Benepali (Etanercept): Uses, Dosage & Side Effects

What Is Benepali and What Is It Used For?

Benepali is a prescription biologic medicine manufactured by Samsung Bioepis and approved by the European Medicines Agency (EMA) as a biosimilar to the reference product Enbrel. It contains the active substance etanercept, a recombinant human tumour necrosis factor receptor fusion protein produced using Chinese hamster ovary (CHO) cell expression technology. The medication belongs to a class of drugs known as TNF inhibitors or anti-TNF agents, which are part of the broader category of biologic disease-modifying antirheumatic drugs (bDMARDs).

Etanercept works by a unique mechanism compared to other TNF inhibitors. It is a soluble receptor that mimics the naturally occurring TNF receptor found on cell surfaces. The protein consists of the extracellular ligand-binding domain of the human p75 (75 kilodalton) TNF receptor (TNFR2) fused to the Fc domain of human immunoglobulin G1 (IgG1). This structure allows it to competitively bind to both TNF-alpha and TNF-beta (lymphotoxin-alpha) in the bloodstream, effectively acting as a molecular sponge that prevents these pro-inflammatory cytokines from interacting with their cell surface receptors and triggering the downstream inflammatory cascade.

By neutralizing TNF activity, Benepali reduces the levels of matrix metalloproteinases (enzymes that degrade cartilage and bone), adhesion molecules (which attract inflammatory cells to joints), and other pro-inflammatory mediators including interleukin-1 (IL-1) and interleukin-6 (IL-6). This leads to a reduction in joint inflammation, slowing of structural joint damage, improvement in physical function, and clearing of skin lesions in psoriasis.

Approved Indications in Adults

In adults aged 18 years and older, Benepali is approved for the following conditions:

• Moderate to severe rheumatoid arthritis (RA): In combination with methotrexate when the response to disease-modifying antirheumatic drugs (DMARDs) including methotrexate alone has been inadequate. It can also be used as monotherapy when methotrexate is inappropriate. Etanercept has been shown to slow the progression of structural joint damage and improve physical function in RA, as demonstrated in landmark clinical trials such as the TEMPO study.
• Psoriatic arthritis: For active and progressive disease when the response to previous DMARD therapy has been inadequate. Benepali can improve both joint symptoms and skin manifestations in patients with multiple swollen and tender joints.
• Severe axial spondyloarthritis, including ankylosing spondylitis (AS): For adults with severe active disease who have had an inadequate response to conventional therapy. It reduces inflammation in the spine and sacroiliac joints, relieving pain and improving mobility.
• Moderate to severe plaque psoriasis: For adults who have failed to respond to, have a contraindication to, or are intolerant of other systemic therapies including ciclosporin, methotrexate, or phototherapy. Treatment typically begins with 50 mg twice weekly for up to 12 weeks, followed by 50 mg once weekly for maintenance.

Approved Indications in Children and Adolescents

Benepali is also approved for use in certain pediatric populations, although the specific age and weight requirements vary by indication. Etanercept formulations with appropriate dosage forms are available for children who meet these criteria:

• Juvenile idiopathic arthritis (JIA): Including polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis in patients from 2 years of age weighing 62.5 kg or more, when methotrexate has been inadequate or is not tolerated. Also for psoriatic arthritis and enthesitis-related arthritis in patients from 12 years of age weighing 62.5 kg or more.
• Severe plaque psoriasis: In children from 6 years of age weighing 62.5 kg or more who have had an inadequate response to phototherapy or other systemic therapies, or in whom these treatments are not appropriate.

Benepali is typically prescribed when other commonly used treatments have not worked well enough or are unsuitable for the patient. For rheumatoid arthritis specifically, it is most commonly used in combination with methotrexate, although it can be used alone if methotrexate treatment is inappropriate. Whether used as monotherapy or in combination, etanercept has consistently demonstrated its ability to slow joint damage progression and improve patients' quality of life.

What Should You Know Before Using Benepali?

Contraindications

There are absolute situations where Benepali must not be used. You should not use Benepali under the following circumstances:

• Allergy to etanercept: If you are allergic to etanercept or any of the other ingredients in Benepali (including sucrose, sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate heptahydrate, and water for injections). If you experience allergic reactions such as difficulty breathing, wheezing, dizziness, or skin rash, stop injecting and contact your doctor immediately.
• Active infection: If you have an infection of any kind, including localized infections. Treatment should not be started until the infection has fully resolved.
• Sepsis or risk of sepsis: If you have or are at risk of developing a serious bloodstream infection (sepsis). If you are unsure, consult your doctor.

Warnings and Precautions

Before and during treatment with Benepali, your doctor needs to be informed about various conditions and situations that may affect the safety of your therapy. The following precautions are essential:

• Tuberculosis (TB): All patients must be screened for tuberculosis before starting Benepali. This typically includes a detailed medical history, chest X-ray, and a tuberculin skin test or interferon-gamma release assay (IGRA). If latent TB is detected, anti-TB treatment must be completed before starting Benepali. Patients should remain vigilant for TB symptoms (persistent cough, weight loss, low-grade fever, night sweats) throughout treatment and report them immediately.
• Hepatitis B: Tell your doctor if you have or have ever had hepatitis B. Screening for hepatitis B should be performed before starting treatment, as Benepali can cause reactivation of hepatitis B virus in patients who were previously infected. If reactivation occurs, Benepali should be discontinued.
• Hepatitis C: Tell your doctor if you have hepatitis C. Your doctor may want to monitor your treatment if the infection worsens.
• Blood disorders: Seek immediate medical help if you develop persistent fever, sore throat, bruising, bleeding, or pallor. These symptoms may indicate a potentially life-threatening blood disorder (pancytopenia, aplastic anemia) that may require discontinuation of Benepali.
• Nervous system and eye disorders: Tell your doctor if you have multiple sclerosis, optic neuritis (inflammation of the optic nerve), or transverse myelitis (inflammation of the spinal cord). TNF inhibitors have been associated with demyelinating disorders, and your doctor will determine whether Benepali is the appropriate treatment.
• Heart failure: Tell your doctor if you have a history of congestive heart failure, as Benepali must be used with caution in these patients. TNF inhibitors may worsen heart failure, and new-onset heart failure has been reported.
• Cancer: Inform your doctor if you have or have ever had lymphoma or any other type of cancer. Patients with long-standing severe rheumatoid arthritis may have a higher-than-average risk of developing lymphoma. Some children and adolescents who have received etanercept or similar TNF-blocking agents have developed cancers, including rare types that sometimes resulted in death. Patients should also report any new skin changes or growths to their doctor.
• Chickenpox exposure: Tell your doctor if you have been exposed to chickenpox during treatment. Your doctor will determine whether preventive treatment for chickenpox is needed.
• Granulomatosis with polyangiitis (Wegener's): Benepali is not recommended for the treatment of this rare inflammatory disease.
• Diabetes medications: If you have diabetes or take diabetes medications, your doctor may need to reduce your diabetes medication dose during Benepali treatment, as TNF inhibition can affect blood glucose levels.
• Alcohol-related hepatitis: Benepali should not be used for the treatment of hepatitis related to alcohol misuse.

Pregnancy and Breastfeeding

If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your doctor before using Benepali. Women of childbearing potential should be advised to use appropriate contraception to avoid becoming pregnant during treatment and for at least 3 weeks after the last dose.

Benepali should only be used during pregnancy if clearly necessary, as determined by your doctor. Etanercept crosses the placenta, meaning it can reach the developing baby and potentially affect their immune system. In one study, more birth defects were found when the mother had received etanercept during pregnancy compared to mothers who had not received etanercept or other similar medicines (TNF antagonists), although no specific type of birth defect was reported. Another study showed no increased risk of birth defects when the mother received etanercept during pregnancy.

If you received Benepali during pregnancy, your baby may have a higher risk of getting an infection. It is important to tell your baby's doctors and other healthcare professionals about your use of Benepali before the baby receives any vaccine. Breastfeeding mothers should consult their doctor before breastfeeding during treatment, as etanercept is excreted in breast milk in small amounts.

Driving and Operating Machinery

There is no evidence that etanercept affects the ability to drive or use machines. However, patients should consider their overall health status, including fatigue (a common symptom of the underlying autoimmune conditions being treated), when assessing their fitness to drive.

How Does Benepali Interact with Other Drugs?

While Benepali has a relatively specific mechanism of action, it can interact with several other medications in clinically important ways. Because Benepali modulates the immune system, particular caution is needed with other immunomodulatory agents and vaccines. Always inform your doctor, pharmacist, or nurse about all medications, herbal remedies, and supplements you are taking or plan to take.

Major Interactions

Common Combinations and Monitoring

It is important to note that Benepali should not be used in combination with other biologic DMARDs (such as adalimumab, infliximab, certolizumab, golimumab, rituximab, or tocilizumab), as the risk of serious infections increases substantially without additional therapeutic benefit. When switching between biologic agents, an appropriate washout period should be observed as determined by your rheumatologist.

What Is the Correct Dosage of Benepali?

Benepali should always be used exactly as your doctor has prescribed. The dose and frequency of administration depend on the condition being treated, the patient's age, and body weight. Treatment should be initiated and supervised by a specialist physician experienced in the diagnosis and treatment of the relevant conditions.

Adults (18 years and older)

Children and Adolescents

Missed Dose

If you forget a dose, inject it as soon as you remember, unless your next scheduled dose is due the following day, in which case skip the missed dose entirely. Continue to inject the medicine on the usual scheduled day. If you do not remember the missed dose until the day the next injection is normally due, do not take a double dose (two doses on the same day) to make up for the forgotten dose.

Overdose

If you have injected more Benepali than prescribed (either by injecting too much at one time or by using it too frequently), contact your doctor or pharmacist immediately. Always bring the labeled outer carton of the medicine with you, even if it is empty. There is no known specific antidote for etanercept overdose. Treatment of overdose should consist of general supportive measures and monitoring for signs of adverse effects.

Stopping Treatment

Do not stop using Benepali without first discussing it with your doctor, as your symptoms may return if treatment is stopped. If you and your doctor decide to stop Benepali, your doctor may monitor you for a period afterward and may recommend restarting treatment if your symptoms flare.

What Are the Side Effects of Benepali?

Like all medicines, Benepali can cause side effects, although not everybody gets them. It is important to be aware of both common and serious side effects so you can seek appropriate medical attention when needed. Most injection site reactions diminish after the first month of treatment.

Side Effects in Children and Adolescents

The side effects observed in children and adolescents are similar in type and frequency to those described above for adults. Parents and caregivers should monitor for signs of infection, injection site reactions, and any unusual symptoms, and report them to the child's doctor promptly.

How Should You Store Benepali?

Proper storage of Benepali is essential to maintain the effectiveness and safety of the medication. Follow these guidelines carefully:

• Refrigeration: Store in a refrigerator at 2°C to 8°C (36°F to 46°F). Keep the pre-filled pens in the outer carton to protect them from light.
• Do not freeze: Never freeze Benepali. If the medicine has been accidentally frozen, it must be discarded.
• Before injection: Remove the pre-filled pen from the refrigerator approximately 30 minutes before injection to allow it to reach room temperature. Do not use external heat sources such as a microwave or warm water to speed up the warming process.
• Room temperature storage: Benepali can be stored outside the refrigerator at temperatures up to 30°C (86°F) for a single period of up to 31 days. Once removed from the refrigerator for room temperature storage, it should not be returned to the refrigerator. If not used within 31 days of removal from the refrigerator, the medicine must be discarded. Record the date you remove Benepali from the refrigerator.
• Visual inspection: Before each injection, inspect the solution through the transparent inspection window of the pen. The solution should be clear to slightly opalescent, colourless to pale yellow, and may contain small white or nearly transparent protein particles. This appearance is normal. Do not use the medicine if the solution is discoloured, cloudy, or contains particles other than those described.
• Expiry date: Do not use Benepali after the expiry date printed on the carton and pen label (EXP). The expiry date refers to the last day of that month.
• Damaged pens: Do not use a pre-filled pen that has been dropped on a hard surface, as internal components may be broken. Do not use the pen if the needle shield is missing or not securely attached.

Keep this medicine out of the sight and reach of children. Do not dispose of medicines in wastewater or household waste. Ask your pharmacist how to properly dispose of used pens and medicines that are no longer needed, as these measures help protect the environment.

What Does Benepali Contain?

Active Substance

The active substance is etanercept. Each Benepali pre-filled pen contains 50 mg of etanercept in 1 ml of solution for injection. Etanercept is a recombinant human tumour necrosis factor receptor p75 Fc fusion protein produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. Each molecule consists of 934 amino acids with a molecular weight of approximately 150 kilodaltons.

Other Ingredients (Excipients)

• Sucrose (a sugar used as a stabilizer)
• Sodium chloride (table salt)
• Sodium dihydrogen phosphate monohydrate (a buffer)
• Disodium hydrogen phosphate heptahydrate (a buffer)
• Water for injections

Appearance and Packaging

Benepali is supplied as a clear to slightly opalescent, colourless to pale yellow solution for injection in a pre-filled pen. The pens are available in packs containing 4 pre-filled pens, and in multipacks containing 3 cartons of 4 pre-filled pens each (12 pens total). Not all pack sizes may be marketed in every country. Benepali is manufactured by Samsung Bioepis NL B.V. (Delft, Netherlands) and Biogen Netherlands B.V. (Badhoevedorp, Netherlands).

How Do You Inject Benepali?

Read the instructions for use carefully before you start using Benepali. Do not attempt self-injection unless your doctor or nurse has shown you how to do it properly. The following steps describe the general procedure for using the Benepali pre-filled pen:

Preparation

1. Gather your supplies: A new Benepali pre-filled pen, an alcohol swab, a cotton ball or gauze pad, an adhesive bandage if needed, and a sharps disposal container.
2. Check the pen: Verify the expiry date on the label. Do not use the pen after the expiry date, if it has been dropped, or if the needle shield is missing or loose.
3. Inspect the solution: Look through the inspection window. The liquid should be clear to slightly opalescent, colourless to pale yellow. Small protein particles are normal. Do not use if discoloured, cloudy, or containing unusual particles.
4. Allow to reach room temperature: Remove the pen from the refrigerator and wait approximately 30 minutes. Do not remove the needle cap until you are ready to inject. Do not use heat sources to warm the pen.

Choosing an Injection Site

Suitable injection sites include the front of the thighs, the abdomen (at least 5 cm from the navel), or the back of the upper arms. Rotate the injection site each time. Do not inject into areas that are red, hard, bruised, or tender. Do not inject into scar tissue or stretch marks. If you have psoriasis, avoid injecting into raised, thickened, red, or scaly skin patches or lesions.

Performing the Injection

1. Wash your hands thoroughly with soap and water.
2. Clean the injection site with an alcohol swab and allow it to air dry completely. Do not touch the cleaned area again before injecting.
3. Remove the needle cap by pulling it straight off. Dispose of it in the sharps container. Do not twist, bend, or re-cap the needle.
4. Gently stretch the skin at the cleaned injection site to create a firm surface. Do not pinch the skin.
5. Press the pen firmly against the skin at approximately a 90-degree angle to start the injection. You will hear a first click when the injection begins.
6. Continue holding the pen pressed against the skin. A second click will be heard. After the second click, count slowly to 15 to ensure the injection is complete.
7. Remove the pen from the skin. The needle guard will automatically cover the needle. Look for the yellow plunger rod in the inspection window to confirm that the full dose has been delivered.

After Injection

If there is bleeding at the injection site, press a cotton ball or gauze pad over the area. Do not rub the injection site. Cover with an adhesive bandage if needed. Dispose of the entire used pen in an approved sharps disposal container. Do not recycle the container or throw it in household waste. Keep the sharps container out of the reach of children.