivation occurs, discontinue therapy and get antiviral therapy.

• Infections [US Boxed Warning]

  • Patients who receive etanercept have a higher risk of serious infections that could lead to hospitalization or death. Infections usually develop in patients who are also taking immunosuppressive drugs (eg, methotrexate and corticosteroids). They may also present as disseminated disease (rather than local)
  • Reports of active tuberculosis (including the reactivation or latent tuberculosis), invasive candidiasis (including aspergillosis blastomycosis, candidiasis and pneumocysis), and bacterial, viral or other opportunistic infection (including Legionellosis as well as Listeria) have been made.
  • During and after treatment, be sure to monitor for any signs or symptoms of infection.
  • Stop using if you have a serious infection or sepsis.
  • Before initiating treatment for patients with chronic or persistent infection, consider the risks and benefits.
  • Patients at high risk of invasive fungal infection or who have a severe systemic condition should consider empiric antifungal therapy.
  • Patients with active infections, or a clinically important localized infection, should not be given etanercept therapy.
  • Patients with a new infection that develops during treatment should be closely monitored.
  • Patients with chronic or recurrent infections, elderly patients, patients who have been exposed to tuberculosis, those with a history should be cautious. Also, it is important to exercise caution when using the product in patients who are susceptible to infection (eg, advanced diabetes or poorly controlled diabetes), residents or travelers from areas with endemic mycoses (blastomycosis or coccidioidomycosis), and patients with latent infections.

• Malignancy: [US Boxed Warning]

  • Children and adolescents who have received TNF-blocking drugs, such as etanercept, have had lymphoma and other malignancies (some of them fatal) reported.
  • Half of all malignancies in children and adolescents were lymphomas, both Hodgkin and Non-Hodgkin.
  • Other cases included rare malignancies and immunosuppression that are not common in this population.
  • It is unclear what the impact of etanercept has on malignancy development and progression.
  • Clinical trials have shown that lymphoma is more common in the elderly than in the general population.
  • However, it has previously been found that rheumatoid arthritis alone can be associated with an increase in lymphoma or leukemia rates.
  • Adult patients who received etanercept were also afflicted by lymphomas and other malignancies at higher rates than was expected.
  • There have been reports of Merkel cell carcinoma, non-melanoma skin tumors, and melanoma.
  • All patients undergoing therapy should have periodic skin exams, especially those who are at higher risk for skin cancer.
  • Hepatosplenic T cell lymphoma (HSTCL), which is a rare form of T-cell lymphoma has been linked to TNF-blocking drugs.
  • It's most commonly seen in young adults with Crohn disease and ulcerative colitis.

• Tuberculosis: [US-Boxed Warning]

  • Patients who received etanercept have been diagnosed with active tuberculosis (disseminated and extrapulmonary), as well as reactivation or latent tuberculosis.
  • Evaluate patients for tuberculosis risk factors and latent tuberculosis infection (with a tuberculin skin test) prior to and during therapy.
  • Before using, it is important to start treatment for latent tuberculosis.
  • Patients who have had initial positive tuberculin skin test results should be monitored for tuberculosis throughout and after treatment.
  • Patients who had negative tests before starting therapy may have an active infection. Tests for latent tuberculosis can be falsely negative during etanercept therapy.
  • Patients who have been to areas where tuberculosis has become an epidemic should be cautious.
  • Anti-tuberculosis treatment may be considered if a course of treatment is not possible for patients with a history or risk factors of active or latent tuberculosis.
  • All patients should be monitored for symptoms and signs of tuberculosis.

• Hepatitis A:

  • Patients with severe or moderate alcoholic liver disease should be cautious.
  • Patients treated with etanercept had a lower mortality rate than patients receiving placebo. However, it was significantly lower after six months.

• Seizure disorders:

  • Patients with a history seizures should be cautious.
  • New-onset seizures or an exacerbation have been reported.

• Wegener granulomatosis:

  • Patients with Wegener Granulomatosis should not use it if they are on immunosuppressive therapy. This is because of the higher incidence of solid non-cutaneous malignancies.

Etanercept (including biosimilars of etanercept): Drug Interaction

Monitoring parameters:

• Monitor the improvement of symptoms and physical function assessments.
• Latent TB screening prior to initiating and during therapy;
• signs and symptoms of infection (prior to, during, and following therapy);
• CBC with differential;
• signs/symptoms of worsening of heart failure;
• HBV screening prior to initiating (all patients), HBV carriers (during and for several months following therapy);
• signs and symptoms of hypersensitivity reaction;
• symptoms of the lupus-like syndrome;
• signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).

How to administer etanercept (Enbrel)?

SubQ:

• Administer subcutaneously. Rotate injection sites; may inject into the thigh (preferred), abdomen (avoiding the 2-inch area around the navel), or outer areas of the upper arm.
• New injections should be given at least 1 inch from an old site and never into areas where the skin is bruised, red, tender, or hard; any raised thick, red, or scaly skin patches or lesions; or areas with scars or stretch marks.
• For a more comfortable injection, allow autoinjectors, prefilled syringes, and dose trays to reach room temperature for 15 to 30 minutes (30 minutes or more than 30 minutes for autoinjector) prior to injection; do not remove the needle cover while allowing the product to reach room temperature.
• There may be small white particles of protein in the solution; this is not unusual for proteinaceous solutions.

Note: If the health care provider determines that it is appropriate, patients may self-inject after proper training in injection technique.

Mechanism of action of etanercept (Enbrel):

• Recombinant DNA-derived Protein Etanercept consists of the tumor necrosis factor (TNFR), which is linked to the Fc portion human IgG1.
• Etanercept blocks the interaction of tumor necrosis factor and cell surface receptors by binding to TNF.
• TNF is a key component in the inflammatory process and joint pathology of rheumatoid (RA), polyarticular course juvenile idiopathic (JIA), and ankylosing spondylitis.

The beginning of action:

• 2 to 3-weeks; RA: 1 - 2 weeks
• Maximum Effect: RA: Full effects are usually visible within three months

Absorption:

• SubQ injections are slow to abort

Bioavailability:

• SubQ: 60%

Half-life elimination:

• SubQ: Adolescents >=4 Years and Children (JIA: Mean range 70-94 hours (range 31.2 to 104.8 Hours)
• Adults (RA: 102 + - 30 Hours)

Time to reach peak:

• RA: SubQ 69 +- 34 Hours
• Clearance: Children and adolescents 4-17 years old: 46 mL/hour/m2 Enbrel prescribing Information 1998; Adults: 160 + 80 mL/hour

International Brand Names of Etanercept:

• Enbrel
• Enbrel Mini
• Enbrel SureClick
• Brenzys
• Erelzi
• Infinatam
• Lifmior
• Benepali
• Brenzys
• Enbrol
• Erelzi

Etanercept Brand Names in Pakistan:

Enbrel Injection - Wyeth Pharmaceuticals

• Price in Pakistan: Rs. 100,000/ 4 injections

Momentum Injection - Macter Pharmaceuticals

• Price in Pakistan: Rs. 12075 per single 25 mg vial