Adcetris 50 mg

/ Takeda

ADCETRIS should be administered under the supervision of a physician experienced in the use of anti-cancer agents.
Previously Untreated HL: 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.
Primary prophylaxis with growth factor support (G-CSF), beginning with the first dose, is recommended for all patients with previously untreated HL receiving combination therapy.
Refer to the summary of product characteristics (SmPC) of chemotherapy agents given in combination with ADCETRIS for patients with previously untreated HL.
HL at increased risk of relapse or progression: 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.
Relapsed or refractory HL: 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.
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).
Previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas: 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.
Primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all patients with previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas, receiving combination therapy.
Refer to the SmPCs of chemotherapy agents given in combination with ADCETRIS for patients with previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas.
Relapsed or refractory 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.
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).
CTCL: 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.
General: Treatment should be continued until disease progression or unacceptable toxicity.
If the patient’s weight is more than 100 kg, the dose calculation should use 100 kg.
Complete blood counts should be monitored prior to administration of each dose of this treatment.
Patients should be monitored during and after infusion.
Dose adjustments:
Neutropenia: If neutropenia develops during treatment it should be managed by dose delays. See Table 1 and Table 2 at the attached doctor’s leaflet for appropriate dosing recommendations for monotherapy and combination therapy, respectively.
Peripheral neuropathy: If peripheral sensory or motor neuropathy emerges or worsens during treatment see Table 3 and 4 at the attached doctor’s leaflet for appropriate dosing recommendations for monotherapy and combination therapy, respectively.
Special patient populations
Renal and hepatic impairment: 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.
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.
Elderly: The safety and efficacy in patients aged 65 and older have not been established. No data are available.
Paediatric population: The safety and efficacy of ADCETRIS in children less than 18 years have not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2 at the attached doctor’s leaflet, but no recommendation on a posology can be made.
In nonclinical studies, thymus depletion has been observed.
Method of administration: The recommended dose of ADCETRIS is infused over 30 minutes.
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.

Hodgkin lymphoma: ADCETRIS is indicated for the treatment of adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine.
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).
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):
– following ASCT, or
– following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.
Systemic anaplastic large cell lymphoma and Peripheral T-cell lymphomas (PTCL): ADCETRIS is indicated for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone.
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory sALCL.
Cutaneous T‑cell lymphoma: ADCETRIS is indicated for the treatment of adult patients with CD30+ cutaneous T-cell lymphoma (CTCL) after at least 1 prior systemic therapy.

Hypersensitivity to the active substance or to any of the excipients. Combined use of bleomycin and brentuximab vedotin causes pulmonary toxicity.

Progressive multifocal leukoencephalopathy: 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 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 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.
See prescribing information for full details.
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.  ADCETRIS-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 resolution or improvement 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 ADCETRIS or discontinuation of treatment. See prescribing information for full details.
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 refer to prescribing information for full details.
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.
In combination therapy with AVD or CHP, advanced age was a risk factor for febrile neutropenia. When ADCETRIS is administered in combination with AVD or CHP, primary prophylaxis with G-CSF, beginning with the first dose is recommended for all patients regardless of age.
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.
See prescribing information for full details.
CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of brentuximab vedotin, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Nevertheless, Adcetris should be used with caution in other CD30+ CTCL patients after careful consideration of the potential benefit-risk on an individual basis. See prescribing information for full details.
Sodium Content In Excipients: This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
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.

Adverse reactions (monotherapy)
Very common (≥1/10): Infection, upper respiratory tract infection, neutropenia, peripheral sensory neuropathy, peripheral motor neuropathy, cough, dyspnea, diarrhoea, nausea, vomiting, constipation, abdominal pain, rash, pruritus, myalgia, arthralgia, fatigue, pyrexia, infusion-related reactions, weight decreased.
Common (≥1/100 to <1/10): Herpes zoster, pneumonia, herpes simplex,
oral candidiasis, anaemia, thrombocytopenia, hyperglycemia, dizziness, Alanine aminotransferase/aspartate Aminotransferase (ALT/AST) increased, alopecia, back pain, chills.
Adverse reactions (combination therapy)
Very common (≥1/10): Infection , upper respiratory tract infection,
Neutropenia, anaemia, febrile neutropenia, Decreased appetite, Peripheral sensory neuropathy, peripheral motor neuropathy, dizziness, Cough, dyspnoea, Nausea, constipation, vomiting, diarrhoea, abdominal pain, stomatitis, Alopecia, rash, Bone pain, arthralgia, myalgia back pain, Fatigue, pyrexia, Weight decreased.
Common (≥1/100 to <1/10): Pneumonia, oral candidiasis, sepsis/septic shock, herpes zoster, Thrombocytopenia, Hyperglycaemia, Alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased,
Pruritus, Infusion-related reactionsa, chills.
See prescribing information for full details.

Interaction with medicinal products metabolized through CYP3A4 route (CYP3A4 inhibitors/inducers): Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73%, and did not alter the plasma exposure to brentuximab vedotin. Therefore, co-administration of brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of neutropenia. If neutropenia develops, refer to prescribing information for dosing recommendations.
Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter the plasma exposure to brentuximab vedotin. Though PK data are limited, co administration of rifampicin appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter the metabolism of midazolam; therefore brentuximab vedotin is not expected to alter the exposure to medicines that are metabolised by CYP3A4 enzymes.
Doxorubicin, vinblastine and dacarbazine (AVD): The serum and plasma pharmacokinetic characteristics of antibody drug conjugate (ADC) and MMAE respectively following administration of brentuximab vedotin in combination with AVD were similar to that in monotherapy.
Co-administration of brentuximab vedotin did not affect the plasma exposure of AVD.
Cyclophosphamide, Doxorubicin and Prednisone (CHP): The serum and plasma pharmacokinetic characteristics of ADC and MMAE, respectively, following administration of brentuximab vedotin in combination with CHP were similar to that in monotherapy.
Co‑administration of brentuximab vedotin is not expected to affect the exposure of CHP.
Bleomycin: There were no formal drug-drug interaction studies with brentuximab vedotin and bleomycin(B). In a phase 1 dose finding and safety study (SGN35-009), unacceptable pulmonary toxicity (including 2 fatal events) was noted in 11 of 25 patients (44%) treated with brentuximab vedotin plus ABVD. No pulmonary toxicity or fatal events were reported with brentuximab vedotin + AVD. Therefore, co-administration of ADCETRIS with bleomycin is contraindicated.
See prescribing information for full details.

Pregnancy: There are no data from the use of ADCETRIS in pregnant women. Studies in animals have shown reproductive toxicity.
ADCETRIS 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.
See the fertility section below pertaining to advice for women whose male partners are being treated with ADCETRIS.
Lactation: 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 breast-feeding or to discontinue/abstain from this therapy, taking into account a potential risk of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: In non-clinical studies, ADCETRIS 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.
Women of childbearing potential: Women of childbearing potential should be using two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment.

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 prescribing information for full details.

Effects on ability to drive and use machines: ADCETRIS may have a moderate influence on the ability to drive and use machines (e.g. dizziness).
Storage: Store in a refrigerator (2°C-8°C). Do not freeze. Keep the vial in the original carton in order to protect from light.
Shelf life: The expiry date of the product is indicated on the packaging materials. 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.