Brentuximab Vedotin

Registered South African indications:

• Advanced Hodgkin lymphoma
• Hodgkin lymphoma at risk of relapse or progression following autologous stem cell transplant
• Relapsed or refractory Hodgkin lymphoma
• Relapsed or refractory systemic anaplastic large cell lymphoma
• Cutaneous T-cell lymphoma which requires systemic therapy

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with bleomycin

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Men intending to father a child during treatment or in the next 6 months (following the last dose)
• Coadministration with bleomycin

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Risk factors for hepatotoxicity
  - Pre-existing liver disease
  - Comorbidities
  - Coadministered medications
• Men intending to father a child during treatment or in the next 6 months (following the last dose)
• Risk factor for febrile neutropenia
  - Advanced age
• Multiple prior chemotherapy regimens
• Antibodies to brentuximab vedotin
• Prior infusion-related reactions
• Rapidly proliferating tumour and high tumour burden
• Elevated body mass index (BMI) with or without a history of diabetes mellitus
• CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL)
• Sodium restricted diet
• May impair ability to drive and operate machinery

South African manufacturer recommendations

• Renal impairment
• Hepatic impairment
• Risk factors for hepatotoxicity
  - Pre-existing liver disease
  - Comorbidities
  - Coadministered medications
• Multiple prior chemotherapy regimens
• Prior infusion-related reactions
• Rapidly proliferating tumour and high tumour burden
• Elevated body mass index (BMI) with or without a history of diabetes mellitus
• Antibodies to brentuximab vedotin
• Coadministration with ritonavir
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inf

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used for the treatment of

• Previously untreated CD30+ Stage IV Hodgkin lymphoma (Additional agents required)
• CD30+ Hodgkin lymphoma at increased risk of relapse or progression following autologous stem cell transplant (ASCT)
• Relapsed or refractory CD30+ Hodgkin lymphoma
  - Following ASCT
  - Following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option
• Previously untreated systemic anaplastic large cell lymphoma (sALCL) (Additional agents required)
• Relapsed or refractory sALCL
• CD30+ cutaneous T-cell lymphoma after at least 1 prior systemic therapy

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Consult specialist for dosages and regimens

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South African manufacturer recommendations

Used for the treatment of

• CD30+ advanced Hodgkin lymphoma (Additional agent required)
• CD30+ Hodgkin lymphoma at risk of relapse or progression following autologous stem cell transplant (ASCT)
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Relapsed or refractory CD30+ systemic anaplastic large cell lymphoma (sALCL)
• CD30+ cutaneous T-cell lymphoma (CTCL) which requires systemic therapy

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Consult specialist for dosages and regimens

Not established for use in children below 18 years 

Pregnancy

International manufacturer recommendations

• Caution; not recommended
• There are no data from the use of brentuximab vedotin in pregnant women. Studies in animals have shown reproductive toxicity. Brentuximab vedotin should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the foetus. If a pregnant woman needs to be treated she should be clearly advised on the potential risk to the foetus
• Women of childbearing potential should be using two methods of effective contraception during treatment with brentuximab vedotin and until 6 months after treatment

South African manufacturer recommendations

• Contraindicated
• Brentuximab vedotin is contraindicated in women who are pregnant or intend to become pregnant
• Studies in animals have shown reproductive toxicity
• Women of childbearing potential should be using two methods of effective contraception during treatment with brentuximab vedotin and until 6 months after treatment

Breastfeeding

International manufacturer recommendations

• Caution; not recommended

• There are no data as to whether brentuximab vedotin or its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded.  A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from this therapy, taking into account a potential risk of breastfeeding for the child and the benefit of therapy for the woman

South African manufacturer recommendations

• Contraindicated
• Women who are using brentuximab vedotin should not breastfeed their infants

Fertility

International manufacturer recommendations

• In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity and may alter male fertility. MMAE has been shown to have aneugenic properties. Therefore, men being treated with this medicine are advised to have sperm samples frozen and stored before treatment
• Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose

South African manufacturer recommendations

• In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity and may alter male fertility. Men being treated with brentuximab vedotin are advised to have sperm samples frozen and stored before treatment
• Men being treated with brentuximab vedotin are advised not to father a child during treatment and for up to 6 months following the last dose

Renal Impairment

International manufacturer recommendations

Monotherapy

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  IV: 1.2mg/kg, as an infusion over 30mins, every 3 weeks
  Patients with renal impairment should be closely monitored for adverse events

Combination therapy

• Mild to moderate (CrCl>40ml/min): Caution; no dose adjustment recommended
• Severe (CrCl≤40ml/min): Caution; no information available
  There is no clinical trial experience using brentuximab vedotin in combination with chemotherapy in patients with renal impairment, where serum creatinine is ≥2.0mg/dL and/or CrCl or calculated CrCl is ≤40ml/min
  Patients with renal impairment should be closely monitored for adverse events
  Use of brentuximab vedotin in combination with chemotherapy should be avoided in patients with severe renal impairment

South African manufacturer recommendations

Monotherapy

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  IV: 1.2mg/kg, as an infusion over 30mins, every 3 weeks
  Patients with renal impairment should be closely monitored for adverse events

Combination therapy

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Caution; no information available
  There is no clinical trial experience using brentuximab vedotin in combination with chemotherapy in patients with severe renal impairment
  Patients with renal impairment should be closely monitored for adverse events

Hepatic Impairment

International manufacturer recommendations

Monotherapy

• Caution; dose adjustment recommended
  IV: 1.2mg/kg, as an infusion over 30mins every 3 weeks
  Patients with hepatic impairment should be closely monitored for adverse events

Combination therapy

• Mild: In combination with doxorubicin, vinblastine and dacarbazine: Caution; dose adjustment recommended
  IV: 0.9mg/kg, as an infusion over 30mins every 2 weeks
• Mild: In combination with cyclophosphamide, doxorubicin and prednisone: Caution; dose adjustment recommended
  IV: 1.2mg/kg, as an infusion over 30mins every 3 weeks
• Moderate to severe: Caution; no information available
  There is no clinical trial experience using brentuximab vedotin in combination with chemotherapy, where total bilirubin is >1.5 times the upper limit of normal (ULN) (unless due to Gilbert syndrome), or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are >3 times the ULN, or >5 times the ULN if their elevation may be reasonably ascribed to the presence of Hodgkin lymphoma in the liver
  Use of brentuximab vedotin in combination with chemotherapy should be avoided in patients with moderate and severe hepatic impairment
  Patients with hepatic impairment should be closely monitored for adverse events 

South African manufacturer recommendations

Monotherapy

• Caution; dose adjustment recommended
  IV: 1.2mg/kg, as an infusion over 30mins every 3 weeks
  Patients with hepatic impairment should be closely monitored for adverse events

Combination therapy

• Caution; no information available 
  There is no clinical trial experience using brentuximab vedotin in combination with chemotherapy, where total bilirubin is >1.5 times the upper limit of normal (ULN) (unless due to Gilbert syndrome), or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are >3 times the ULN, or >5 times the ULN if their elevation may be reasonably ascribed to the presence of Hodgkin lymphoma in the liver
  Patients with hepatic impairment should be closely monitored for adverse events

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Monotherapy

Central Nervous System Disorders

• Peripheral sensory neuropathy
• Peripheral motor neuropathy
• Dizziness
• Demyelinating polyneuropathy
• Progressive multifocal leukoencephalopathy
• Fatigue

Respiratory Disorders

• Upper respiratory tract infection
• Pneumocystis jiroveci pneumonia
• Pneumonia
• Cough
• Dyspnoea

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Abdominal pain
• Diarrhoea
• Oral candidiasis

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase

Endocrine and Metabolic Disorders

• Tumour lysis syndrome
• Acute pancreatitis
• Hyperglycaemia
• Decreased weight

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Back pain

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Alopecia
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Infusion site extravasation
  - Redness
  - Pain
  - Swelling
  - Blistering
  - Sloughing

Immune, Blood and Lymphatic System Disorders

• Anaphylactic reaction
• Infections
• Neutropenia
• Anaemia
• Thrombocytopenia
• Febrile neutropenia
• Fever
• Herpes zoster
• Herpes simplex
• Staphylococcal bacteraemia
• Cytomegalovirus infection or reactivation
• Sepsis
• Septic shock
• Infusion-related reactions

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Combination therapy

Central Nervous System Disorders

• Peripheral sensory neuropathy
• Peripheral motor neuropathy
• Dizziness
• Fatigue
• Insomnia

Respiratory Disorders

• Upper respiratory tract infection
• Pneumocystis jiroveci pneumonia
• Pneumonia
• Cough
• Dyspnoea

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Abdominal pain
• Diarrhoea
• Oral candidiasis
• Stomatitis

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase

Endocrine and Metabolic Disorders

• Tumour lysis syndrome
• Acute pancreatitis
• Hyperglycaemia
• Decreased appetite
• Decreased weight

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Back pain
• Bone pain

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Alopecia
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Immune, Blood and Lymphatic System Disorders

• Anaphylactic transfusion reaction
• Infections
• Neutropenia
• Anaemia
• Thrombocytopenia
• Febrile neutropenia
• Fever
• Herpes zoster
• Herpes simplex
• Sepsis
• Septic shock
• Infusion-related reactions

• Bleomycin
• Strong CYP3A4 inhibitors
• Strong P-gp inhibitors
• Ketoconazole

• Hepatic function
• Renal function
• Full blood count with differential

Specific cases may require

• Pregnancy test
• Serum glucose
• Magnetic resonance imaging
• Lumbar puncture
• Brain biopsy
• Serum amylase
• Serum lipase

Additional observations

• Monitor for infusion reaction
• Signs and symptoms of
  - Progressive multifocal leukoencephalopathy
  - Neuropathy
  - Dermatologic toxicity
  - Pulmonary toxicity
  - Gastrointestinal toxicity
  - Pulmonary toxicity
  - Tumor lysis syndrome
  - Infection
  - Acute pancreatitis

Dosing recommendations for neutropenia with monotherapy

International manufacturer recommendations

Severity grade of neutropenia (signs and symptoms -[abbreviated description of CTCAEa])	Modification of dosing schedule
Grade 1 (<LLN-1500/mm3 <LLN-1.5 x 109/L) or Grade 2 (<1500-1000/mm3 <1.5-1.0 x 109/L)	Continue with the same dose and schedule
Grade 3 (<1,000- 500/mm3 <1.0-0.5 x 109/L) or Grade 4 (<500/mm3 <0.5 x 109/L)	Withhold dose until toxicity returns to ≤Grade 2 or baseline then resume treatment at the same dose and scheduleb. Consider growth factor support (G-CSF or GM-CSF) in subsequent cycles for patients who develop Grade 3 or Grade 4 neutropenia

^a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0; LLN = lower limit of normal

^b. Patients who develop Grade 3 or Grade 4 lymphopenia may continue treatment without interruption

Dosing recommendations for neutropenia during combination therapy

Severity grade of neutropenia (signs and symptoms -  [abbreviated description of CTCAEa])	Modification of dosing schedule
Grade 1 (<LLN - 1500/mm3 <LLN-1.5 x 109/L) or Grade 2 (< 1500-1000/mm3 <1.5-1.0 x 109/L) Grade 3 (< 1,000-500/mm3 <1.0-0.5 x 109/L) or Grade 4 (< 500/mm3 <0.5 x 109/L)	Primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all patients receiving combination therapy. Continue with the same dose and schedule

^a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0; LLN = lower limit of normal

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

General precautions

• Procedures for proper handling and disposal of anticancer medicinal products should be considered
• Proper aseptic technique throughout the handling of this medicinal product should be followed

Instructions for reconstitution

• Each single-use vial must be reconstituted with 10.5ml of water for injections to a final concentration of 5mg/ml. Each vial contains a 10% overfill giving 55mg of brentuximab vedotin per vial and a total reconstituted volume of 11ml
  - Direct the stream toward the wall of the vial and not directly at the cake or powder
  - Gently swirl the vial to aid dissolution. DO NOT SHAKE
  - The reconstituted solution in the vial is a clear to slightly opalescent, colourless solution with a final pH of 6.6
  - The reconstituted solution should be inspected visually for any foreign particulate matter and/or discolouration. In the event of either being observed, discard the medicinal product

Preparation of infusion solution

• The appropriate amount of reconstituted brentuximab vedotin must be withdrawn from the vial(s) and added to an infusion bag containing sodium chloride 9mg/ml (0.9%) solution for injection in order to achieve a final concentration of 0.4-1.2mg/ml brentuximab vedotin
• The recommended diluent volume is 150ml. The already reconstituted brentuximab vedotin can also be diluted into 5% dextrose for injection or Lactated Ringer's for injection
• Gently invert the bag to mix the solution containing brentuximab vedotin. DO NOT SHAKE
• Any portion left in the vial, after withdrawal of the volume to be diluted, must be disposed of in accordance with local requirements
• Do not add other medicinal products to the prepared brentuximab vedotin infusion solution or intravenous infusion set. The infusion line should be flushed following administration with sodium chloride 9mg/ml (0.9%) solution for injection, 5% dextrose for injection, or Lactated Ringer's for injection
• Following dilution, infuse the brentuximab vedotin solution immediately at the recommended infusion rate
• Total storage time of the solution from reconstitution to infusion should not exceed 24hrs

Brentuximab vedotin is an antibody-drug conjugate (ADC) that delivers an antineoplastic agent that results in apoptotic cell death selectively in CD30-expressing tumour cells. The biological activity of brentuximab vedotin results from a multi-step process. ADC binds to CD30 on the cell surface initiating internalisation of the ADC-CD30 complex, which then moves to the lysosomal compartment. Intracellularly, a single defined active species, MMAE, is released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest and results in apoptotic death of the CD30-expressing tumour cell. 

Injection (per vial) 50mg

• Adcetris (Takeda) originator