ADCETRIS: Uses, Dosage & Side Effects

What Is ADCETRIS and What Is It Used For?

ADCETRIS contains the active substance brentuximab vedotin, which is an innovative type of anticancer medication known as an antibody-drug conjugate (ADC). The ADC technology represents a major advancement in targeted cancer therapy: it combines the specificity of a monoclonal antibody with the potent cell-killing ability of a cytotoxic drug. In the case of ADCETRIS, the monoclonal antibody component is engineered to recognize and bind to CD30, a protein expressed on the surface of certain cancer cells, particularly those found in Hodgkin lymphoma and anaplastic large cell lymphoma.

Once the antibody binds to CD30 on the cancer cell surface, the entire ADC complex is internalized (taken inside the cell). Within the cell, the linker connecting the antibody to the cytotoxic payload is cleaved by lysosomal enzymes, releasing monomethyl auristatin E (MMAE). MMAE is a highly potent antimicrotubule agent that disrupts the microtubule network essential for cell division. By interfering with microtubules, MMAE causes cell cycle arrest at the G2/M phase and ultimately triggers apoptotic cell death. Because the drug is delivered preferentially to CD30-expressing cells, ADCETRIS achieves a higher concentration of the cytotoxic agent at the tumor site while reducing systemic toxicity compared with conventional chemotherapy.

The CD30 protein (also known as TNFRSF8) is a member of the tumor necrosis factor receptor superfamily. It is characteristically expressed on the Reed-Sternberg cells of classical Hodgkin lymphoma and on the malignant cells of systemic anaplastic large cell lymphoma (sALCL). CD30 expression is also found on a subset of cutaneous T-cell lymphomas. Importantly, CD30 expression on normal healthy cells is limited, which makes it an excellent therapeutic target.

ADCETRIS is approved by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and regulatory authorities in numerous other countries for the following indications:

• Previously untreated advanced classical Hodgkin lymphoma (cHL): ADCETRIS is used in combination with chemotherapy as front-line treatment. The approved combinations include ADCETRIS plus doxorubicin, vinblastine, and dacarbazine (A+AVD), and ADCETRIS plus etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD). The landmark ECHELON-1 trial demonstrated superior progression-free survival for A+AVD compared with the historical ABVD regimen.
• Consolidation after autologous stem cell transplantation (ASCT): ADCETRIS is used as a single agent to reduce the risk of relapse in patients with classical Hodgkin lymphoma who have certain risk factors for relapse or disease progression following ASCT. The AETHERA trial showed significant improvement in progression-free survival with ADCETRIS consolidation.
• Relapsed or refractory classical Hodgkin lymphoma: ADCETRIS is used as monotherapy for patients whose disease has returned after ASCT, or who have relapsed after or never responded to at least two prior treatment lines and cannot receive further combination chemotherapy or ASCT.
• Previously untreated systemic anaplastic large cell lymphoma (sALCL): ADCETRIS is given in combination with cyclophosphamide, doxorubicin, and prednisone (A+CHP) as front-line therapy. The ECHELON-2 trial demonstrated significantly improved progression-free survival and overall survival with A+CHP compared with CHOP.
• Relapsed or refractory systemic anaplastic large cell lymphoma (sALCL): ADCETRIS is used as monotherapy for patients with sALCL that has relapsed after or not responded to previous cancer treatment.
• CD30-positive cutaneous T-cell lymphoma (CTCL): ADCETRIS is used for the treatment of CD30-positive CTCL in adult patients who have received at least one prior systemic therapy. The ALCANZA trial demonstrated superior objective response rates and progression-free survival compared with physician’s choice of methotrexate or bexarotene.

Hodgkin lymphoma and non-Hodgkin lymphomas such as sALCL are cancers of the white blood cells (lymphocytes) that form part of the immune system. Classical Hodgkin lymphoma is characterized by the presence of distinctive Reed-Sternberg cells that consistently express CD30. Systemic anaplastic large cell lymphoma is an aggressive subtype of peripheral T-cell lymphoma that may involve lymph nodes and/or other parts of the body. Cutaneous T-cell lymphoma primarily affects the skin and progresses slowly, but advanced disease can be difficult to manage.

What Should You Know Before Receiving ADCETRIS?

Contraindications

There are specific situations in which ADCETRIS must not be used. Understanding these absolute contraindications is essential before treatment begins.

• Hypersensitivity: Do not receive ADCETRIS if you are allergic to brentuximab vedotin or any of the other ingredients in the product (citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, or polysorbat 80).
• Concurrent use with bleomycin: ADCETRIS must not be used together with bleomycin (another anticancer drug). The combination has been associated with an unacceptable risk of severe pulmonary toxicity (lung damage), which can be fatal. This is an absolute contraindication.

Warnings and Precautions

Before and during treatment with ADCETRIS, inform your doctor if any of the following apply to you:

• Pancreatitis: Severe and persistent abdominal pain, with or without nausea and vomiting, may indicate pancreatitis (inflammation of the pancreas), a serious and potentially fatal condition. Report these symptoms immediately.
• Pulmonary toxicity: New or worsening shortness of breath or cough may indicate serious lung complications. Cases of pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS) have been reported, some with fatal outcomes.
• Infections: ADCETRIS treatment may increase your susceptibility to infections. Some infections can be serious, including opportunistic infections caused by viruses (including cytomegalovirus reactivation and JC virus causing PML), bacteria, or fungi. Sepsis and septic shock have also been reported.
• Peripheral neuropathy: Changes in skin sensation, especially in the hands or feet – including numbness, tingling, burning, pain, discomfort, or weakness – are common with ADCETRIS. Your doctor will monitor you and may adjust the dose or delay treatment if neuropathy becomes significant.
• Hematological toxicity: ADCETRIS can cause significant decreases in white blood cells (neutropenia), platelets (thrombocytopenia), and red blood cells (anemia). Regular blood tests are performed to monitor these. Febrile neutropenia (fever with low white blood cell counts) can indicate a serious infection.
• Tumor lysis syndrome (TLS): Rapid destruction of cancer cells may lead to dizziness, decreased urination, confusion, vomiting, nausea, swelling, breathlessness, or heart rhythm disturbances. This is a potentially life-threatening complication.
• Severe skin reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Watch for flu-like symptoms followed by painful red or purple rashes with blistering and widespread skin peeling. DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) may also occur.
• Gastrointestinal complications: New or worsening abdominal pain, nausea, vomiting, or constipation may indicate serious gastrointestinal problems including perforation, obstruction, or colitis, which can be life-threatening.
• Hepatotoxicity: Liver damage has been reported, including elevated liver enzymes and, in rare cases, serious hepatotoxicity. The risk may be higher if you have pre-existing liver disease or are taking other hepatotoxic medications. Liver function will be monitored regularly.
• Hyperglycemia: Fatigue, frequent urination, increased thirst, increased appetite with unintentional weight loss, or irritability may indicate elevated blood sugar levels.
• Infusion-related reactions: These reactions may occur during or within hours after infusion and can include rash, shortness of breath, cough, chest tightness, fever, back pain, chills, headache, nausea, or vomiting. In rare cases, severe anaphylactic reactions may occur. Pre-medication with antihistamines, corticosteroids, or paracetamol may be given if you have previously experienced infusion reactions.
• Extravasation: If you feel burning, pain, or tenderness at or around the infusion site during the infusion, tell your doctor or nurse immediately. Leakage of the drug outside the vein can cause skin redness, pain, discoloration, swelling, blistering, skin peeling, or deep skin infection (cellulitis) in the days or weeks following.
• Kidney or liver impairment: If you have kidney or liver problems, tell your doctor, as dose adjustments may be necessary.

Your doctor will perform regular blood tests and clinical assessments to monitor for these potential complications throughout your treatment.

Other Medications

Tell your doctor about all medications you are currently taking or have recently taken, including herbal supplements and over-the-counter products. ADCETRIS can interact with other drugs, particularly those metabolized by or affecting the CYP3A4 enzyme system, which is involved in the breakdown of MMAE, the cytotoxic component released from brentuximab vedotin.

Pregnancy and Breastfeeding

ADCETRIS should not be used during pregnancy unless the potential clinical benefit clearly outweighs the risk to the unborn child. Animal studies have shown that MMAE, the cytotoxic payload released from brentuximab vedotin, has teratogenic properties (can cause birth defects) and is embryotoxic (can harm the developing embryo). Both the patient and their partner must use two effective methods of contraception during treatment. Women must continue contraception for at least 6 months after the last dose of ADCETRIS.

It is important to tell your doctor before and during treatment if you are pregnant, think you may be pregnant, or are planning to become pregnant. If you become pregnant during treatment, your doctor will discuss the risks and benefits of continuing therapy.

It is not known whether brentuximab vedotin or its metabolites are excreted in human breast milk. A risk to the breastfed infant cannot be excluded. If you are breastfeeding, discuss with your doctor whether you should receive ADCETRIS.

Men being treated with ADCETRIS are advised to have sperm samples cryopreserved (frozen) before starting treatment, as the drug may affect fertility. Men should not father a child during treatment or for 6 months after the last dose.

Driving and Operating Machinery

ADCETRIS may affect your ability to drive or operate machinery. If you experience side effects such as dizziness, fatigue, or blurred vision during treatment, do not drive or use machines until these symptoms have resolved. Discuss with your doctor if you have any concerns about your ability to perform these activities safely.

Important Information About Ingredients

Each vial of ADCETRIS contains 13.2 mg of sodium (the main component of table salt), which corresponds to approximately 0.7% of the WHO-recommended maximum daily dietary sodium intake for adults. This should be taken into consideration if you are on a sodium-restricted diet.

ADCETRIS also contains polysorbate 80 (2.0 mg per vial, equivalent to 0.2 mg/mL after reconstitution). Polysorbates can cause allergic reactions in some individuals. Inform your doctor if you have any known allergies to polysorbate.

How Does ADCETRIS Interact with Other Drugs?

Drug interactions with ADCETRIS primarily involve the cytotoxic payload MMAE, which is metabolized by the CYP3A4 enzyme system after release from the antibody-drug conjugate. Medications that inhibit or induce CYP3A4 can therefore alter the levels of MMAE in the body, potentially affecting both efficacy and toxicity. It is essential to inform your doctor about all medications, supplements, and herbal products you are taking.

Major Interactions

Minor Interactions

ADCETRIS is often used in combination with established chemotherapy regimens. When given with doxorubicin, vinblastine, and dacarbazine (A+AVD) or with cyclophosphamide, doxorubicin, and prednisone (A+CHP), the safety profiles of the individual agents should also be considered. Your oncologist will carefully plan your treatment to minimize the risk of cumulative toxicities.

What Is the Correct Dosage of ADCETRIS?

ADCETRIS is always administered by a doctor or nurse as an intravenous infusion over 30 minutes. You will be monitored during and after each infusion. The dose is calculated individually based on your body weight. Your doctor will determine the appropriate dosing schedule and duration based on your specific condition and treatment regimen.

Combination Therapy Dosing

Monotherapy Dosing

Dose Adjustments

Your doctor may need to adjust your dose in the following situations:

• Kidney impairment: If you have kidney problems, your doctor may reduce the starting dose to 1.2 mg/kg.
• Liver impairment: If you have liver problems, the starting dose may be reduced to 1.2 mg/kg. ADCETRIS should be avoided in patients with severe hepatic impairment.
• Peripheral neuropathy: If you develop new or worsening neuropathy, your doctor may delay treatment, reduce the dose (e.g., to 1.2 mg/kg), or discontinue ADCETRIS depending on severity.
• Neutropenia: If your white blood cell counts drop significantly, treatment may be delayed until counts recover. Growth factor support may be added.
• Body weight: For patients weighing more than 100 kg, the dose is calculated based on 100 kg (maximum dose of 180 mg for 1.8 mg/kg dosing or 120 mg for 1.2 mg/kg dosing).

Children

ADCETRIS is intended for use in adult patients only. The safety and efficacy of brentuximab vedotin in children and adolescents below 18 years of age have not been established, and it is not recommended for use in this population outside of clinical trials.

How ADCETRIS Is Given

ADCETRIS is supplied as a white to off-white powder (lyophilized cake) in a glass vial. Before administration, the powder must be reconstituted with water for injection and then further diluted in an infusion bag containing sodium chloride 0.9% solution (normal saline), glucose 5% solution, or Ringer-lactate solution. The final infusion concentration should be 0.4–1.2 mg/mL, and the recommended dilution volume is 150 mL.

The prepared infusion is given intravenously over 30 minutes. You should not receive ADCETRIS as an intravenous push or bolus injection. Your doctor or nurse will monitor you during and after each infusion for signs of infusion-related reactions or other adverse effects. The reconstituted and diluted solution should be used immediately or stored in a refrigerator (2–8°C) and used within 24 hours.

What Are the Side Effects of ADCETRIS?

Like all medicines, ADCETRIS can cause side effects, although not everyone gets them. The side effect profile differs depending on whether ADCETRIS is given as a single agent or in combination with chemotherapy. Your medical team will monitor you closely and manage side effects as they arise.

Infusion-Related Reactions

As a monoclonal antibody-based therapy, ADCETRIS can cause infusion-related reactions, which occur in more than 1 in 10 patients. Symptoms may include rash, shortness of breath, difficulty breathing, cough, chest tightness, fever, back pain, chills, headache, nausea, or vomiting. These reactions typically occur within minutes to several hours after infusion completion. In rare cases, they can be severe or life-threatening (anaphylaxis). If you have previously experienced infusion reactions, you may receive pre-medications such as antihistamines, corticosteroids, or paracetamol before your next infusion.

Side Effects When ADCETRIS Is Given as a Single Agent

Additional Side Effects When Given with Chemotherapy

When ADCETRIS is administered in combination with chemotherapy (such as A+AVD or A+CHP), the side effect profile broadens due to the additive effects of the chemotherapy agents. The following additional or more frequent side effects have been reported:

If you experience any side effects, including those not listed here, tell your doctor or nurse. You can also report suspected side effects to your national pharmacovigilance authority (e.g., the EMA in Europe, the FDA MedWatch program in the United States, or the MHRA Yellow Card Scheme in the United Kingdom) to help monitor the ongoing benefit-risk profile of ADCETRIS.

How Should ADCETRIS Be Stored?

Keep this medicine out of the sight and reach of children. Do not use after the expiry date stated on the vial label and outer carton after EXP. The expiry date refers to the last day of that month.

• Unopened vials: Store in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze.
• Light protection: Keep the vial in the outer carton to protect from light.
• Reconstituted/diluted solution: Should be used immediately. If not used immediately, the solution may be stored at 2°C to 8°C and used within 24 hours from the time of reconstitution.
• Inspection: Do not use if you observe any particles or discoloration before administration.

As ADCETRIS is prepared and administered in a hospital or clinic, storage will be handled by your healthcare team and pharmacy. Do not dispose of any medicines via wastewater or household waste. The doctor or nurse will ensure proper disposal of unused medicine to protect the environment.

What Does ADCETRIS Contain?

Active Substance

The active substance is brentuximab vedotin. Each single-use vial contains 50 mg of brentuximab vedotin. Due to a 10% overfill, each vial actually contains 55 mg to ensure the labeled 50 mg can be withdrawn. After reconstitution with 10.5 mL of sterile water for injection, the concentration is 5 mg/mL with a total recoverable volume of 11 mL.

Inactive Ingredients (Excipients)

• Citric acid monohydrate (E330)
• Sodium citrate dihydrate (E331)
• α,α-Trehalose dihydrate
• Polysorbate 80 (E433)

Appearance

ADCETRIS is a white to off-white cake or powder supplied in a glass vial. After reconstitution, the solution is a clear to slightly opalescent, colorless liquid with a final pH of 6.6. Each package contains one single-use vial.

Manufacturer

ADCETRIS is marketed by Takeda. The manufacturing site is Takeda Austria GmbH, Linz, Austria. The marketing authorization holder is Takeda Pharma A/S, Vallensbaek Strand, Denmark.