Adcetris

Name: Adcetris

Brentuximab vedotin Side Effects

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); 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.

Overdose

There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

What other drugs will affect brentuximab vedotin?

Many drugs can interact with brentuximab vedotin. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with brentuximab vedotin, especially:

  • St. John's wort;

  • an antibiotic or antifungal medicine;

  • antiviral medicine to treat hepatitis, HIV, or AIDS;

  • heart medication;

  • seizure medicine; or

  • tuberculosis medications.

This list is not complete and many other drugs can interact with brentuximab vedotin. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Cautions for Adcetris

Contraindications

  • Concomitant use with bleomycin.1 (See Respiratory Effects under Cautions.)

Warnings/Precautions

Warnings

Progressive Multifocal Leukoencephalopathy

JC virus infection causing PML (sometimes fatal) reported;1 15 signs and symptoms may develop over several weeks or months.15 Other risk factors for PML include prior therapies and underlying disease that may cause immunosuppression.1

Consider PML in any patient with new signs or symptoms suggestive of PML.1 (See Advice to Patients.) If PML is suspected, withhold the drug and initiate diagnostic evaluation (e.g., consultation with a neurologist, brain magnetic resonance imaging [MRI] scan, lumbar puncture, brain biopsy) as clinically indicated.1 If PML is confirmed, permanently discontinue brentuximab vedotin.1

Other Warnings and Precautions

Respiratory Effects

Concomitant use with bleomycin in contraindicated; increased risk of pulmonary toxicity.1 Incidence of noninfectious pulmonary reactions (e.g., cough, dyspnea, interstitial infiltration, inflammation) in patients receiving brentuximab vedotin with bleomycin-containing chemotherapy was higher than historical incidence of pulmonary reactions in patients receiving bleomycin-based regimens (e.g., doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]).1 15 Most patients responded to corticosteroid therapy.1

Peripheral Neuropathy

Peripheral neuropathy (mainly sensory neuropathy) occurs commonly;1 median time to onset is 12.4 weeks.19

Monitor patients for manifestations of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, weakness).1 Dosage reduction, treatment delay, or drug discontinuance may be required in patients with new or worsening symptoms.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Sensitivity Reactions

Infusion-related reactions (e.g., chills, nausea, dyspnea, pruritus, pyrexia, cough), including anaphylaxis, reported.1

Monitor for manifestations of infusion reactions during the infusion.1

If infusion-related effects occur, interrupt the infusion and initiate appropriate treatment.1 If anaphylaxis occurs, immediately and permanently discontinue brentuximab vedotin.1

If an infusion-related reaction occurs, administer premedication regimen (e.g., corticosteroid, antihistamine, and acetaminophen) before each subsequent dose.1

Hematologic Effects

Risk of severe and prolonged neutropenia, grade 3 or 4 anemia, or thrombocytopenia.1 Febrile neutropenia reported.1

Monitor CBCs prior to each dose; consider more frequent monitoring in patients with grade 3 or 4 neutropenia.1 Monitor for fever.1 If grade 3 or 4 neutropenia occurs, use of G-CSF, temporary interruption of therapy, dosage reduction, or drug discontinuance may be required.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Infectious Complications

Serious infections and opportunistic infections (i.e., pneumonia, bacteremia, sepsis/septic shock), sometimes fatal, reported.1

Monitor closely for signs and symptoms of bacterial, fungal, or viral infections.1

Tumor Lysis Syndrome

Possible tumor lysis syndrome following rapid lysis of malignant cells.1 Increased risk in patients with large tumor burden; closely monitor such patients and take appropriate precautions.1

Dermatologic Effects

Stevens-Johnson syndrome reported.1 Discontinue therapy and administer appropriate treatment if Stevens-Johnson syndrome occurs.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Immunogenicity

Antibodies to brentuximab vedotin, including neutralizing antibodies to the drug, reported.1 Clinical relevance is not known.1 Higher incidence of infusion-related reactions observed in patients persistently positive for anti-brentuximab vedotin antibodies.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1 Insufficient experience in pediatric patients to determine whether they respond differently than adults.1

Geriatric Use

Safety and efficacy not established.1 Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Systemic exposure may be increased.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Dosage adjustment and careful monitoring for adverse effects required in patients with hepatic impairment (Child-Pugh class A, B, or C).1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Systemic exposure may be increased.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Dosage adjustment and careful monitoring for adverse effects required in patients with severe renal impairment (Clcr <30 mL/minute).1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Neutropenia,1 5 7 peripheral neuropathy,1 5 6 7 fatigue,1 5 6 7 nausea,1 5 6 7 anemia,1 upper respiratory tract infection,1 diarrhea,1 5 7 pyrexia,1 5 7 rash,1 thrombocytopenia,1 cough,1 vomiting.1

Interactions for Adcetris

MMAE (the microtubule-inhibiting component of brentuximab vedotin) is a substrate and inhibitor of CYP3A4/5.1 Does not inhibit other CYP enzymes at clinically relevant concentrations and does not induce CYP enzymes.1

MMAE is a substrate of P-glycoprotein (P-gp) and is not a potent inhibitor of P-gp.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased serum concentrations of MMAE).1 Monitor closely for adverse effects.1

Potent CYP3A4 inducers: Possible pharmacokinetic interaction (decreased serum concentrations of MMAE);1 however, clinically important effects on MMAE concentrations are not expected.19 22

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4: Pharmacokinetic interaction not observed to date.1

Drugs Affecting Efflux Transport Systems

P-gp inhibitors: Possible pharmacokinetic interaction (increased serum concentrations of MMAE).1 Monitor closely for adverse effects.1

Specific Drugs

Drug

Interaction

Comments

Bleomycin

Increased risk of noninfectious pulmonary reactions (e.g., cough, dyspnea, interstitial infiltration, inflammation) with concomitant use in chemotherapy regimens containing bleomycin.1 15

Concomitant use contraindicated.1 15

Carbamazepine

Clinically important pharmacokinetic interaction not expected19 22

Dexamethasone

Clinically important pharmacokinetic interaction not expected19 22

Ketoconazole

Increased systemic exposure of MMAE1

Monitor closely for adverse effects1

Midazolam

No change in systemic exposure of midazolam1

Phenobarbital

Clinically important pharmacokinetic interaction not expected19 22

Phenytoin

Clinically important pharmacokinetic interaction not expected19 22

Rifampin

Decreased systemic exposure of MMAE1 22

Dosage adjustment not required22

Uses For Adcetris

Brentuximab injection is used to treat Hodgkin lymphoma and systemic anaplastic large cell lymphoma, which are blood cancers. It is given to patients who have received a bone marrow (autologous stem cell) transplant or other cancer treatments that did not work well. Brentuximab interferes with the growth of cancer cells, which are then destroyed by the body.

This medicine is to be given only by or under the direct supervision of your doctor.

Precautions While Using Adcetris

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Women should use an effective form of birth control to avoid pregnancy during treatment and for at least 6 months after the last dose. Men should use an effective form of birth control to avoid pregnancy in sexual partners during treatment and for 6 months after the last dose. If you think a pregnancy has occurred with the medicine, tell your doctor right away.

Talk with your doctor if you plan to have children after receiving this medicine. Some men may become infertile (unable to have children).

Do not use this medicine together with bleomycin (Blenoxane®). Using these medicines together may cause serious side effects, such as cough or troubled breathing.

Check with your doctor right away if you have burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet. These could be symptoms of a condition called peripheral neuropathy.

This medicine may cause an infusion reaction. This can be life-threatening and requires immediate medical attention. Tell your doctor or nurse right away if you have a fever, chills, trouble breathing, lightheadedness, fainting, or chest pain within a few hours after you receive it.

This medicine may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are receiving this medicine.

Check with your doctor if you have a fever, chills, sore throat, or painful urination. These could be symptoms of an infection.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

This medicine may cause a serious type of reaction called tumor lysis syndrome. Your doctor may give you a medicine to help prevent this. Call your doctor right away if you have a decrease or change in urine amount, joint pain, stiffness, or swelling, lower back, side, or stomach pain, rapid weight gain, swelling of the feet or lower legs, or unusual tiredness or weakness.

Serious skin reactions can occur with this medicine. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills.

This medicine may cause a rare and serious brain infection called progressive multifocal leukoencephalopathy (PML). Check with your doctor right away if you have vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, or muscle weakness in the legs.

This medicine may cause new or worsening lung problems. Tell your doctor right away if you have a cough or trouble breathing after receiving this medicine.

Stomach or bowel problems may occur with this medicine. Tell your doctor right away if you have severe stomach pain, heartburn, or indigestion, bloody or black stools, trouble breathing, or if you vomit material that looks like coffee grounds.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Uses of Adcetris

  • It is used to treat lymphoma.

What are some things I need to know or do while I take Adcetris?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Very bad and sometimes deadly infections can happen with this medicine (Adcetris). Talk with the doctor.
  • Some people have unsafe allergic effects or bad side effects during the infusion or within 24 hours of the infusion. Talk with the doctor.
  • Side effects and death happened with this medicine more often in people with very bad kidney problems than in people without kidney problems. Side effects and death also happened with this medicine (Adcetris) more often in people with moderate or very bad liver problems than in people without liver problems. Talk with the doctor.
  • Very bad and sometimes deadly pancreas problems (pancreatitis) have happened with this medicine. Call your doctor right away if you have very bad stomach pain, very bad back pain, or very upset stomach or throwing up.
  • Very bad and sometimes deadly liver problems have happened with this medicine (Adcetris). Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Very bad and sometimes deadly lung problems have happened with this medicine. Call your doctor right away if you have lung or breathing problems that are new or worse like cough or shortness of breath.
  • Patients with cancer who take this medicine (Adcetris) may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.
  • This medicine may affect being able to father a child. Talk with the doctor.
  • If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 6 months after care ends. Use birth control that you can trust.
  • If you are a man and your sex partner gets pregnant while you take this medicine or within 6 months after your last dose, call your doctor right away.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant.
  • If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting this medicine (Adcetris). Talk with your doctor.
  • Use birth control that you can trust to prevent pregnancy while taking this medicine and for 6 months after stopping this medicine (Adcetris).
  • If you get pregnant while taking this medicine or within 6 months after your last dose, call your doctor right away.

Adcetris Dosage and Administration

Dosage Recommendations

Administer Adcetris as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.  See Table 1 for the recommended starting dosage.

For classical HL post-auto-HSCT consolidation treatment, initiate Adcetris treatment within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT.  These patients should continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity.

Table 1: Recommended Adcetris Dosage
  Recommended Starting Dosage
Normal renal and hepatic function 1.8 mg/kg up to 180 mg
Renal impairment
       Mild (creatinine clearance >50–80 mL/min)
       or moderate (creatinine clearance 30–50 mL/min)
1.8 mg/kg up to 180 mg
       Severe (creatinine clearance less than 30 mL/min) Avoid use
[see Warnings and Precautions (5.6)]
Hepatic impairment
       Mild (Child-Pugh A) 1.2 mg/kg up to 120 mg
       Moderate (Child-Pugh B) or severe (Child-Pugh C) Avoid use
[see Warnings and Precautions (5.7)]

Dose Modification

Peripheral Neuropathy:  For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg.  For Grade 4 peripheral neuropathy, Adcetris should be discontinued.

Neutropenia:  The dose of Adcetris should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower.  Consider G-CSF prophylaxis for subsequent cycles in patients who experience Grade 3 or 4 neutropenia in the previous cycle.  In patients with recurrent Grade 4 neutropenia despite the use of G-CSF prophylaxis, consider discontinuation or dose reduction of Adcetris to 1.2 mg/kg.

Instructions for Preparation and Administration

Administration

  • Administer Adcetris as an intravenous infusion only.
  • Do not mix Adcetris with, or administer as an infusion with, other medicinal products.

Reconstitution

  • Follow procedures for proper handling and disposal of anticancer drugs [see References (15)].
  • Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.
  • Determine the number of 50 mg vials needed based on the patient’s weight and the prescribed dose [see Dosage and Administration (2.1)].
  • Reconstitute each 50 mg vial of Adcetris with 10.5 mL of Sterile Water for Injection, USP, to yield a single-use solution containing 5 mg/mL brentuximab vedotin.
  • Direct the stream toward the wall of vial and not directly at the cake or powder.
  • Gently swirl the vial to aid dissolution.  DO NOT SHAKE.
  • Inspect the reconstituted solution for particulates and discoloration.  The reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates.
  • Following reconstitution, dilute immediately into an infusion bag.  If not diluted immediately, store the solution at 2–8°C (36–46°F) and use within 24 hours of reconstitution.  DO NOT FREEZE.
  • Discard any unused portion left in the vial.

Dilution

  • Calculate the required volume of 5 mg/mL reconstituted Adcetris solution needed.
  • Withdraw this amount from the vial and immediately add it to an infusion bag containing a minimum volume of 100 mL of 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer's Injection to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL brentuximab vedotin.
  • Gently invert the bag to mix the solution.
  • Following dilution, infuse the Adcetris solution immediately.  If not used immediately, store the solution at 2–8°C (36–46°F) and use within 24 hours of reconstitution.  DO NOT FREEZE.

Patient Handout

Print without Office InfoPrint with Office Info

Side effects

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:

  • Peripheral Neuropathy [see WARNINGS AND PRECAUTIONS]
  • Anaphylaxis and Infusion Reactions [see WARNINGS AND PRECAUTIONS]
  • Hematologic Toxicities [see WARNINGS AND PRECAUTIONS]
  • Serious Infections and Opportunistic Infections [see WARNINGS AND PRECAUTIONS]
  • Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
  • Increased Toxicity in the Presence of Severe Renal Impairment [see WARNINGS AND PRECAUTIONS]
  • Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment [see WARNINGS AND PRECAUTIONS]
  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • Progressive Multifocal Leukoencephalopathy [see WARNINGS AND PRECAUTIONS]
  • Pulmonary Toxicity [see WARNINGS AND PRECAUTIONS]
  • Serious Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Complications [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to ADCETRIS as monotherapy in 327 patients with classical Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), including 160 patients in two uncontrolled single-arm trials (Studies 1 and 2) and 167 patients in one placebo-controlled randomized trial (Study 3).

In Studies 1 and 2, the most common adverse reactions ( ≥ 20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. The most common adverse reactions occurring in at least 10% of patients in either Study 1 or 2, regardless of causality, using the NCI Common Toxicity Criteria (CTC) Version 3.0, are shown in Table 2.

In Study 3, the most common adverse reactions ( ≥ 20%) in the ADCETRIS-treatment arm, regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea. The most common adverse reactions occurring in at least 10% of patients, using the NCI CTC Version 4, are shown in Table 3.

Experience In Classical Hodgkin Lymphoma

Summary of Clinical Trial Experience in Relapsed Classical HL (Study 1)

ADCETRIS was studied in 102 patients with classical HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 9 cycles (range, 1-16) [see Clinical Studies].

The most common adverse reactions ( ≥ 20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.

Summary of Clinical Trial Experience in Classical HL Post-auto-HSCT Consolidation (Study 3)

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks or placebo for up to 16 cycles. Of the 329 enrolled patients, 327 (167 brentuximab vedotin, 160 placebo) received at least one dose of study treatment. The median number of treatment cycles in each study arm was 15 (range, 1-16) and 80 patients (48%) in the ADCETRIS-treatment arm received 16 cycles [see Clinical Studies].

Standard international guidelines were followed for infection prophylaxis for herpes simplex virus (HSV), varicella-zoster virus (VZV), and Pneumocystis jiroveci pneumonia (PCP) post-auto-HSCT. Overall, 312 patients (95%) received HSV and VZV prophylaxis with a median duration of 11.1 months (range, 0-20) and 319 patients (98%) received PCP prophylaxis with a median duration of 6.5 months (range, 0-20).

Experience In Systemic Anaplastic Large Cell Lymphoma

Summary of Clinical Trial Experience in Relapsed sALCL (Study 2)

ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 7 cycles (range, 1-16) [see Clinical Studies].

The most common adverse reactions ( ≥ 20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain.

Table 2: Most Commonly Reported ( ≥ 10%) Adverse Reactions in Studies 1 and 2

Adverse Reaction Classical HL Total
N = 102 % of patients
sALCL Total
N = 58 % of patients
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Blood and lymphatic system disorders
  Neutropenia* 54 15 6 55 12 9
  Anemia* 33 8 2 52 2 -
  Thrombocytopenia* 28 7 2 16 5 5
  Lymphadenopathy 11 - - 10 - -
Nervous system disorders
  Peripheral sensory neuropathy 52 8 - 53 10 -
  Peripheral motor neuropathy  16 4 - 7 3 -
  Headache 19 - - 16 2 -
  Dizziness 11 - - 16 - -
General disorders and administration site conditions
  Fatigue 49 3 - 41 2 2
  Pyrexia 29 2 - 38 2 -
  Chills 13 - - 12 - -
  Pain 7 - - 28 - 5
  Edema peripheral 4 - - 16 - -
Infections and infestations
  Upper respiratory tract infection 47 - - 12 - -
Gastrointestinal disorders
  Nausea 42 - - 38 2 -
  Diarrhea 36 1 - 29 3 -
  Abdominal pain 25 2 1 9 2 -
  Vomiting 22 - - 17 3 -
  Constipation 16 - - 19 2 -
Skin and subcutaneous tissue disorders
  Rash 27 - - 31 - -
  Pruritus 17 - - 19 - -
  Alopecia 13 - - 14 - -
  Night sweats 12 - - 9 - -
  Dry skin 4 - - 10 - -
Respiratory, thoracic and mediastinal disorders
  Cough 25 - - 17 - -
  Dyspnea 13 1 - 19 2 -
  Oropharyngeal pain 11 - - 9 - -
Musculoskeletal and connective tissue disorders
  Arthralgia 19 - - 9 - -
  Myalgia 17 - - 16 2 -
  Back pain 14 - - 10 2 -
  Pain in extremity 10 - - 10 2 2
  Muscle spasms 9 - - 10 2 -
Psychiatric disorders
  Insomnia 14 - - 16 - -
  Anxiety 11 2 - 7 - -
Metabolism and nutrition disorders
  Decreased appetite 11 - - 16 2 -
Investigations
  Weight decreased 6 - - 12 3 -
*Derived from laboratory values and adverse reaction data

Table 3: Most Commonly Reported ( ≥ 10% in the ADCETRIS arm) Adverse Reactions in Study 3

Adverse Reaction ADCETRIS Total
N = 167
% of patients
Placebo Total
N = 160
% of patients
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Blood and lymphatic system disorders
  Neutropenia* 78 30 9 34 6 4
  Thrombocytopenia* 41 2 4 20 3 2
  Anemia* 27 4 - 19 2 -
Nervous system disorders
  Peripheral sensory neuropathy 56 10 - 16 1 -
  Peripheral motor neuropathy 23 6 - 2 1 -
  Headache 11 2 - 8 1 -
Infections and infestations
  Upper respiratory tract infection 26 - - 23 1 -
General disorders and administration site conditions
  Fatigue 24 2 - 18 3 -
  Pyrexia 19 2 - 16 - -
  Chills 10 - - 5 - -
Gastrointestinal disorders
  Nausea 22 3 - 8 - -
  Diarrhea 20 2 - 10 1 -
  Vomiting 16 2 - 7 - -
  Abdominal pain 14 2 - 3 - -
  Constipation 13 2 - 3 - -
Respiratory, thoracic and mediastinal disorders
  Cough 21 - - 16 - -
  Dyspnea 13 - - 6 - 1
Investigations
  Weight decreased 19 1 - 6 - -
Musculoskeletal and connective tissue disorders
  Arthralgia 18 1 - 9 - -
  Muscle spasms 11 - 6 - -
  Myalgia 11 1 - 4 - -
Skin and subcutaneous tissue disorders
  Pruritus 12 1 - 8 - -
Metabolism and nutrition disorders
  Decreased appetite 12 1 - 6 - -
*Derived from laboratory values and adverse reaction data

Additional Important Adverse Reactions

Peripheral Neuropathy

In Studies 1 and 2, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation.

In Study 3, 67% of patients treated with ADCETRIS experienced any grade of neuropathy. The median time to first onset of any grade was 14 weeks (range, 0.1-47), of Grade 2 was 27 weeks (range, 0.4-52) and of Grade 3 was 34 weeks (range, 7-106). The median time from onset to resolution or improvement of any grade was 23 weeks (range, 0.1-138), of Grade 2 was 24 weeks (range, 1-108), and of Grade 3 was 25 weeks (range, 2-98). Of the patients who reported neuropathy, 59% had complete resolution and 41% had residual neuropathy (26% partial improvement, 15% no improvement) at the time of their last evaluation.

Infusion Reactions

Two cases of anaphylaxis were reported in the dose-finding trials. There were no Grade 3 or 4 infusion-related reactions reported in Studies 1 and 2; however, Grade 1 or 2 infusion-related reactions were reported for 19 patients (12%). In Studies 1 and 2, the most common adverse reactions ( ≥ 2%) associated with infusion-related reactions were chills (4%), nausea (3%), dyspnea (3%), pruritus (3%), pyrexia (2%), and cough (2%).

In Study 3, infusion-related reactions were reported in 25 patients (15%) in the ADCETRIS-treated arm and 3 patients (2%) in the placebo arm. Grade 3 events were reported in 3 of the 25 patients treated with ADCETRIS who experienced infusion-related reactions. No Grade 4 infusion-related reactions were reported. The most common adverse reactions ( ≥ 2%) associated with infusion-related reactions were nausea (4%), chills (4%), dyspnea (2%), headache (2%), pruritus (2%), rash (2%), back pain (2%), and vomiting (2%).

Pulmonary Toxicity

In a trial in patients with classical HL that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids. The concomitant use of ADCETRIS with bleomycin is contraindicated [see CONTRAINDICATIONS].

Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS. In Study 3, pulmonary toxicity was reported in 8 patients (5%) in the ADCETRIS-treated arm and 5 patients (3%) in the placebo arm. A causal association with single-agent ADCETRIS has not been established.

Serious Adverse Reactions

In Studies 1 and 2, serious adverse reactions, regardless of causality, were reported in 31% of patients receiving ADCETRIS. The most common serious adverse reactions experienced by patients with classical HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%). The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%). Other important serious adverse reactions reported include PML, Stevens-Johnson syndrome, and tumor lysis syndrome.

In Study 3, serious adverse reactions, regardless of causality, were reported in 25% of ADCETRIS-treated patients. The most common serious adverse reactions were pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%), and peripheral sensory neuropathy (2%).

Dose Modifications

Adverse reactions that led to dose delays in more than 5% of patients in Studies 1 and 2 were neutropenia (14%) and peripheral sensory neuropathy (11%) [see DOSAGE AND ADMINISTRATION].

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients in Study 3 were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and peripheral motor neuropathy (6%) [see DOSAGE AND ADMINISTRATION].

Discontinuations

Adverse reactions led to treatment discontinuation in 21% of patients in Studies 1 and 2. Adverse reactions that led to treatment discontinuation in 2 or more patients with classical HL or sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%).

Adverse reactions led to treatment discontinuation in 32% of ADCETRIS-treated patients in Study 3. Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress syndrome (1%), paraesthesia (1%), and vomiting (1%).

Post Marketing Experience

The following adverse reactions have been identified during post-approval use of ADCETRIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: febrile neutropenia [see WARNINGS AND PRECAUTIONS].

Gastrointestinal disorders:

  • Pancreatitis (including fatal outcomes). Consider the diagnosis of pancreatitis for patients presenting with severe abdominal pain.
  • Gastrointestinal complications (including fatal outcomes) [see WARNINGS AND PRECAUTIONS].

Hepatobiliary disorders: hepatotoxicity [see WARNINGS AND PRECAUTIONS].

Infections: PML [see BOXED WARNING, WARNINGS AND PRECAUTIONS], serious infections and opportunistic infections [see WARNINGS AND PRECAUTIONS].

Metabolism and nutrition disorders: hyperglycemia.

Respiratory, thoracic and mediastinal disorders: noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes) [see WARNINGS AND PRECAUTIONS and Clinical Trial Experience above].

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes [see WARNINGS AND PRECAUTIONS].

Immunogenicity

Patients with classical HL and sALCL in Studies 1 and 2 [see Clinical Studies] were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent immunoassay. Approximately 7% of patients in these trials developed persistently positive antibodies (positive test at more than 2 timepoints) and 30% developed transiently positive antibodies (positive in 1 or 2 post-baseline timepoints). The anti-brentuximab antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently or persistently positive antibodies. Two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment. Overall, a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies.

A total of 58 patient samples that were either transiently or persistently positive for antibrentuximab vedotin antibodies were tested for the presence of neutralizing antibodies. Sixty-two percent of these patients had at least one sample that was positive for the presence of neutralizing antibodies. The effect of anti-brentuximab vedotin antibodies on safety and efficacy is not known.

Immunogenicity assay results are 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 incidence of antibodies to ADCETRIS with the incidence of antibodies to other products may be misleading.

Read the entire FDA prescribing information for Adcetris (Brentuximab Vedotin)

Read More »

Before taking this medicine

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

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

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

  • liver disease;

  • kidney disease; or

  • peripheral vascular disease such as Raynaud's syndrome.

Adcetris 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. Use of this medicine by either parent may cause birth defects.

If you are a woman, do not use Adcetris 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 Adcetris . 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 Adcetris.

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 this medicine.

Adcetris side effects

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 Adcetris infusion.

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

Adcetris 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 Adcetris, 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 Adcetris 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.

(web3)