This section is intended for UK healthcare professionals. If you are a member of the public click here. If you have been prescribed ADCETRIS click here.

Administering ADCETRIS1

Dosing schedule
  • The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks
  • For consolidation in patients with HL at increased risk of relapse or progression following ASCT, ADCETRIS treatment should start following recovery from ASCT based on clinical judgement
  • The recommended starting dose for the reuse of ADCETRIS in patients with relapsed or refractory HL or sALCL, who have previously responded to treatment, is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Alternatively, treatment may be started at the last tolerated dose
Dose Calculation

Calculation to determine the total ADCETRIS dose (ml) to be further diluted:

ADCETRIS dose (mg/kg) x patient's body weight (kg)
÷
Reconstituted vial concentration (5 mg/ml)
=
Total ADCETRIS dose (ml) to be further diluted

Note: If patient's weight is more than 100 kg, the dose calculation should use 100 kg. The maximal recommended dose is 180 mg.

Calculation to determine the total number of ADCETRIS vials needed:

Total ADCETRIS dose (ml) to be administered
÷
Total volume per vial (10 ml/vial)
=
Number of ADCETRIS vials needed

Sample calculations for patients receiving the recommended dose of 1.8 mg/kg of ADCETRIS for weights ranging from 60 kg to 120 kg

Patient weight (kg) Total dose = patient weight multiplied by recommended dose [1.8 mg/kga]) Total volume to be dilutedb = total dose divided by reconstituted vial concentration [5 mg/ml]) Number of vials needed = total volume to be diluted divided by total volume per vial [10 ml/vial])
60 kg 108 mg 21.6 ml 2.16 vials
80 kg 144 mg 28.8 ml 2.88 vials
100 kg 180 mg 36 ml 3.6 vials
120 kgc 180 mgd 36 ml 3.6 vials

a. For a reduced dose, use 1.2 mg/kg for the calculation.
b. To be diluted in 150 ml of diluent and administered by intravenous infusion over 30 minutes every 3 weeks.
c. If patient's weight is more than 100 kg, the dose calculation should use 100 kg.
d. The maximal recommended dose is 180 mg

Dose modification
  • If the patient's weight is more than 100 kg, the dose calculation should use 100 kg
  • The recommended starting dose in patients with hepatic impairment or severe renal impairment is 1.2 mg/kg
Treatment cycles
  • Treatment should be continued until disease progression or unacceptable toxicity
  • Patients who achieve stable disease or better should receive a minimum of 8 cycles and up to a maximum of 16 cycles (approximately 1 year)
  • For patients with HL at increased risk of relapse or progression following ASCT, ADCETRIS treatment should start following recovery from ASCT based on clinical judgement. These patients should receive up to 16 cycles
  • The recommended starting dose for the reuse of ADCETRIS in patients with relapsed or refractory HL or sALCL who have previously responded to treatment, is 1.8mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Alternatively treatment may start at the last tolerated dose
Reconstitution and infusion preparation
  • Aseptic technique throughout the handling of ADCETRIS should be followed
  • Reconstitution
    • Each single use vial must be reconstituted with 10.5ml of water for injection to a final concentration of 5mg/ml
    • Direct the stream to the wall of the vial. Gently swirl the vial to aid dissolution. Do not shake
    • The reconstituted solution in the vial is a clear to slightly opalescent, colourless solution
    • Visually inspect the reconstituted solution for any foreign particles. Discard if you observe any particles.
  • Preparation of infusion solution
    • The calculated amount of reconstituted ADCETRIS must be withdrawn from the vials and added to an infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection to achieve a final concentration of 0.4-1.2 mg/ml ADCETRIS. The recommended diluent volume is 150ml. The already reconstituted ADCETRIS can also be diluted into 5% dextrose for injection or Lactated Ringer's for injection.
    • For example, an 80kg patient, would require a total dose of 144mg (28.8 ml to be further diluted by adding an infusion bag)
      • If a 100ml infusion bag is used then the final concentration is: 1.44 mg/ml - This is outside the recommended concentration range
      • If a 150ml infusion bag is used then the final concentration is: 0.96 mg/ml - This is within the recommended concentration range
      • If a 200ml infusion bag is used then the final concentration is: 0.72 mg/ml - This is within the recommended concentration range
      • If a 250ml infusion bag is used then the final concentration is: 0.58 mg/ml - This is within the recommended concentration range
  • Gently invert the bag to mix. DO NOT SHAKE
    • Do not add other medicinal products to the prepared ADCETRIS infusion solution or intravenous infusion set. The infusion line should be flushed following administration with sodium chloride 9 mg/ml (0.9%), 5% dextrose for injection, or Lactated Ringer's for injection.
    • Following dilution, the ADCETRIS solution should be infused immediately at the recommended infusion rate
    • Total storage time of the solution from reconstitution to infusion should not exceed 24 hours
Administration
  • The recommended dose of ADCETRIS is infused over 30 minutes and can be administered in the outpatient setting
    • ADCETRIS must not be administered as an intravenous push or bolus
    • ADCETRIS should be administered through a dedicated intravenous line and it must not be mixed with other medicinal products
    • Patients should be monitored during and after infusion
  • No premedication is generally required
  • Complete blood counts should be monitored prior to administration of each dose of this treatment
Storage
  • Keep vial in original carton to protect from light and store in refrigerator (2-8°C)
  • Do not freeze
  • After reconstitution/dilution, from a microbiological point of view, the product should be used immediately. However, chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C

Warnings and precautions1

Patients should not take ADCETRIS if they are allergic to brentuximab vedotin or any of the other ingredients or if they are currently receiving bleomycin

For full details of all warnings and precautions associated with ADCETRIS view the Summary of Product Characteristics.

Progressive multifocal leukoencephalopathy (PML)

John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in brentuximab vedotin-treated patients. PML has been reported in patients who received this treatment after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.

Patients should be closely monitored for new or worsening neurological, cognitive, or behavioural signs or symptoms, which may be suggestive of PML. Brentuximab vedotin dosing should be held for any suspected case of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established. Brentuximab vedotin dosing should be permanently discontinued if a diagnosis of PML is confirmed.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological, or psychiatric symptoms).

Pancreatitis

Acute pancreatitis has been observed in patients treated with brentuximab vedotin. Fatal outcomes have been reported.

Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Brentuximab vedotin should be held for any suspected case of acute pancreatitis. Brentuximab vedotin should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Pulmonary Toxicity

Cases of pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported in patients receiving brentuximab vedotin. Although a causal association with brentuximab vedotin has not been established, the risk of pulmonary toxicity cannot be ruled out. In the event of new or worsening pulmonary symptoms (e.g. cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients should be treated appropriately. Consider holding brentuximab vedotin dosing during evaluation and until symptomatic improvement.

Serious infections and opportunistic infections

Serious infections such as pneumonia, staphylococcal bacteraemia, sepsis/septic shock (including fatal outcomes) and herpes zoster, cytomegalovirus (CMV) (reactivation) and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with brentuximab vedotin. Patients should be carefully monitored during treatment for the emergence of possible serious and opportunistic infections.

Infusion-related reactions

Immediate and delayed infusion-related reactions (IRR), as well as anaphylactic reactions, have been reported.

Patients should be carefully monitored during and after infusion. If an anaphylactic reaction occurs, administration of brentuximab vedotin should be immediately and permanently discontinued and appropriate medical therapy should be administered.

If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. Premedication may include paracetamol, an antihistamine and a corticosteroid.

IRRs are more frequent and more severe in patients with antibodies to brentuximab vedotin.

Tumour lysis syndrome

Tumour lysis syndrome (TLS) has been reported with brentuximab vedotin. Patients with rapidly proliferating tumour and high tumour burden are at risk of tumour lysis syndrome. These patients should be monitored closely and managed according to best medical practice. Management of TLS may include aggressive hydration, monitoring of renal function, correction of electrolyte abnormalities, anti-hyperuricaemic therapy, and supportive care.

Peripheral neuropathy

Brentuximab vedotin treatment may cause peripheral neuropathy, both sensory and motor. Brentuximab vedotin-induced peripheral neuropathy is typically an effect of cumulative exposure to this medicinal product and is reversible in most cases.

In clinical trials, the majority of patients had improvement or resolution of their symptoms. Patients should be monitored for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay and a dose reduction of brentuximab vedotin or discontinuation of treatment.

Haematological toxicities

Grade 3 or Grade 4 anaemia, thrombocytopenia, and prolonged (≥1 week) Grade 3 or Grade 4 neutropenia can occur with brentuximab vedotin. Complete blood counts should be monitored prior to administration of each dose. If Grade 3 or Grade 4 neutropenia develops during treatment, it should be managed by dose delays. Refer to SmPC for details of dosing recommendations.

Febrile neutropenia

Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count <1.0 x 109/L, fever ≥38.5°C; ref CTCAE v3) has been reported with treatment with brentuximab vedotin. Complete blood counts should be monitored prior to administration of each dose of this treatment. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.

Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with brentuximab vedotin. Fatal outcomes have been reported. If SJS or TEN occur, treatment with brentuximab vedotin should be discontinued and appropriate medical therapy should be administered.

Gastrointestinal Complications

Gastrointestinal (GI) complications including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, some with fatal outcomes, have been reported in patients treated with brentuximab vedotin. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.

Hepatotoxicity

Hepatotoxicity in the form of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) has been reported with brentuximab vedotin. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Liver function should be tested before initiating the treatment and routinely monitored in patients receiving brentuximab vedotin. Patients experiencing hepatotoxicity may require a delay, change in dose or discontinuation of brentuximab vedotin.

Hyperglycaemia

Hyperglycaemia has been reported during clinical trials in patients with an elevated Body Mass Index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycaemia should have their serum glucose closely monitored. Anti-diabetic treatment should be administered as appropriate.

Renal and hepatic impairment

There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations.

Sodium content in excipients

This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

Tolerability1

The safety profile of ADCETRIS is based on available clinical trial data, the Named Patient Program (NPP), and post-marketing experience to date.

For a full summary of the safety profile of ADCETRIS please consult the Summary of Product Characteristics.

The tabulated list of adverse reactions for ADCETRIS has been determined based on data generated from clinical studies and are listed by MedDRA System Organ Class and Preferred Term.

Within each System Organ Class, adverse reactions are listed under frequency categories of:

  • Very common (≥1/10)
  • Common (≥1/100 to <1/10)
  • Uncommon (≥1/1,000 to <1/100)
  • Rare (≥1/10,000 to <1/1,000)
  • Very rare (<1/10,000)
  • Not known (cannot be estimated from the available data)
Infections and infestations
System organ class Adverse reactions
Very common: Infectiona, upper respiratory tract infection
Common: Herpes zoster, pneumonia, herpes simplex, oral candidiasis
Uncommon: Pneumocystis jiroveci pneumonia, staphylococcal bacteraemia, cytomegalovirus infection or reactivation, sepsis/septic shock
Frequency not known: Progressive multifocal leukoencephalopathy

a. Represents pooling of preferred terms.

Blood and lymphatic system disorders
System organ class Adverse reactions
Very common: Neutropenia
Common: Anaemia, thrombocytopenia
Uncommon: Febrile neutropenia
Immune system disorders
System organ class Adverse reactions
Uncommon: Anaphylactic reaction
Metabolism and nutrition disorders
System organ class Adverse reactions
Common: Hyperglycaemia
Uncommon: Tumour lysis syndrome
Nervous system disorders
System organ class Adverse reactions
Very common: Peripheral sensory neuropathy, peripheral motor neuropathy
Common: Dizziness
Uncommon: Demyelinating polyneuropathy
Respiratory, thoracic and mediastinal disorders
System organ class Adverse reactions
Very common: Cough, dyspnoea
Gastro-intestinal disorders
System organ class Adverse reactions
Very common: Diarrhoea, nausea, vomiting, constipation, abdominal pain
Uncommon: Pancreatitis acute
Hepatobiliary disorders
System organ class Adverse reactions
Common: Alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased
Skin and subcutaneous tissue disorders
System organ class Adverse reactions
Very common: Rasha, pruritus
Common: Alopecia
Uncommon: Stevens-Johnson syndrome/toxic epidermal necrolysis

a. Represents pooling of preferred terms.

Musculoskeletal and connective tissue disorders
System organ class Adverse reactions
Very common: Myalgia, arthralgia
Common: Back pain
General disorders and administration site conditions
System organ class Adverse reactions
Very common: Fatigue, pyrexia, infusion-related reactionsa
Common: Chills

a. Represents pooling of preferred terms.

Investigations
System organ class Adverse reactions
Very common: Weight decreased

Adverse events should be reported. In the United Kingdom, reporting forms and information can be found at https://yellowcard.mhra.gov.uk/.

Adverse events should also be reported to Takeda on 01628 537900 or e-mail DSO-UK@takeda.com.