Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark, medinfoEMEA@takeda.com
ADCETRIS is indicated for adult patients with previously untreated CD30+ Stage III or IV Hodgkin lymphoma (HL) in combination with doxorubicin, vinblastine and dacarbazine (AVD) (see sections 4.2 and 5.1).
ADCETRIS is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT) (see section 5.1).
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):
1. following ASCT, or
2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
ADCETRIS in combination with cyclophosphamide, doxorubicin and prednisone (CHP) is indicated for adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) (see section 5.1).
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory sALCL.
ADCETRIS is indicated for the treatment of adult patients with CD30+ cutaneous T-cell lymphoma (CTCL) after at least 1 prior systemic therapy (see section 5.1).
ADCETRIS should be administered under the supervision of a physician experienced in the use of anti-cancer agents.
The recommended dose in combination with chemotherapy (doxorubicin [A], vinblastine [V] and dacarbazine [D] [AVD]) is 1.2 mg/kg administered as an intravenous infusion over 30 minutes on days 1 and 15 of each 28-day cycle for 6 cycles (see section 5.1).
Primary prophylaxis with growth factor support (G-CSF), beginning with the first dose, is recommended for all adult patients with previously untreated HL receiving combination therapy (see section 4.4).
Refer to the summary of product characteristics (SmPC) of chemotherapy agents given in combination with ADCETRIS for patients with previously untreated HL.
The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
ADCETRIS treatment should start following recovery from ASCT based on clinical judgment. These patients should receive up to 16 cycles (see section 5.1).
The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
The recommended starting dose for the retreatment of patients who have previously responded to treatment with ADCETRIS 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 (see section 5.1).
Treatment should be continued until disease progression or unacceptable toxicity (see section 4.4).
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) (see section 5.1).
The recommended dose in combination with chemotherapy (cyclophosphamide [C], doxorubicin [H] and prednisone [P] [CHP]) is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks for 6 to 8 cycles (see section 5.1).
Primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all adult patients with previously untreated sALCL receiving combination therapy (see section 4.4).
Refer to the SmPCs of chemotherapy agents given in combination with ADCETRIS for patients with previously untreated sALCL.
The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
The recommended starting dose for the retreatment of patients who have previously responded to treatment with ADCETRIS 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 (see section 5.1).
Treatment should be continued until disease progression or unacceptable toxicity (see section 4.4).
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) (see section 5.1).
The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.
Patients with CTCL should receive up to 16 cycles (see section 5.1).
If the patient’s weight is more than 100 kg, the dose calculation should use 100 kg (see section 6.6).
Complete blood counts should be monitored prior to administration of each dose of this treatment (see section 4.4).
Patients should be monitored during and after infusion (see section 4.4).
If neutropenia develops during treatment it should be managed by dose delays. See Table 1 and Table 2 for appropriate dosing recommendations for monotherapy and combination therapy, respectively (see also section 4.4).
Table 1. Dosing recommendations for neutropenia with monotherapy:
| Severity grade of neutropenia (signs and symptoms [abbreviated description of CTCAEa]) | Modification of dosing schedule |
| Grade 1 (< LLN-1500/mm³ < LLN-1.5 × 109/L) or Grade 2 (< 1500-1000/mm³ < 1.5-1.0 × 109/L) | Continue with the same dose and schedule. |
| Grade 3 (< 1,000-500/mm³ < 1.0-0.5 × 109/L) or Grade 4 (< 500/mm³ < 0.5 × 109/L) | Withhold dose until toxicity returns to ≤ Grade 2 or baseline then resume treatment at the same dose and scheduleb. Consider 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; see Neutrophils/granulocytes; LLN = lower limit of normal.
b Patients who develop Grade 3 or Grade 4 lymphopenia may continue treatment without interruption.
Table 2. 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 × 109/L) or Grade 2 (< 1500-1000/mm³ < 1.5-1.0 × 109/L) Grade 3 (< 1,000-500/mm³ < 1.0-0.5 × 109/L) or Grade 4 (< 500/mm³ < 0.5 × 109/L) | Primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all adult 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) v4.03; see Neutrophils/granulocytes; LLN = lower limit of normal.
If peripheral sensory or motor neuropathy emerges or worsens during treatment see Table 3 and 4 for appropriate dosing recommendations for monotherapy and combination therapy, respectively (see section 4.4).
Table 3. Dosing recommendations for new or worsening peripheral sensory or motor neuropathy with monotherapy:
| Severity of peripheral sensory or motor neuropathy (signs and symptoms [abbreviated description of CTCAEa]) | Modification of dose and schedule |
| Grade 1 (paraesthesia and/or loss of reflexes, with no loss of function) | Continue with the same dose and schedule. |
| Grade 2 (interfering with function but not with activities of daily living) | Withhold dose until toxicity returns to ≤ Grade 1 or baseline, then restart treatment at a reduced dose of 1.2 mg/kg up to a maximum of 120 mg every 3 weeks. |
| Grade 3 (interfering with activities of daily living) | Withhold dose until toxicity returns to ≤ Grade 1 or baseline, then restart treatment at a reduced dose of 1.2 mg/kg up to a maximum of 120 mg every 3 weeks. |
| Grade 4 (sensory neuropathy that is disabling or motor neuropathy that is life threatening or leads to paralysis) | Discontinue treatment. |
a Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0; see neuropathy: motor; neuropathy: sensory; and neuropathic pain.
Table 4. Dosing recommendations for new or worsening peripheral sensory or motor neuropathy during combination therapy:
| Combination therapy with AVD | Combination therapy with CHP | |
| Severity of peripheral sensory or motor neuropathy (signs and symptoms [abbreviated description of CTCAEa]) | Modification of dose and schedule | Modification of dose and schedule |
| Grade 1 (paraesthesia and/or loss of reflexes, with no loss of function) | Continue with the same dose and schedule. | Continue with the same dose and schedule. |
| Grade 2 (interfering with function but not with activities of daily living) | Reduce dose to 0.9 mg/kg up to a maximum of 90 mg every 2 weeks. | Sensory neuropathy: Continue treatment at same dose level. Motor neuropathy: Reduce dose to 1.2 mg/kg, up to a maximum of 120 mg every 3 weeks. |
| Grade 3 (interfering with activities of daily living) | Withhold treatment with ADCETRIS until toxicity is ≤ Grade 2, then restart treatment at a reduced dose to 0.9 mg/kg up to a maximum of 90 mg every 2 weeks. | Sensory neuropathy: Reduce dose to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks. Motor neuropathy: Discontinue treatment. |
| Grade 4 (sensory neuropathy which is disabling or motor neuropathy that is life-threatening or leads to paralysis) | Discontinue treatment. | Discontinue treatment. |
a Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; see neuropathy: motor; neuropathy: sensory; and neuropathic pain.
Combination therapy:
Patients with renal impairment should be closely monitored for adverse events. There is no clinical trial experience using ADCETRIS in combination with chemotherapy in patients with renal impairment, where serum creatinine is ≥2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance is ≤40 mL/minute. Use of ADCETRIS in combination with chemotherapy should be avoided in patients with severe renal impairment.
Patients with hepatic impairment should be closely monitored for adverse events. The recommended starting dose in patients with mild hepatic impairment receiving ADCETRIS in combination with AVD is 0.9 mg/kg administered as an intravenous infusion over 30 minutes every 2 weeks. The recommended starting dose in patients with mild hepatic impairment receiving ADCETRIS in combination with CHP is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. There is no clinical trial experience using ADCETRIS in combination with chemotherapy in patients with hepatic impairment, 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 HL in the liver. Use of ADCETRIS in combination with chemotherapy should be avoided in patients with moderate and severe hepatic impairment.
Monotherapy:
The recommended starting dose in patients with severe renal impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with renal impairment should be closely monitored for adverse events (see section 5.2).
The recommended starting dose in patients with hepatic impairment is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Patients with hepatic impairment should be closely monitored for adverse events (see section 5.2).
The dosing recommendations for patients aged 65 and older are the same as for adults. Currently available data are described in sections 4.8, 5.1 and 5.2.
The safety and efficacy of ADCETRIS in children less than 18 years have not been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
The recommended dose of ADCETRIS is infused over 30 minutes.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
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 (see section 6.2).
There is no known antidote for overdose of ADCETRIS. In case of overdose, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered (see section 4.4).
4 years.
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.
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vial in the original carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
Type I glass vial with a butyl rubber stopper and an aluminium/plastic flip-off seal, containing 50 mg powder.
Pack of 1 vial.
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.
Each single use vial must be reconstituted with 10.5 mL of water for injections to a final concentration of 5 mg/ mL. Each vial contains a 10% overfill giving 55 mg of ADCETRIS per vial and a total reconstituted volume of 11 mL.
1. Direct the stream toward the wall of the vial and not directly at the cake or powder.
2. Gently swirl the vial to aid dissolution. DO NOT SHAKE.
3. The reconstituted solution in the vial is a clear to slightly opalescent, colourless solution with a final pH of 6.6.
4. 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.
The appropriate amount of reconstituted ADCETRIS must be withdrawn from the vial(s) and added to an infusion bag containing sodium chloride 9 mg/ mL (0.9%) solution for injection in order to achieve a final concentration of 0.4-1.2 mg/ mL ADCETRIS. The recommended diluent volume is 150 mL. The already reconstituted ADCETRIS can also be diluted into 5% dextrose for injection or Lactated Ringer’s for injection.
Gently invert the bag to mix the solution containing ADCETRIS. 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 ADCETRIS infusion solution or intravenous infusion set. The infusion line should be flushed following administration with sodium chloride 9 mg/ mL (0.9%) solution for injection, 5% dextrose for injection, or Lactated Ringer’s for injection.
Following dilution, infuse the ADCETRIS solution immediately at the recommended infusion rate.
Total storage time of the solution from reconstitution to infusion should not exceed 24 hours.
Calculation to determine the total ADCETRIS dose (mL) to be further diluted (see section 4.2):
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
Table 19. Sample calculations for patients receiving the recommended dose of 1.8 mg/kg, 1.2 mg/kg or 0.9 mg/kg of ADCETRIS for weights ranging from 60 kg to 120 kga,b:
| Recommended dose | Patient weight (kg) | Total dose = patient weight multiplied by recommended dose | Total volume to be dilutedc = 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] |
|---|---|---|---|---|
| 1.8 mg/kg (up to a maximum of 180 mg) | 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 kgd | 180 mg | 36 mL | 3.6 vials | |
| 1.2 mg/kg (up to a maximum of 120 mg) | 60 kg | 72 mg | 14.4 mL | 1.44 vials |
| 80 kg | 96 mg | 19.2 mL | 1.92 vials | |
| 100 kg | 120 mg | 24 mL | 2.4 vials | |
| 120 kgd | 120 mg | 24 mL | 2.4 vials | |
| 0.9 mg/kg (up to a maximum of 90 mg) | 60 kg | 54 mg | 10.8 mL | 1.08 vials |
| 80 kg | 72 mg | 14.4 mL | 1.44 vials | |
| 100 kg | 90 mg | 18 mL | 1.8 vials | |
| 120 kgd | 90 mg | 18 mL | 1.8 vials |
a This table provides sample calculations for adult patients.
b For paediatric patients studied in clinical trials (6-17 years of age), body surface area-based dosing was calculated as 48 mg/m² every two weeks in combination with AVD in a 28-day cycle or 72 mg/m² every three weeks as monotherapy. (See sections 5.1 and 5.2 for information on clinical studies conducted in paediatric patients.)
c To be diluted in 150 mL of diluent and administered by intravenous infusion over 30 minutes.
d If patient’s weight is more than 100 kg, the dose calculation should use 100 kg.
ADCETRIS is for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
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