Adcetris

Brentuximab vedotin is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Brentuximab vedotin is used to treat Hodgkin's lymphoma or anaplastic large cell lymphoma.

Brentuximab vedotin is given after a stem cell transplant or other cancer medications have been tried without successful treatment.

Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) on an "accelerated" basis. In clinical studies, brentuximab vedotin produced complete or partial remission in many people. However, further studies are needed to determine if this medicine can lengthen survival time.

Brentuximab vedotin may also be used for purposes not listed in this medication guide.

You should not receive brentuximab vedotin if you are also receiving another cancer medicine called bleomycin (Blenoxane).

Brentuximab vedotin may cause a serious viral infection of the brain that can lead to disability or death. Call your doctor right away if you have any change in your mental state, decreased vision, weakness on one side of your body, or problems with speech or walking. These symptoms may start gradually and get worse quickly.

You should not receive brentuximab vedotin if you are allergic to it, or:

• if you are also receiving another cancer medicine called bleomycin (Blenoxane).

To make sure brentuximab vedotin is safe for you, tell your doctor if you have:

• liver disease;
• kidney disease; or
• peripheral vascular disease such as Raynaud's syndrome.

Do not receive brentuximab vedotin if you are pregnant. It could harm the unborn baby. Use effective birth control to avoid pregnancy during your treatment with brentuximab vedotin. Follow your doctor's instructions about how long to prevent pregnancy after your treatment ends.

It is not known whether brentuximab vedotin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using brentuximab vedotin.

Before receiving brentuximab vedotin injection,

• tell your doctor and pharmacist if you are allergic to brentuximab vedotin, any other medications, or any of the ingredients in brentuximab vedotin injection. Ask your pharmacist for a list of the ingredients.
• tell your doctor if you are receiving bleomycin (Blenoxane). Your doctor will probably tell you not to use brentuximab vedotin injection if you are receiving this medication.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: clarithromycin (Biaxin, in PrevPac), indinavir (Crixivan), itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone, nelfinavir (Viracept), rifampin (Rifadin, in Rifamate, in Rifater, Rimactane), and ritonavir (Norvir, in Kaletra). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while receiving brentuximab vedotin injection, call your doctor. Brentuximab vedotin injection may harm the fetus.

You should not receive brentuximab vedotin if you are also receiving another cancer medicine called bleomycin (Blenoxane).

Brentuximab vedotin may cause a serious viral infection of the brain that can lead to disability or death. Call your doctor right away if you have any change in your mental state, decreased vision, weakness on one side of your body, or problems with speech or walking. These symptoms may start gradually and get worse quickly.

You should not receive brentuximab vedotin if you are allergic to it, or:

• if you are also receiving another cancer medicine called bleomycin (Blenoxane).

To make sure brentuximab vedotin is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease; or

• peripheral vascular disease such as Raynaud's syndrome.

Brentuximab vedotin can harm an unborn baby. Use birth control to prevent pregnancy while you are using this medicine, whether you are a man or a woman. Brentuximab vedotin use by either parent may cause birth defects.

If you are a woman, do not use brentuximab vedotin if you are pregnant. Use effective birth control while using this medicine and for at least 6 months after your last dose.

If you are a man, use effective birth control if your sexual partner is able to get pregnant. An unborn baby can be harmed if a man fathers the child while he is using brentuximab vedotin. Keep using birth control for at least 6 months after your last dose.

Tell your doctor right away if a pregnancy occurs while either the mother or the father is using brentuximab vedotin.

It is not known whether brentuximab vedotin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using brentuximab vedotin.

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, nauseated, chilled or feverish, or if you have itching or trouble breathing. Infusion reactions often occur within the first 24 hours after the start of your brentuximab vedotin infusion.

Get emergency medical help if you have signs of an allergic reaction: hives; wheezing, chest tightness, trouble breathing; swelling of your face, lips, tongue, or throat.

Brentuximab vedotin may cause a serious viral infection of the brain that can lead to disability or death. Call your doctor right away if you have any change in your mental state, decreased vision, weakness on one side of your body, or problems with speech or walking. These symptoms may start gradually and get worse quickly.

Also call your doctor at once if you have any of these other side effects, even if they occur several months after you receive brentuximab vedotin, or after your treatment ends.

• numbness, weakness, burning pain, tingly feeling, or loss of feeling in your arms or legs;

• sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath;

• low red blood cells (anemia)--pale skin, easy bruising or bleeding, feeling light-headed or short of breath, trouble concentrating;

• signs of infection--fever, chills, mouth or throat pain, skin sores, cough, pain or burning when you urinate;

• signs of tumor cell breakdown--lower back pain, blood in your urine, little or no urinating; numbness or tingly feeling around your mouth; muscle weakness or tightness; fast or slow heart rate, weak pulse, confusion, fainting;

• liver or pancreas problems--severe pain in your upper stomach (may spread to your back), nausea and vomiting, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• stomach problems--severe constipation, new or worsening stomach pain, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• fever, infections, easy bruising or bleeding;

• cold symptoms such as stuffy nose, sneezing, sore throat;

• numbness or tingling;

• nausea, vomiting, diarrhea;

• feeling tired;

• cough; or

• skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General

• Monitor CBC prior to each dose; consider more frequent monitoring in patients with grade 3 or 4 neutropenia.1

• If the patient has experienced an infusion-related reaction to the drug, administer a premedication regimen (e.g., corticosteroid, antihistamine, and acetaminophen) prior to each subsequent dose.1 (See Sensitivity Reactions under Cautions.)

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Brentuximab vedotin powder for injection must be reconstituted and diluted prior to administration.1 Use within 24 hours following reconstitution.1 (See Storage under Stability.)

Do not mix with any other drug or administer any other drug simultaneously in the same IV line.1

Reconstitute vial containing 50 mg of brentuximab vedotin with 10.5 mL of sterile water for injection to provide a solution containing 5 mg/mL; direct diluent toward the wall of the vial.1 Gently swirl vial to ensure dissolution.1 Do not shake reconstituted solution.1

Reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates.1

Dilute appropriate dose in a minimum volume of 100 mL of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection to yield a final concentration of 0.4–1.8 mg/mL.1 Mix the diluted solution by gentle inversion.1 Discard any partially used vial.1

Administer by IV infusion over 30 minutes.1

Dosage

Adults

1.8 mg/kg every 3 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Body weight ≤100 kg: Calculate dosage based on actual body weight.19

Body weight >100 kg: Calculate dosage based on 100 kg.1

1.8 mg/kg every 3 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Body weight ≤100 kg: Calculate dosage based on actual body weight.19

Body weight >100 kg: Calculate dosage based on 100 kg.1

If grade 2 or 3 peripheral neuropathy occurs, interrupt therapy until toxicity resolves to grade 1 or to baseline; resume therapy at reduced dosage of 1.2 mg/kg every 3 weeks.1 (See Peripheral Neuropathy under Cautions.)

If grade 4 peripheral neuropathy occurs, discontinue drug.1

If grade 3 or 4 neutropenia occurs, interrupt therapy until neutropenia resolves to grade 2 or less or to baseline; upon resumption of therapy, consider use of a granulocyte colony-stimulating factor (G-CSF) for subsequent cycles.1 20

If grade 4 neutropenia recurs despite use of a G-CSF, consider drug discontinuance or dosage reduction (i.e., reduced dosage of 1.2 mg/kg every 3 weeks).1 (See Hematologic Effects under Cautions.)

Special Populations

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C, respectively): 1.2 mg/kg every 3 weeks.1 Monitor for adverse effects.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Severe renal impairment (Clcr <30 mL/minute): 1.2 mg/kg every 3 weeks.1 Monitor for adverse effects.1 (See Renal Impairment under Cautions.)

Mild to moderate renal impairment: No specific dosage recommendations.1

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Absorption

Bioavailability

Brentuximab vedotin is an anti-CD30 antibody conjugated with the tubulin inhibitor MMAE; MMAE is released via proteolytic cleavage of the dipeptide bond.1 3 4 5 10 Peak plasma concentrations of MMAE are attained approximately 1–3 days after IV administration of brentuximab vedotin.1 5 10

AUCs of the antibody-drug conjugate and free MMAE are dose proportional over the brentuximab vedotin single-dose range of 1.2–2.7 mg/kg; minimal systemic accumulation when administered every 3 weeks.1 5 10 11 12 22

Special Populations

In patients with hepatic impairment (Child-Pugh class A, B, or C), systemic exposure of MMAE is increased 2.3-fold compared with individuals with normal hepatic function.1

In patients with severe renal impairment (Clcr <30 mL/minute), systemic exposure of MMAE is increased 1.9-fold compared with individuals with normal renal function.1

Distribution

Extent

Not known whether brentuximab vedotin is distributed into milk.1

Plasma Protein Binding

68–82%.1

Elimination

Metabolism

Small fraction of free MMAE is metabolized in the liver, primarily via oxidation by CYP3A4/5.1

Elimination Route

Following brentuximab vedotin administration, approximately 24% of the total administered dose of MMAE is excreted over 1 week in feces (72%) and to a lesser extent in urine, mainly as unchanged drug.1

Half-life

Antibody-drug conjugate: 4–6 days.1 5 10

MMAE: 3–4 days.5 10 Elimination of MMAE apparently is limited by rate of release from the antibody-drug conjugate.1

Special Populations

Gender, race, and age do not have meaningful effects on pharmacokinetics of brentuximab vedotin.1

• Brentuximab vedotin is an anti-CD30 antibody (a chimeric human-murine IgG1) conjugated via dipeptide bond with the microtubule inhibitor monomethyl auristatin E (MMAE).1 3 4 5 10 Average of 4 MMAE molecules attached to each antibody molecule.1 4 10

• The antibody-drug conjugate binds to antigen CD30 on the surface of CD30-expressing cells, the resultant complex is taken up by the cell, and MMAE is released via proteolytic cleavage.1 4 5 10 MMAE then binds to tubulin, disrupting microtubule activity and resulting in cell cycle arrest and apoptosis.1 3 4 5 10

Before receiving this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

You will receive this medicine in a hospital or cancer treatment center. A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins.

You may also receive medicines (eg, acetaminophen, antihistamines, steroids) to help prevent possible allergic reactions to the injection.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Swollen gland.
• Very bad dizziness or passing out.
• Feeling very tired or weak.
• Chest pain or pressure.
• Coughing up blood.
• A burning, numbness, or tingling feeling that is not normal.
• Muscle pain or weakness.
• Swelling in the arms or legs.
• Any unexplained bruising or bleeding.
• A very bad skin reaction (Stevens-Johnson syndrome/toxic epidermal necrolysis) may happen. It can cause very bad health problems that may not go away, and sometimes death. Get medical help right away if you have signs like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in your mouth, throat, nose, or eyes.
• Very bad and sometimes deadly stomach or bowel problems like bleeding, blockage, holes or tears, ulcers, and swelling have happened with this medicine. Call your doctor right away if you have fever or chills; black, tarry, or bloody stools; very bad constipation, diarrhea, or stomach pain; swelling of the stomach; or throwing up blood or throw up that looks like coffee grounds.

• If you need to store this medicine (Adcetris) at home, talk with your doctor, nurse, or pharmacist about how to store it.

IV Incompatibilities

Do not mix or administer with other medicinal products

IV Compatibilities

0.9% NaCl

Dextrose 5%

Lactated Ringer’s

IV Preparation

Adhere to procedures for proper handling, dispensing, and administration of anticancer drugs

Reconstitution

• Reconstitute each 50 mg vial of lyophilized powder with 10.5 mL sterile water for injection to yield 5 mg/mL
• Direct stream toward vial wall and not directly at cake or powder to prevent foaming
• Do not shake vial; gently swirl the vial to aid dissolution
• Reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates
• Following reconstitution, dilute immediately into infusion bag, or store solution at 2-8 degrees C (36-46 degrees F) and use within 24 hours of reconstitution; do not freeze

Dilution

• Calculate dosage volume (mL) and withdraw dose from vial(s)
• The dose for patients weighing >100 kg should be calculated for 100 kg
• Dilute reconstituted solution in at least 100 mL (NS, D5W, LR) to final concentration range of 0.4-1.8 mg/mL
• Gently invert bag to mix solution
• Contains no bacteriostatic preservatives, use immediately or refrigerate solution and use within 24 hours

IV Administration

Administer diluted solution IV over 30 minutes

Do not administer as an IV push or bolus

Storage

Store unopened vials in refrigerator at 2-8 degrees C (36-46 degrees F) in the original carton to protect from light

May refrigerate reconstituted or diluted solution if administered within 24 hr

Do not freeze

You should not receive brentuximab vedotin if you are allergic to it, or if you are also receiving another cancer medicine called bleomycin (Blenoxane).

Some people receiving a brentuximab vedotin injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel nauseated, itchy, or if you have a fever, chills, cough, or trouble breathing during the injection. Infusion reactions often occur within the first 24 hours after the start of your brentuximab vedotin infusion.

Brentuximab vedotin can lower blood cells that help your body fight infections and help your blood clot. Your blood may need to be tested often. Avoid being near people who are sick or have infections. Avoid activities that may increase your risk of bleeding injury. Tell your doctor at once if you develop signs of infection.

While using brentuximab vedotin, you may need frequent blood tests at your doctor's office.

Brentuximab vedotin may cause a serious viral infection of the brain that can lead to disability or death. Call your doctor right away if you notice any change in your mental state, problems with speech or walking, or decreased vision. These symptoms may start gradually and get worse quickly.

Call your doctor if you miss an appointment for your brentuximab vedotin injection.

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comment: -A risk to the nursing child cannot be excluded.

No information is available on the use of this drug during breastfeeding. Because it is a large protein molecule with a molecular weight of about 153,000, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant GI tract.