Adcetris - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

ADCETRIS 50 mg powder for concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 50 mg of brentuximab vedotin.

After reconstitution (see section 6.6), each mL contains 5 mg of brentuximab vedotin.

ADCETRIS is an antibody-drug conjugate composed of a CD30-directed monoclonal antibody (recombinant chimeric immunoglobulin G1 [IgG1], produced by recombinant DNA technology in Chinese Hamster ovary cells) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE).

Excipient with known effect

Each vial contains approximately 13.2 mg of sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

White to off-white cake or powder.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Hodgkin lymphoma

ADCETRIS is indicated for adult patients with previously untreated CD30+ Stage 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.

Systemic anaplastic large cell lymphoma

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.

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 (see section 5.1).

4.2 Posology and method of administration

ADCETRIS should be administered under the supervision of a physician experienced in the use of anti-cancer agents.

Posology

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 (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.

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 (see section 5.1).

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 (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).

Previously untreated sALCL

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.

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 (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).

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 (see section 5.1).

General

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).

Dose adjustments

Neutropenia

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

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

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

Table 2: Dosing recommendations for neutropenia during combination therapy

Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; see Neutrophils/gra­nulocytes; LLN = lower limit of normal.

Peripheral neuropathy

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

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

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.

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 (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).

Elderly

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.

Paediatric population

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.

Method of administration

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).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Combined use of bleomycin and ADCETRIS causes pulmonary toxicity (see section 4.5).

4.4 Special warnings and precautions for use

Progressive multifocal leukoencephalo­pathy

John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in ADCETRIS-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. ADCETRIS 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. ADCETRIS 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 ADCETRIS. 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. ADCETRIS should be held for any suspected case of acute pancreatitis. ADCETRIS 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 ADCETRIS. Although a causal association with ADCETRIS 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 ADCETRIS 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 ADCETRIS. 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 ADCETRIS 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 section 4.8).

Tumour lysis syndrome

Tumour lysis syndrome (TLS) has been reported with ADCETRIS. 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

ADCETRIS 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 (see section 4.8). 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 section 4.2).

Haematological toxicities

Grade 3 or Grade 4 anaemia, thrombocytopenia, and prolonged (> 1 week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose. If Grade 3 or Grade 4 neutropenia develops, refer to section 4.2.

Febrile neutropenia

Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count < 1.0 × 109/L, fever > 38.5 0C; ref CTCAE v3) has been reported with treatment with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose of 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 adult patients regardless of age.

Severe cutaneous adverse reactions (SCARs)

Cases of SCARs, including_Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with

ADCETRIS. Fatal outcomes have been reported for SJS and TEN. If SJS, TEN or DRESS occur, ADCETRIS 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 ADCETRIS. 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 ADCETRIS. 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 ADCETRIS. Patients experiencing hepatotoxicity may require a delay, change in dose or discontinuation of ADCETRIS.

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.

Infusion site extravasation

Extravasation during intravenous infusion has occurred. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration.

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 section 5.2).

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 ADCETRIS, disease activity has been shown in the subtypes Sezary 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 section 5.1).

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.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction with medicinal products metabolised 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 Tables 1 and 2 for dosing recommendations for neutropenia (see section 4.2).

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 section 4.3).

4.6 Fertility, pregnancy and lactation

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.

Pregnancy

There are no data from the use of ADCETRIS in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

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.

Breast-feeding

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, brentuximab vedotin treatment has resulted in testicular toxicity, and may alter male fertility. MMAE has been shown to have aneugenic properties (see section 5.3). 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.

4.7 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), see section 4.8.

4.8 Undesirable effects

Summary of the safety profile

The safety profile of ADCETRIS is based on available clinical trial data, the Named Patient Program (NPP), and post-marketing experience to date. Frequencies of adverse reactions described below and in Table 5 have been determined based on data generated from clinical studies.

Monotherapy

In the pooled dataset of ADCETRIS as monotherapy across HL, sALCL and CTCL studies (SG035–0003, SG035–0004, SGN35–005, SGN35–006, C25001 and C25007, see section 5.1) the most frequent adverse reactions (> 10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain.

Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was < 1%.

Adverse events led to treatment discontinuation in 24% of patients receiving ADCETRIS.

The safety data in patients retreated with ADCETRIS (SGN35–006, see section 5.1) were consistent with those observed in the combined pivotal phase 2 studies, with the exception of peripheral motor neuropathy, which had a higher incidence (28% vs. 9% in the pivotal phase 2 studies) and was primarily Grade 2. Patients also had a higher incidence of arthralgia, Grade 3 anaemia, and back pain compared to patients observed in the combined pivotal phase 2 studies.

The safety data in patients with relapsed or refractory HL who had not received an autologous stem cell transplant and were treated with the recommended dose of 1.8 mg/kg every three weeks in a single-arm phase 4 study (n = 60), the phase 1 dose escalation and clinical pharmacology studies (n = 15 patients) and in the NPP (n = 26 patients) (see section 5.1) were consistent with the safety profile of the pivotal clinical studies.

Combination therapy

For safety information of chemotherapy agents given in combination with ADCETRIS (doxorubicin, vinblastine and dacarbazine (AVD) or cyclophosphamide, doxorubicin and prednisone (CHP)), refer to their summary of product characteristics.

In the studies of ADCETRIS as combination therapy in 662 patients with previously untreated advanced HL (C25003) and 223 patients with previously untreated CD30+ peripheral T-cell lymphoma (PTCL) (SGN35–014), the most common adverse reactions (> 10%) were: infections, neutropenia, peripheral sensory neuropathy, nausea, constipation, vomiting, diarrhoea, fatigue, pyrexia, alopecia, anaemia, weight decreased, stomatitis, febrile neutropenia, abdominal pain, decreased appetite, insomnia, bone pain, rash, cough, dyspnoea, arthralgia, myalgia, back pain, peripheral motor neuropathy, upper respiratory tract infection, and dizziness.

In patients receiving ADCETRIS combination therapy, serious adverse reactions occurred in 34% of patients. Serious adverse reactions occurring in > 3% of patients included febrile neutropenia (15%), pyrexia (5%), and neutropenia (3%).

Adverse events led to treatment discontinuation in 10% of patients. Adverse events that led to treatment discontinuation in > 2% of patients included peripheral sensory neuropathy, and peripheral neuropathy.

Tabulated list of adverse reactions

Adverse reactions for ADCETRIS are listed by MedDRA System Organ Class and Preferred Term (see Table 5). 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 5: Adverse reactions to ADCETRIS

a.

b.

c.

Represents pooling of preferred terms.

Toxic epidermal necrolysis was not reported in the combination therapy setting.

Extravasation may result in related reactions include skin redness, pain, swelling, blistering, exfoliation, or cellulitis at or surrounding the infusion site.

Description of selected adverse reactions

Neutropenia and febrile neutropenia

Monotherapy

In clinical trials, neutropenia led to dose delays in 14% of patients. Grade 3 neutropenia was reported in 13% and Grade 4 neutropenia was reported in 5% of patients. No patients required dose reduction or discontinued treatment for neutropenia.

Severe and prolonged (> 1 week) neutropenia can occur with this treatment which may increase the risk of patients developing serious infections. Febrile neutropenia reported in < 1% of the patients (see section 4.2).

In the pivotal phase 2 population (SG035–0003 and SG035–0004), the median duration of Grade 3 or Grade 4 neutropenia was limited (1 week); 2% of patients had Grade 4 neutropenia that lasted > 7 days. Less than half of the patients in the pivotal phase 2 population with Grade 3 or Grade 4 neutropenia had temporally associated infections, and the majority of temporally associated infections were Grade 1 or Grade 2.

Combination therapy

In the clinical trials of ADCETRIS as combination therapy, neutropenia led to dose delays in 19% of patients. Grade 3 neutropenia was reported in 17% and Grade 4 neutropenia was reported in 41% of patients. Two percent of patients required dose reduction and < 1% discontinued one of more of the study drugs due to neutropenia.

Febrile neutropenia was reported in 20% of the patients who did not receive primary prophylaxis with G-CSF (see section 4.2). The frequency of febrile neutropenia was 13% in patients who received primary prophylaxis with G-CSF.

Serious infections and opportunistic infections

Monotherapy

In clinical trials, serious infections and opportunistic infections occurred in 10% of patients, sepsis or septic shock occurred in < 1% of the patients. The most commonly reported opportunistic infections were herpes zoster and herpes simplex.

Combination therapy

In the clinical trials of ADCETRIS as combination therapy, serious infections including opportunistic infections occurred in 15% of patients; sepsis, neutropenic sepsis, septic shock or bacteraemia occurred in 4% of the patients. The most commonly reported opportunistic infections were herpes viral infections.

Peripheral neuropathy

Monotherapy

In clinical trials treatment emergent neuropathy occurred in 59% of the population, peripheral motor neuropathy occurred in 14% of patients. Peripheral neuropathy led to treatment discontinuation in 15%, dose reductions in 15%, and dose delays in 17% of patients. For patients who experienced peripheral neuropathy the median time of onset of peripheral neuropathy was 12 weeks. The median duration of treatment for patients who discontinued due to peripheral neuropathy was 12 cycles.

Among patients who experienced peripheral neuropathy in the pivotal phase 2 studies (SG035–0003 and SG035–0004) and randomised phase 3 monotherapy studies (SGN35–005 and C25001), the median follow up time from end of treatment until last evaluation ranged from 48.9 to 98 weeks. At the time of last evaluation, most of the patients (82–85%) who experienced peripheral neuropathy had resolution or improvement of their peripheral neuropathy symptoms. The median time from onset to resolution or improvement for all events ranged from 16 to 23.4 weeks.

In patients with relapsed or refractory HL or sALCL who were retreated with ADCETRIS (SGN35–006), the majority of patients (80%) also had improvement or resolution of their peripheral neuropathy symptoms at the time of last evaluation.

Combination therapy

In the clinical trial of ADCETRIS as combination therapy with AVD, treatment emergent neuropathy occurred in 67% of the population; peripheral motor neuropathy occurred in 11% of patients.

Peripheral neuropathy led to treatment discontinuation in 7%, dose reductions in 21%, and dose delays in 1% of patients. For patients who experienced peripheral neuropathy the median time of onset of peripheral neuropathy was 8 weeks. Patients who discontinued due to peripheral neuropathy received a median of 8 doses of ADCETRIS+AVD (A+AVD) before discontinuation of one or more agents.

Among patients who experienced peripheral neuropathy, the median follow up time from end of treatment until last evaluation was approximately 91 weeks. At the time of last evaluation, most of the patients (76%) who experienced peripheral neuropathy had resolution or improvement of their peripheral neuropathy symptoms. The median time from onset to resolution or improvement of peripheral neuropathy events was 10 weeks (ranged from 0 weeks to 139 weeks).

In the clinical trial of ADCETRIS as combination therapy with CHP, treatment emergent neuropathy occurred in 52% of the population; peripheral motor neuropathy occurred in 9% of patients. Peripheral neuropathy led to treatment discontinuation in 1%, dose reductions in 7% and dose delays in < 1% of patients. For patients who experienced peripheral neuropathy the median time of onset was 9.1 weeks. Patients who discontinued due to peripheral neuropathy received a median of 5 doses of ADCETRIS + CHP (A+CHP) before discontinuation of one or more agents.

Among patients who experienced peripheral neuropathy, the median follow up time from end of treatment until last evaluation was approximately 177 weeks. At the time of last evaluation, 64% who experienced peripheral neuropathy had resolution or improvement of their peripheral neuropathy symptoms. The median time from onset to resolution or improvement of peripheral neuropathy events was 19.0 weeks (ranged from 0 weeks to 205 weeks).

Infusion-related reactions

Monotherapy

IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus and cough were reported in 13% of patients. Anaphylactic reactions have been reported (see section 4.4). Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm.

Combination therapy

IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus, cough, infusion site pain and pyrexia were reported in 8% of patients. Anaphylactic reactions have been reported (see section 4.4). Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm.

Immunogenicity

In clinical trials, patients were periodically tested for antibodies to brentuximab vedotin using a sensitive electrochemilu­minescent immunoassay. There was a higher incidence of infusion-related reactions observed in patients with antibodies to brentuximab vedotin relative to patients who tested transiently positive or negative.

The presence of antibodies to brentuximab vedotin did not correlate with a clinically meaningful reduction in serum brentuximab vedotin levels and did not result in a decrease in the efficacy of brentuximab vedotin. While the presence of antibodies to brentuximab vedotin does not necessarily predict the development of an IRR, there was a higher incidence of IRRs observed in patients with persistently positive anti-drug antibodies (ADA) relative to patients with transiently positive ADA and never positive ADA.

Monotherapy Study C25002

There was a trend of increased clearance of brentuximab vedotin in paediatric patients confirmed positive for ADAs. No patients aged < 12 years (0 of 11) and 2 patients aged > 12 years (2 of 23) became persistently ADA positive.

Combination Use Study C25004

The rate of ADA positivity was low in Study C25004; 4 patients (aged > 12 years) of 59 patients became transiently ADA positive, and no patients became persistently ADA positive. Due to the small number of transiently ADA positive patients, the impact of ADA on efficacy is inconclusive.

Paediatric population

Monotherapy Study C25002

Safety was evaluated in a phase 1/2 study in paediatric patients aged 7–17 years of age (n = 36) with relapsed or refractory (r/r) HL and sALCL (see section 5.1). In this study in 36 patients, no new safety concerns were reported.

Combination Use Study C25004

Safety was evaluated in an open-label, multicenter trial in 59 paediatric patients aged 6–17 years of age with previously untreated advanced-stage classical CD30+ HL in combination with chemotherapy (see section 5.1). In this study, no new safety concerns were reported. The most common serious adverse reaction reported in this study was febrile neutropenia (17%). G-CSF prophylaxis was considered at the physician’s dis­cretion. Peripheral neuropathy events (per Standardized MedDRA Query) were reported in 24% of paediatric patients in this study.

Elderly

Monotherapy

The safety profile in elderly patients is generally in line with that of adult patients. However, elderly patients may be more susceptible to events such as pneumonia, neutropenia and febrile neutropenia.

Combination therapy

In older patients (> 60 years of age; n = 186 [21%]), the incidence of adverse events was similar across treatment arms. More serious adverse events and dose modifications (including dose delays, reductions, and discontinuations) were reported in the older patients compared with the overall study population. Advanced age was a risk factor for febrile neutropenia in patients in both arms. Older patients who received G-CSF primary prophylaxis had lower incidence of neutropenia and febrile neutropenia than those who did not receive G-CSF primary prophylaxis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

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).

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

5.2   Pharmacokinetic properties

5.3 Preclinical safety data

MMAE has been shown to have aneugenic properties in an in vivo rat bone marrow micronucleus study. These results were consistent with the pharmacological effect of MMAE on the mitotic apparatus (disruption of the microtubule network) in cells.

The effects of brentuximab vedotin on human male and female fertility have not been studied. However, results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin to impair male reproductive function and fertility. Testicular atrophy and degeneration were partially reversible following a 16-week treatment-free period.

Brentuximab vedotin caused embryo-foetal lethality in pregnant female rats.

In nonclinical studies, lymphoid depletion and reduced thymic weight were observed, consistent with the pharmacologic disruption of microtubules caused by MMAE derived from brentuximab vedotin.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Citric acid monohydrate (for pH-adjustment)

Sodium citrate dihydrate (for pH-adjustment) a,a-Trehalose dihydrate

Polysorbate 80

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life 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.

6.4 Special precautions for 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.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I glass vial with a butyl rubber stopper and an aluminium/plastic flip-off seal, containing 50 mg powder.

Pack of 1 vial.

6.6 Special precautions for disposal and other handling

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 10.5 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.

7. MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S

Delta Park 45

2665 Vallensbaek Strand

Denmark

8. MARKETING AUTHORISATION NUMBER

EU/1/12/794/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2012

Date of latest renewal: 16 September 2021