Adcetris

Name: Adcetris

What happens if I miss a dose?

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

Introduction

Antineoplastic agent; an anti-CD30 antibody conjugated with a microtubule inhibitor (monomethyl auristatin E [MMAE]).1 3 4 5 10

Uses for Adcetris

Hodgkin Lymphoma

Treatment of Hodgkin lymphoma following failure of autologous stem cell transplantation (ASCT) or following failure of ≥2 multiple-agent chemotherapy regimens in patients who are not ASCT candidates1 (designated an orphan drug by FDA for treatment of this cancer13 ). Efficacy determined based on overall response rate in a noncomparative, open-label study in patients with relapsed Hodgkin lymphoma.1 6 20

Anaplastic Large Cell Lymphoma

Treatment of systemic anaplastic large cell lymphoma (sALCL) following failure of ≥1 multiple-agent chemotherapy regimens1 (designated an orphan drug by FDA for treatment of this cancer14 ). Efficacy determined based on overall response rate in a noncomparative, open-label study in patients with relapsed sALCL.1 7 21

Adcetris Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common
  • Black, tarry stools
  • bleeding gums
  • blood in the urine or stools
  • body aches or pain
  • burning, numbness, tingling, or painful sensations
  • chills
  • cough
  • difficult or labored breathing
  • difficulty with breathing
  • ear congestion
  • fever
  • headache
  • loss of voice
  • lower back or side pain
  • pain
  • painful or difficult urination
  • pale skin
  • pinpoint red spots on the skin
  • sneezing
  • sore throat
  • stuffy or runny nose
  • swollen, painful, or tender lymph glands in the neck, armpit, or groin
  • tightness in the chest
  • troubled breathing with exertion
  • ulcers, sores, or white spots in the mouth
  • unsteadiness or awkwardness
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • weakness in the arms, hands, legs, or feet
Less common
  • Anxiety
  • back pain
  • bladder pain
  • blistering, peeling, or loosening of the skin
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • blurred vision
  • chest pain
  • cloudy urine
  • confusion
  • convulsions
  • diarrhea
  • dizziness or lightheadedness
  • drowsiness
  • fainting
  • fast heartbeat
  • frequent urge to urinate
  • general feeling of discomfort or illness
  • irregular heartbeat
  • itching
  • joint pain, stiffness, or swelling
  • muscle pain
  • rapid weight gain
  • red skin lesions, often with a purple center
  • red, irritated eyes
  • severe pain in the chest
  • stomach pain
  • sudden onset of severe breathing difficulty
  • sudden shortness of breath or troubled breathing
  • thickening of bronchial secretions
  • unusual weight gain or loss
Incidence not known
  • Bloody stools
  • heartburn
  • indigestion
  • nausea
  • severe abdominal pain, cramping, or burning
  • severe constipation
  • severe vomiting
  • vomiting of material that looks like coffee grounds

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Decreased appetite or weight
  • difficulty having a bowel movement (stool)
  • difficulty with moving
  • hair loss or thinning of the hair
  • muscle spasms
  • muscle stiffness
  • night sweats
  • pain in the arms or legs
  • rash
  • trouble sleeping
  • vomiting
Less common
  • Dry skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

What are some other side effects of Adcetris?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Feeling tired or weak.
  • Joint pain.
  • Dizziness.
  • Headache.
  • Upset stomach or throwing up.
  • Belly pain.
  • Hard stools (constipation).
  • Loose stools (diarrhea).
  • Back pain.
  • Dry skin.
  • Hair loss.
  • Muscle spasm.
  • Not hungry.
  • Weight loss.
  • Night sweats.
  • Not able to sleep.
  • Anxiety.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Review Date: October 4, 2017

Contraindications

Adcetris is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation) [see Adverse Reactions (6.1)].

Drug Interactions

Effect of Other Drugs on Adcetris

CYP3A4 Inhibitors/Inducers: In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate of CYP3A4/5. MMAE is primarily metabolized by CYP3A[see Clinical Pharmacology (12.3)].  Co-administration of Adcetris with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%.  Patients who are receiving strong CYP3A4 inhibitors concomitantly with Adcetris should be closely monitored for adverse reactions.  Co-administration of Adcetris with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

P-gp Inhibitors: In vitro data indicate that MMAE is a substrate of the efflux transporter P‑glycoprotein (P-gp). Co-administration of Adcetris with P-gp inhibitors may increase exposure to MMAE.  Patients who are receiving P-gp inhibitors concomitantly with Adcetris should be closely monitored for adverse reactions.

Effect of Adcetris on Other Drugs

In vitro data indicate that MMAE is an inhibitor of CYP3A4/5.  Co-administration of Adcetris did not affect exposure to midazolam, a CYP3A4 substrate.  MMAE does not inhibit other CYP enzymes at relevant clinical concentrations [see Clinical Pharmacology (12.3)].  Adcetris is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations

Pregnancy

Risk Summary

Adcetris can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)].  In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal toxicities, including congenital malformations [see Data].  Consider the benefits and risks of Adcetris and possible risks to the fetus when prescribing Adcetris to a pregnant woman.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal Data

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13).  Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs).  Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with classical HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Lactation

Risk Summary

There is no information regarding the presence of brentuximab vedotin in human milk, the effects on the breastfed infant, or the effects on milk production.  Because of the potential for serious adverse reactions in a breastfed infant from Adcetris, including cytopenias and neurologic or gastrointestinal toxicities, advise patients that breastfeeding is not recommended during Adcetris treatment.

Females and Males of Reproductive Potential

Adcetris can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Use in Specific Populations (8.1),Clinical Pharmacology (12.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Adcetris therapy.

Contraception

Females

Advise females of reproductive potential to avoid pregnancy during Adcetris treatment and for at least 6 months after the final dose of Adcetris.  Advise females to immediately report pregnancy [see Use in Specific Populations (8.1)].

Males

Adcetris may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities.  Males with female sexual partners of reproductive potential should use effective contraception during Adcetris treatment and for at least 6 months after the final dose of Adcetris [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on findings in rats, male fertility may be compromised by treatment with Adcetris [see Nonclinical Toxicology (13.1)].

Pediatric Use

Safety and effectiveness of Adcetris have not been established in pediatric patients.

Geriatric Use

Clinical trials of Adcetris did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Renal Impairment

Avoid the use of Adcetris in patients with severe renal impairment (CLcr <30 mL/min) [See Warnings and Precautions (5.6)].

The kidney is a route of excretion for monomethyl auristatin E (MMAE).  The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of Adcetris to patients with mild (CLcr >50–80 mL/min; n=4), moderate (CLcr 30–50 mL/min; n=3) and severe (CLcr <30 mL/min; n=3) renal impairment.  In patients with severe renal impairment, the rate of Grade 3 or worse adverse reactions was 3/3 (100%) compared to 3/8 (38%) in patients with normal renal function.  Additionally, the AUC of MMAE (component of Adcetris) was approximately 2-fold higher in patients with severe renal impairment compared to patients with normal renal function.  Due to higher MMAE exposure, ≥Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function.

Hepatic Impairment

Avoid the use of Adcetris in patients with moderate or severe hepatic impairment [See Warnings and Precautions (5.7)].

The liver is a route of clearance for MMAE.  The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of Adcetris to patients with mild (Child-Pugh A; n=1), moderate (Child-Pugh B; n=5) and severe (Child-Pugh C; n=1) hepatic impairment.  In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function.  Additionally, the AUC of MMAE was approximately 2.2-fold higher in patients with hepatic impairment compared to patients with normal hepatic function.

Overdosage

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.

Dosing & Uses

Dosage Forms & Strengths

lyophilized powder for injection

  • 50mg/vial

Hodgkin Lymphoma

Indicated for treatment of classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplant (auto-HSCT) or after failure of at least 2 prior multiagent chemotherapy regimens in patients who are not stem cell transplant candidates

1.8 mg/kg IV infused over 30 minutes q3Weeks; not to exceed 180 mg/dose  

Continue treatment until disease progression or unacceptable toxicity

Classical HL post-auto-HSCT consolidation

  • Indicated post-auto-HSCT in patients with HL at high risk for relapse or progression
  • Initiate within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT
  • 1.8 mg/kg IV infused over 30 minutes q3Weeks; not to exceed 180 mg/dose
  • Continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity

Systemic Anaplastic Large Cell Lymphoma

Indicated for treatment of systemic anaplastic large cell lymphoma after failure of at least one prior multiagent chemotherapy regimen

1.8 mg/kg IV infused over 30 minutes q3Weeks  

If patient weighs >100 kg, calculate dose based on a weight of 100 kg

Continue treatment until disease progression or unacceptable toxicity

Dosage Modifications

Renal impairment

  • Mild or moderate (CrCl 30-80 mL/min): No dosage adjustment required
  • Severe (CrCl <30 mL/min): Avoid use

Hepatic impairment

  • Mild (Child-Pugh A): 1.2 mg/kg/dose; not to exceed 120 mg/dose
  • Moderate or severe (Child-Pugh B or C): Avoid use

Peripheral neuropathy

  • New or worsening grade 2 or 3 peripheral neuropathy: Hold dose until neuropathy improves to grade 1 or baseline, and then restart at 1.2 mg/kg
  • Grade 4 peripheral neuropathy: Discontinue brentuximab vedotin

Neutropenia

  • Grade 3 or 4 neutropenia: Hold dose until resolution to baseline or grade 2 or lower
  • Consider growth factor support for subsequent cycles
  • For recurrent grade 4 neutropenia despite use of growth factors, discontinue brentuximab vedotin or reduce dose to 1.2 mg/kg

Orphan Designations

CD30-positive cutaneous T-cell lymphoma including those with primary cutaneous anaplastic large cell lymphoma (pcALCL) (ie, mycosis fungoides)

Peripheral T-cell lymphoma, not otherwise specified

Angioimmunoblastic T-cell lymphoma

Cutaneous T-cell lymphoma

Diffuse large B-cell lymphoma

Adult T-cell leukemia/lymphoma

Enteropathy-associated T-cell lymphoma

Orphan sponsor

  • Seattle Genetics, Inc; 21823 30th Drive Southeast, Bothell, WA 98021

Safety and effectiveness not established

Clinical trials included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients

Pharmacology

Mechanism of Action

CD30-directed antibody-drug conjugate (ADC) consisting of chimeric IgG1 antibody cAC10, specific for human CD30 and the microtubule disrupting agent, monomethyl auristatin E (MMAE, or vedotin); the conjugate binds to cell expressing the CD30 antigen and forms a complex that is internalized within the cell and MMAE is released; MMAE induces cell cycle (G2/M phase) arrest by binding to the tubules and disrupting the cellular microtubule network

Pharmacokinetics

Peak Plasma Time: 20-30 min (ADC); 1-3 days (MMAE)

Protein Bound: 68-82% (MMAE)

Vd: 6-10 L (ADC)

P-gp substrate

Metabolism CYP3A4/5 (MMAE)

MMAE inhibits CYP3A4/5

Half-life: 4-6 days

Excretion: 24% of the total MMAE administered was recovered in both urine and feces over 1 week (72% of which was recovered in the feces)

Where can i get more information?

Your doctor or pharmacist can provide more information about brentuximab vedotin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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What happens if I miss a dose?

Call your doctor if you miss an appointment for your Adcetris injection.

What should I avoid while receiving Adcetris?

Do not receive a "live" vaccine while using Adcetris. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Brentuximab can pass into body fluids (urine, feces, vomit). For at least 48 hours after you receive a dose, avoid allowing your body fluids to come into contact with your hands or other surfaces. Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

In Summary

More frequent side effects include: peripheral motor neuropathy. See below for a comprehensive list of adverse effects.

Brentuximab Pregnancy Warnings

Animal studies have revealed evidence of embryofetotoxicity. There are no controlled data in human pregnancy. If this drug is used during pregnancy or if the patient becomes pregnant during treatment, the patient should be advised of the potential hazard to the developing fetus. AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Use is not recommended. AU TGA pregnancy category: D US FDA pregnancy category: D Comments: -This drug can cause fetal harm when administered to a pregnant woman. -Women of childbearing potential should use two methods of effective contraception during treatment with this drug and until 6 months after treatment. -Men being treated with this drug are advised to have sperm samples frozen and stored before treatment. They should not father a child during treatment and for up to 6 months following the last dose. Effects on spermatogenesis cannot be excluded after a 6 month treatment-free period.

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