Adcetris 50 mg powder for concentrate for solution for infusion

  • Name:

    Adcetris 50 mg powder for concentrate for solution for infusion

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  • Active Ingredients:

    Brentuximab vedotin

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    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 21/02/19

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Summary of Product Characteristics last updated on medicines.ie: 21/2/2019
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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Takeda Products Ireland Ltd

Takeda Products Ireland Ltd

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 21 February 2019 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 2 - excipient warnings
  • Change to section 3 - dose and frequency
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 21 February 2019 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.1 - List of excipients
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 31 January 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 31 January 2018 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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Details of change

4.2     Posology and method of administration

 

The safety and efficacy of children less than 18 years have not yet been established. No data are available. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

 

4.8       Undesirable effects

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.

 

Paediatric population

 

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.

 

5.1       Pharmacodynamic properties

Paediatric Population

 

The safety, pharmacokinetics and anti-tumour activity of brentuximab vedotin in 36 paediatric patients (7-17 years of age) with r/r HL and sALCL (children aged 7-11 years, n=12 and adolescents aged 12 to 17 years, n=24) were evaluated in a phase 1/2 open-label, single-agent, multicentre dose-escalation study (C25002). Phase 1 of the study assessed the safety profile (see section 4.8), determined the paediatric maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and assessed the pharmacokinetics of brentuximab vedotin (see section 5.2). Phase 1 included 3 r/r HL patients treated at 1.4 mg/kg and 9 patients (7 r/r HL and 2 sALCL) treated at 1.8 mg/kg. The MTD was not reached. The RP2D was determined to be 1.8 mg/kg. Across the study, a total of 16 patients with r/r HL and 17 patients with r/r sALCL, of whom 10 were in first relapse, were treated with 1.8 mg/kg of brentuximab vedotin. The best overall response rate (ORR) per independent review facility (IRF) was analysed across both study phases at the RP2D. Of these 33 patients who received the RP2D, 32 were evaluable for response. The ORR was 47% in response-evaluable patients with r/r HL, 53% in patients with r/r sALCL and 60% in sALCL patients in first relapse. Eight HL patients and 9 sALCL patients went on to receive SCT following treatment with brentuximab vedotin.

 

5.2       Pharmacokinetic properties

The pharmacokinetics of brentuximab vedotin ADC and MMAE following a 30-minute intravenous infusion of BV administered at 1.4 mg/kg or 1.8 mg/kg given every 3 weeks were evaluated in a phase 1/2 clinical trial of 36 paediatric patients (7-17 years of age) with r/r HL and sALCL (children aged 7-11 years, n=12 and adolescents aged 12 to 17 years, n=24) (see section 5.1). The Cmax of ADC was typically observed at the end of infusion or the sampling closest to the end of infusion. A multi-exponential decline in ADC serum concentrations was observed with a terminal half-life of approximately 4 to 5 days. Exposures were approximately dose proportional with a trend observed for lower ADC exposures at lower ages/ body weights in the study population.  Median ADC AUC in children and adolescents from this study was approx. 14% and 3% lower than in adult patients, respectively, while MMAE exposures were 53% lower and 13% higher, respectively, than in adult patients. Median Cmax and AUC of ADC after a single 1.8 mg/kg dose were 29.8 µg/mL and 67.9 µg*day/mL, respectively, in patients <12 years of age and 34.4 µg/mL and 77.8 µg*day/mL, respectively, in patients ≥12 years of age. Median Cmax, AUC, and Tmax of MMAE after a single 1.8 mg/kg dose were 3.73 ng/mL, 17.3 ng*day/mL, and 1.92 days, respectively, in patients <12 years of age and 6.33 ng/mL, 42.3 ng*day/mL, and 1.82 days, respectively, in patients ≥12 years of age. 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.

Clinical studies of brentuximab vedotin did not include sufficient numbers of patients below 18 years of age to determine whether the PK profile differs from adult patients.

10.       DATE OF REVISION OF THE TEXT

15 December 201711 January 2017

Updated on 9 January 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 9 January 2018 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to section

Details of change

4.1     Therapeutic indications

 

Addition of the following:

 

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

 

Addition of the following:

 

Patients with CTCL should receive up to 16 cycles (see section 5.1).

 

AND

 

The Based upon population PK analyses (see section 5.2) and the safety profile and efficacy in elderly patients, which are consistent with that of adult patients, the dosing recommendations for patients aged 65 and older have not been established. No data are the same as for adults.available. 

4.4       Special warnings and precautions for use

In the pivotal phase 2 (SG035-0003 and SG035-0004) population, the incidence of pre-existing peripheral neuropathy was 24%. Treatment emergent neuropathy occurred in 56% of the population. At the time of last evaluation, the majority of patients (83%) had improvement or resolution of their peripheral neuropathy symptoms. For patients who reported peripheral neuropathy, brentuximab vedotin treatment discontinuation occurred in 17%, dose reductions were reported in 13%, and dose delays occurred in 21% of patients.

 

The incidence of pre-existing peripheral neuropathy in patients with relapsed or refractory HL or sALCL who were retreated with brentuximab vedotin was 48%. Treatment emergent neuropathy occurred in 69% of the population. At the time of last evaluation, the majority of patients who were retreated and experienced treatment-emergent peripheral neuropathy (80%) had improvement or resolution of their peripheral neuropathy symptoms. Peripheral neuropathy led to discontinuation in 21% and dose modifications in 34% of patients who were retreated.

 

In the phase 3 population, at the time of last evaluation, the majority of patients in the brentuximab vedotin arm (85%) had improvement or resolution of their peripheral neuropathy symptoms. For patients who reported peripheral neuropathy, brentuximab vedotin treatment discontinuation occurred in 23%, dose reductions were reported in 29%, and dose delays occurred in 22% of patients.

 

In clinical trials, the majority of patients had improvement or resolution of their symptoms (see section 4.8)

 

And

 

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 section 5.1).

 

4.8       Undesirable effects

Section 4.8 has been extensively updated

5.1       Pharmacodynamic properties

Classical HL,  and sALCL and subtypes of CTCL (including MF and pcALCL) express CD30 as an antigen on the surface of their malignant cells. This expression is independent of disease stage, line of therapy or transplant status. These features make CD30 a target for therapeutic intervention. Because of the CD30 targeted mechanism of action brentuximab vedotin is able to overcome chemo-resistance as CD30 is consistently expressed in patients who are refractory to multi-agent chemotherapy, irrespective of prior transplant status. The CD30 targeted mechanism of action of brentuximab vedotin, the consistent expression of CD30 throughout the classical HL, and sALCL and CD30+ CTCL disease and therapeutic spectrums and clinical evidence in two CD30 positive malignancies following multiple lines of treatment provide a biologic rationale for its use in patients with relapsed and refractory classical HL, and sALCL with or without prior ASCT and CD30+ CTCL after at least 1 prior systemic therapy.

 

AND

 

Cutaneous T-cell lymphoma

 

Study C25001

 

The efficacy and safety of brentuximab vedotin as a single agent was evaluated in a pivotal phase 3, open-label, randomised, multicentre study in 128 patients with histologically confirmed CD30+  CTCL. CD30 positivity was defined as ≥10% target lymphoid cells demonstrating membrane, cytoplasmic, and/or Golgi staining pattern based on an immunohistochemistry assay (Ventana anti-CD30 [Ber-H2]). Patients with a diagnosis of mycosis fungoides [MF] or primary cutaneous anaplastic large cell lymphoma [pcALCL] were considered eligible for the study. Patients were stratified by these disease types and randomised 1:1 to receive either brentuximab vedotin or the physician’s choice of either methotrexate or bexarotene. Patients with pcALCL received either prior radiation therapy or at least 1 prior systemic therapy and patients with MF received at least 1 prior systemic therapy. Patients with a concurrent diagnosis of systemic ALCL, Sezary syndrome and other non-Hodgkin lymphoma (except for lymphomatoid papulosis [LyP]) were excluded from this study. Patients were treated with 1.8 mg/kg of brentuximab vedotin intravenously over 30 minutes every 3 weeks for up to 16 cycles or physician’s choice for up to 48 weeks. The median number of cycles was approximately 12 cycles in the brentuximab vedotin arm. In the physician’s choice arm, the median duration of treatment (number of cycles) for patients receiving bexarotene was approximately 16 weeks (5.5 cycles) and 11 weeks (3 cycles) for patients receiving methotrexate. Table 11 provides a summary of the baseline patient and disease characteristics.

               

Table 11: Summary of Baseline Patient and Disease Characteristics in the Phase 3 CTCL Study (ITT Population)

 

Patient characteristics    Brentuximab vedotin

N = 64   Physician’s Choice (Methotrexate or Bexarotene)

N= 64

Median age (range)        62 years (22-83)                58.5 years (22-83)

Patients ≥ 65 years old n (%)

Gender n (%)     28 (44%)

33M (52%)/31F (48%)     24 (38%)

37M (58%)/27F (42%)

ECOG status n (%)                          

0              43 (67)  46 (72)

1

2              18 (28)

3 (5)       16 (25)

2 (3)

Disease characteristics                  

Median number of prior therapies (range)           4 (0-13) 3.5 (1-15)

Median number of skin-directed therapies (range)          1 (0-6)   1 (0-9)

Median number of systemic therapies (range)   2 (0-11) 2 (1-8)

MF, n(%)             48 (75)  49 (77)

Early (IA-IIA)      15 (31)  18 (37)

Advanced (IIB-IVBa)       32 (67)  30 (61)

pcALCL, n(%)      16 (25)  15 (23)

Skin only              9 (56)     11 (73)

Extracutaneous disease                7 (44)     4 (27)

a One patient in each arm had incomplete staging data and are not included in the table

 

                The most common prior skin directed therapies in the ITT population were radiotherapy (64%), phototherapy (48%) and topical steroids (17%). The most common prior systemic therapies in the ITT population were chemotherapy (71%), immunotherapy (43%) and bexarotene (38%).

 

               

                The primary endpoint was objective response rate that lasts at least 4 months (ORR4) (duration from first response to last response ≥ 4 months), as determined by an independent review of the Global Response Score (GRS) consisting of skin evaluations (modified severity weighted assessment tool [mSWAT] as assessed per investigator), nodal and visceral radiographic assessment, and detection of circulating Sézary cells (Olsen 2011). Table 12 includes the results for ORR4 and other key secondary endpoints.

               

 

Table 12: Efficacy Results in CTCL Patients Treated with 1.8 mg/kg of Brentuximab Vedotin Every 3 Weeks (ITT Population)

 

 

 

 

                Brentuximab vedotin      (N=64)                 Physician’s Choice (Methatrexate or Bexarotene)

N=64

Objective Response Rate lasting at least 4 months (ORR4) per IRF

N (%)

Percent Difference (95% CI)        36 (56.3)              

43.8 (29.1, 58.4)                8 (12.5)

p-value                 <0.001  

Complete Response (CR) per IRF

N (%)

Percent Difference (95% CI)        10 (15.6)              

14.1 (-4.0, 31.5) 1 (1.6)

Adjusted p-valuea                           0.0046  

Progression Free Survival (PFS) per IRF

Median (months)            16.7                        3.5

Hazard Ratio                       0.270    

95% CI                   (0.17, 0.43)         

Adjusted p-valuea                           <0.001  

a   Calculated from a weighted Holm’s procedure

 

                Pre-specified subgroup analyses of ORR4 per IRF were performed by patients’ CTCL subtype, physicians’ choice of treatment, baseline ECOG status, age, gender, and geographic region. The analyses showed a consistent trend towards benefit for patients who received brentuximab vedotin compared with patients who received physician’s choice. ORR4 was 50% and 75% in the brentuximab vedotin arm versus 10.2% and 20% in the physician’s choice arm for MF and pcALCL, respectively.

               

No meaningful differences in quality of life (assessed by the EuroQol five dimensions questionnaire [EQ-5D] and Functional Assessment of Cancer Therapy-General [FACT-G]) were observed between the treatment arms.

 

The efficacy and safety of ADCETRIS were evaluated in two additional open-label studies in 108 patients with relapsed CD30+ CTCL (including patients with MF and pcALCL as well as SS, Lyp and mixed CTCL histology) regardless of CD30 expression level. Patients were treated with ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles.  The safety and efficacy results in these studies were consistent with results in Study C25001.  Overall response rates for MF were 54-66%; pcALCL, 67%; SS, 50%; LyP, 92%; and mixed CTCL histology, 82-85%. 

 

5.2       Pharmacokinetic properties

The population pharmacokinetics of brentuximab vedotin were examined from several studies, including data from 380 patients up to 87 years old (34 patients ≥65-<75 and 17 patients ≥75 years of age). The influence of age on pharmacokinetics was investigated and it was not a significant covariate (see section 4.2).

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 25 October 2012

Date of renewal: 21 October 2016 10 November 2017

10.       DATE OF REVISION OF THE TEXT

15 December 2017

 

Updated on 9 January 2018 PIL

Reasons for updating

  • Change to Section 1 - what the product is
  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision

Updated on 14 December 2017 PIL

Reasons for updating

  • Change to section 6 - date of revision

Updated on 13 December 2017 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to revision / renwal date  - 10th November 2017.

Updated on 31 July 2017 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

$0Please find below a summary of thechanges to the Adcetris (brentuximab vedotin) SmPC: $0$0 $0$0$0$0$0$0Section$0$0$0$0Details of change$0$0$0$0$0$05.1 Pharmacodynamic Properties$0$0$0$0Within the “Pharmacodynamic effects”section an additional sub-section has been added to the Hodgkin’s Lymphomaclinical efficacy section. Additional text in red.$0$0 $0$0Data in HL Patients Who AreNot Stem Cell Transplant (SCT) Candidates$0$0Study C25007 $0$0A phase 4 single-arm studywas conducted in patients with relapsed or refractory HL (n=60) who hadreceived at least 1 prior chemotherapeutic regimen and at the time oftreatment initiation with brentuximab vedotin were not considered candidatesfor SCT or multiagent chemotherapy.  $0$0The median number of cycleswas 7 (range, 1 to 16 cycles). Patients were treated with 1.8 mg/kg ofbrentuximab vedotin every 3 weeks. Per IRF, the objective response rate (ORR)in the ITT population was 50% (95% CI [37%, 63%]). A best overall response ofCR was reported for 7 patients (12%); PR was reported for 23 patients (38%).  Among these 30 patients, the median time toresponse, defined as the time from first dose to the soonest of PR or CR, was6 weeks (range, 5 to 39 weeks). The median time to best overall response,defined as the time from first dose to the clinical best response of CR orPR, was 11 weeks (range, 5 to 60 weeks). Twenty-eight patients (47%) went onto receive SCT after a median of 7 cycles (range, 4 to 16 cycles) ofbrentuximab vedotin treatment. The 32 patients (53%) who did not receivesubsequent SCT also received brentuximab vedotin for a median of 7 cycles(range, 1 to 16 cycles). $0$0 $0$0Of the study’s 60 patients,49 patients (82%) received >1 prior cancer-related treatment and 11patients (18%) received 1 prior cancer-related treatment. Per IRF, the ORRwas 51% (95% CI [36%, 66%]) for the patients who had received >1 priorcancer-related treatment and 45% (95% CI [17%, 77%]) for the patients who hadreceived 1 prior cancer-related treatment. For the patients who received>1 prior cancer-related treatment, a best overall response of CR wasreported for 6 patients (12%); PR was reported for 19 patients (39%). For thepatients who received 1 prior cancer-related treatment, CR was reported for 1patient (9%) and PR was reported for 4 patients (36%). Out of the 49 patientsreceiving >1 line of prior treatment, 22 patients (45%) receivedsubsequent SCT; of the 11 patients who had received 1 prior treatment, 6patients (55%) received subsequent SCT.$0$0 $0$0Data were also collected from patients (n=15) in phase 1 doseescalation and clinical pharmacology studies, and from patients (n=26) in aNPP, with relapsed or refractory HL who had not received an ASCT, and whowere treated with 1.8 mg/kg of brentuximab vedotin every 3 weeks.$0$0$0$0$0$010.  DATE OF REVISION OF THE TEXT$0$0 $0$0$0$0Updated as follows:$0$020th July 2017$0$0$0$0$0

Updated on 21 July 2017 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

$0Please find below a summary of the main changes to the SmPC:$0$0 $0$0 $0$0$0$0$0$0Section$0$0$0$0Details of change$0$0$0$0$0$04.4 Special warnings and precautions for use$0$0$0$0In the section ‘Serious infections and opportunisticinfections’ the following text in red has been added:$0$0  $0$0 “Serious infections such as pneumonia,staphylococcal bacteraemia, sepsis/septic shock (including fatal outcomes)and herpes zoster, cytomegalovirus (CMV) (reactivation) andopportunistic infections such as Pneumocystis jiroveci pneumonia and oralcandidiasis have been reported in patients treated with brentuximab vedotin.Patients should be carefully monitored during treatment for the emergence ofpossible serious and opportunistic infections.”$0$0 $0$0$0$0$0$04.8          Undesirableeffects$0$0$0$0In the section ‘Tabulated list of adverse reactions’the following text in red has been added:$0$0  $0$0Table 3: Adverse reactions to ADCETRIS $0$0$0$0$0$0System organ class$0$0$0$0Adverse reactions$0$0$0$0$0$0Infections and infestations $0$0$0$0$0$0Very common: $0$0$0$0Infectiona, upper respiratory tractinfection$0$0$0$0$0$0Common:$0$0$0$0Sepsis/septic shock, herpes zoster,pneumonia, herpes simplex$0$0$0$0$0$0Uncommon:$0$0$0$0Oral candidiasis, Pneumocystis jirovecipneumonia, staphylococcal bacteraemia, cytomegalovirusinfection or reactivation$0$0$0$0$0$0Frequency not known:$0$0$0$0Progressive multifocalleukoencephalopathy$0$0$0$0$0$0Blood and lymphatic system disorders$0$0$0$0$0$0Very common:$0$0$0$0Neutropenia$0$0$0$0$0$0Common:$0$0$0$0Anaemia, thrombocytopenia$0$0$0$0$0$0Frequency not known:$0$0$0$0Febrile neutropenia$0$0$0$0$0$0Immune system disorders$0$0$0$0$0$0Frequency not known:$0$0$0$0Anaphylactic reaction$0$0$0$0$0$0Metabolism and nutrition disorders$0$0$0$0$0$0Common$0$0$0$0Hyperglycaemia$0$0$0$0$0$0Uncommon:$0$0$0$0Tumour lysis syndrome$0$0$0$0$0$0Nervous system disorders$0$0$0$0$0$0Very common:$0$0$0$0Peripheral sensory neuropathy, peripheralmotor neuropathy$0$0$0$0$0$0Common:$0$0$0$0Dizziness, demyelinating polyneuropathy$0$0$0$0$0$0Respiratory, thoracic and mediastinaldisorders$0$0$0$0$0$0Very Common:$0$0$0$0Cough, dyspnoea$0$0$0$0$0$0Gastro-intestinal disorders$0$0$0$0$0$0Very common:$0$0$0$0Diarrhoea, nausea, vomiting,constipation, abdominal pain$0$0$0$0$0$0Uncommon:$0$0$0$0Pancreatitis acute$0$0$0$0$0$0Hepatobiliary disorders$0$0$0$0$0$0Common:$0$0$0$0Alanine aminotransferase/aspartate$0$0aminotransferase (ALT/AST) increased$0$0$0$0$0$0Skin and subcutaneous tissue disorders$0$0$0$0$0$0Very common:$0$0$0$0Alopecia, pruritus$0$0$0$0$0$0Common:$0$0$0$0Rash$0$0$0$0$0$0Rare:$0$0$0$0Stevens-Johnson syndrome/toxic epidermalnecrolysis$0$0$0$0$0$0Musculoskeletal and connective tissuedisorders$0$0$0$0$0$0Very common:$0$0$0$0Myalgia, arthralgia$0$0$0$0$0$0Common:$0$0$0$0Back pain$0$0$0$0$0$0General disorders and administration siteconditions$0$0$0$0$0$0Very common:$0$0$0$0Fatigue, chills, pyrexia,infusion-related reactionsb$0$0$0$0$0$0Investigations$0$0$0$0$0$0Very common:$0$0$0$0Weight decreased$0$0$0$0$0$0a.Preferred terms thatwere reported under the Infections and Infestations SOC include sepsis/septicshock, upper respiratory tract infection, herpes zoster, and pneumonia.$0$0b.Preferred termsassociated with IRRs were headache, rash, back pain, vomiting, chills,nausea, dyspnoea, pruritus and cough.$0$0 $0$0 $0$0$0$0$0$010.  DATE OF REVISION OF THE TEXT$0$0 $0$0$0$0Updated as follows:$0$005th July 2017$0$0$0$0$0

Updated on 12 July 2017 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company


Section

Details of change

5.1 Pharmacodynamic properties

In the section ‘Study SG035-0004’ the following text in red has been added:

 

The ORR per IRF assessment was 86% (50 of 58 patients in the ITT set). CR was 59% (34 of 58 patients in the ITT set) and tumour reduction (of any degree) was achieved in 97% of patients. The estimated 36 month overall survival at 5 years was 63% (60% (95% CI [47%,73%]). The median observation time (time to death or last contact) from first dose was 3371.4 months).. The investigator assessments were generally consistent with the independent review of the scans. Of the patients treated, 9 responding patients went on to receive an allogeneic stem cell transplant (SCT) and 9 responding patients went on to autologous SCT. For further efficacy results, see Table 10 and Figure 3.

 

In table 10 the following text in red has been added:

 

Best clinical response (N = 58 )

IRF N (%)

95% CI

    Objective response rate (CR + PR)

50 (86)

74.6, 93.9

          Complete remission (CR)

34 (59)

44.9, 71.4

          Partial remission (PR)

16 (28)

NA

    Disease control rate (CR + PR + SD)

52 (90)

78.8, 96.1

Duration of response

Median per IRF

95% CI

    Objective response (CR + PR)a

13.2

5.7, NEb26.3

    Complete remission (CR)

Not reached26.3

13.0, NE2, NEb

Progression Free Survival

Median per IRF

95% CI

Median

14.6

6.9, 20.6

Overall survival

Median

95% CI

Median

Not reachedcreached

21.3, NENEb

 

a.         The range of DOR was 0.1+ months to 21.739.1+ months and the median follow‑up time from first dose for patients who achieved objective response (OR) per IRF was 11.815.5 months.

b.        Not estimable.

a.            The estimated 36 month overall survival was 63% (the median observation time (time to death or last contact) from first dose was 33.4 months).

 

The following Kaplan-Meier plot has been added:

 

Figure 3: Kaplan-Meier Plot of OS

 

 

 

 

 

 

10.  DATE OF REVISION OF THE TEXT

 

Updated as follows:

28 June 2016

22 June 2017

Updated on 18 November 2016 PIL

Reasons for updating

  • Change to section 6 - manufacturer

Updated on 19 July 2016 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to section

Details of change

6.3 Shelf life

Increase of shelf-life of Adcetris from 3 years to 4 years.

10.  Date of revision of the text

28 June 2016

 

Updated on 12 July 2016 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 12 July 2016 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

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Change to section

Details of change

4.1       Therapeutic indications

 

Addition of following text in red   :

 

ADCETRIS is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapse or progression following ASCT (see section 5.1).

 

4.2       Posology and method of administration

 

Addition of text in red:

 

Patients with relapsed or refractory HL or sALCL 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).

 

For patients with HL at increased risk of relapse or progression following ASCT, ADCETRIS treatment should start following recovery from ASCT based on clinical judgment. These patients should receive up to 16 cycles (see section 5.1).

 

 

 

4.4       Special warnings and precautions for use

 

Addition of text in red:

 

In the phase 3 population, at the time of last evaluation, the majority of patients in the brentuximab vedotin arm (85%) had improvement or resolution of their peripheral neuropathy symptoms. For patients who reported peripheral neuropathy, brentuximab vedotin treatment discontinuation occurred in 23%, dose reductions were reported in 29%, and dose delays occurred in 22% of patients.

 

4.8       Undesirable effects

Section 4.8 (Undesirable effects) has been extensively updated to include safety data from phase 2 and phase 3 studies.

 

5.1 Pharmacodynamic properties

 

Section 5.1( Pharmacodynamic properties) has been extensively updated to include Data from Study SGN35-005 which evaluated the efficacy and safety of brentuximab vedotin in a randomized, double-blind, placebo-controlled, 2-arm multicenter trial in 329 patients with HL at risk of relapse or progression following ASCT.  Text, tables and Kaplan-Meier plots have been added.

 

10. Date of revision of the text

24 June 2016

Updated on 18 May 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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Section

Update

4.4 Special warnings and precautions for use

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.

 

4.4 Special warnings and precautions for use

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 the pivotal phase 2 (SG035-0003 and SG035-0004) population, the incidence of pre-existing peripheral neuropathy was 24%. Treatment emergent neuropathy occurred in 56% of the population. At the time of last evaluation, the majority of patients (83%) had improvement or resolution of their peripheral neuropathy symptoms. For patients who reported peripheral neuropathy, brentuximab vedotin treatment discontinuation occurred in 17%, dose reductions were reported in 13%, and dose delays occurred in 21% of patients.

 

4.4 Special warnings and precautions for use

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.

 

4.5 Interaction with other medicinal products and other forms of interaction

Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter the plasma exposure to brentuximab vedotin.: however it reduced exposure to MMAE by approximately 31%. Though PK data are limited, co administration of rifampicin appeared to reduce plasma concentrations of MMAE metabolites that could be assayed.

 

4.8 Undesirable effects

Serious infections and opportunistic infections have been reported in patients treated with this medicine (see section 4.4). In the pivotal phase 2 population, 17% of patients reported an event term that referred to an infection.

 

Serious adverse drug reactions in the pivotal phase 2 population were: neutropenia, thrombocytopenia, constipation, diarrhoea, vomiting, pyrexia, peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycaemia, demyelinating polyneuropathy, tumour lysis syndrome and Stevens-Johnson syndrome.

 

The most frequently observed adverse reactions in the pivotal phase 2 population were: peripheral sensory neuropathy, fatigue, nausea, diarrhoea, diarrhoea, neutropenia, pyrexia, upper respiratory tract infection, neutropenia, and vomiting.

 

In the pivotal phase 2 population, adverse reactions led to treatment discontinuation in 23% of patients receiving brentuximab vedotin. Adverse reactions that led to treatment discontinuation in two or more HL or sALCL patients were peripheral sensory neuropathy (8%), peripheral motor neuropathy (2%), demyelinating polyneuropathy (2%), and recurrent Hodgkin’s disease (2%).

 

 

 

4.8 Undesirable effects

Description of selected adverse reactions

 

Adverse reactions that led to dose delays of up to 3 weeks in more than 5% of patients were neutropenia (14%) and peripheral sensory neuropathy (13%) (see section 4.2).

 

The adverse reaction that led to a dose reduction in more than 5% of patients was peripheral sensory neuropathy (9%). Eighty-nine percent (89%) of patients in the phase 2 studies remained at the recommended dose of 1.8 mg/kg while on treatment.

 

Severe and prolonged (≥1 week) neutropenia can occur with this treatment which may increase the risk of patients developing serious infections. 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.

 

Among patients who experienced peripheral neuropathy, the median follow up time from end of treatment until last evaluation was approximately 48.9 weeks. At the time of last evaluation, 83% of the 89 patients 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 was 16 weeks (range from 0.3 weeks to 106.6 weeks).

 

4.8 Undesirable effects

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 ATA (27%) relative to patients with transiently positive ATA (12%) and never positive ATA (7%).

 

5.2 Pharmacokinetic properties

MMAE is the major metabolite of brentuximab vedotin. Median Cmax, AUC and Tmax of MMAE after a single 1.8 mg/kg of the ADC in a phase 1 study was approximately 4.97 ng/ml, 37.03 ng/ml x day and 2.09 days respectively. MMAE exposures decreased after multiple doses of brentuximab vedotin with approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses. MMAE is further metabolized mainly to an equally potent metabolite; however, its exposure is an order of magnitude lower than that of MMAE. Thus, it is not likely to have any substantial contribution to the systemic effects of MMAE.

 

10. DATE OF REVISION OF THE TEXT

28 April 2016

Updated on 17 May 2016 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects

Updated on 11 April 2016 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

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Change to section

Details of change

5.1 Pharmacodynamic properties

Tracked changes shown below:

 

Clinical efficacy

Hodgkin Lymphoma

 

Study SG035-0003

The objective response rate (ORR) per IRF assessment was 75% (76 of 102 patients in the intent-to-treat [ITT] set) and tumour reduction was achieved in 94% of patients. Complete remission (CR) was 33% (34 of 102 patients in the ITT set). The median overall survival (OS) is 40.5 months (the median observation time (time to death or last contact) from first dose was 32.7 months).35.1 months (range 1.8 to 72.9+ months). The estimated overall survival rate at 5 years was 41% (95% CI [31%, 51%]). The investigator assessments were generally consistent with the independent review of the scans. Of the patients treated, 78 responding patients went on to receive an allogeneic SCT. For further efficacy results see Table 5.

 

Table 5: Efficacy results in relapsed or refractory Hodgkin lymphoma patients treated with 1.8 mg/kg of brentuximab vedotin every 3 weeks

Best clinical response (N = 102 )

IRF N (%)

95% CI

    Objective response rate (CR + PR)

76 (75)

64.9, 82.6

          Complete remission (CR)

34 (33)

24.3, 43.4

          Partial remission (PR)

42 (41)

NA

    Disease control rate (CR + PR + SD)

98 (96)

90.3, 98.9

Duration of response  

Median per IRF

95% CI

    Objective response rate (CR + PR) a

6.7 months

3.6, 14.8

    Complete remission (CR)

27.9 months

10.8, NEb

Overall survival

Median

95% CI

Median

40.5 months

28.7, NE61.9

Estimated 5-year OS Rate

41%

31%, 51%

a.         The range of DOR was1was 1.2+ months to 26.143+ months and the median follow-up time from first dose for patients who achieved objective response (OR) per IRF was 9.0 months.

b.        Not estimable.

 

 

 

 

10. Date of revision of the text

Updated:

 

1st April 2016

Updated on 21 January 2016 PIL

Reasons for updating

  • Change of manufacturer
  • Change to date of revision

Updated on 21 January 2016 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

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The following sections have been updated:

4.2 Posology and method of administration has been updated with information on retreatment
4.4 Special warnings and precautions for use has additional information on peripheral neuropathy.
4.8 Undesirable effects has information added on retreatment .
5.1 Pharmacodynamic properties has information added on Study SGN35-006 (Retreatment Study).
10. Date of revision of the text has been updated to 19 November 2015.

Updated on 17 April 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change to marketing authorisation holder

Updated on 17 April 2015 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

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7. MARKETING AUTHORISATION HOLDER (address)

From

Takeda Pharma A/S
Langebjerg 1
DK-4000 Roskilde
Denmark

To

Takeda Pharma A/S
Dybendal Alle 10
2630 Taastrup
Denmark

Updated on 23 September 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to dosage and administration

Updated on 23 September 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

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Added:

Renal impairment

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).

Hepatic impairment

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).

 

Added:

Stevens-Johnson syndrome and toxic epidermal necrolysis

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

Renal and hepatic impairment

There is limited experience in patients with renal and hepatic impairment. Population pharmacokinetic (PK) analysis Available data indicated that MMAE clearance might be affected by moderate and severe renal impairment, hepatic impairment, and by low serum albumin concentrations (see section 5.2).

Update/addition:

Uncommon Rare:

Stevens-Johnson syndrome/toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with brentuximab vedotin in clinical trials and post-marketing use. Fatal outcomes have been reported (see section 4.4).

Update/addition:

Hepatic impairment

The liver is a major route of elimination of the unchanged active metabolite MMAE. There is limited pharmacokinetic data in patients with hepatic impairment. A study evaluated the PK of brentuximab vedotin and MMAE after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (Child-Pugh A; n=1), moderate (Child-Pugh B; n=5) and severe (Child-Pugh C; n=1) hepatic impairment. Compared to patients with normal hepatic function, MMAE exposure increased approximately 2.3- fold (90% CI 1.27-4.12 fold) in patients with hepatic impairment.

Renal impairment

The kidney is a route of excretion of the unchanged active metabolite MMAE. Population PK analysis indicated that MMAE clearance might be affected by moderate and severe renal impairment. MMAE clearance was reduced about 2 fold in patients with severe renal impairment (creatinine clearance <30 ml/min). A study evaluated the PK of brentuximab vedotin and MMAE after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (n=4), moderate (n=3) and severe (n=3) renal impairment. Compared to patients with normal renal function, MMAE exposure increased approximately 1.9-fold (90% CI 0.85-4.21 fold) in patients with severe renal impairment (creatinine clearance < 30 ml/min). No effect was observed in patients with mild or moderate renal impairment.

Added:

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.

 

 

Updated on 4 April 2014 PIL

Reasons for updating

  • Change to side-effects

Updated on 3 April 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

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Section 4.4 Special warnings and precautions for use:

Addition of 'sepsis/ septic shock (including fatal outcomes)' under serious infections and opportunistic infections.

Addition of :
Hepatic function

Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Liver function should be routinely monitored in patients receiving brentuximab vedotin.

Section 4.8 Undesirable effects:

Update to wording:

Summary of 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 3 have been determined based on data generated from clinical studies two pivotal phase 2 studies (SG035-0003 and SG035-0004; see section 5.1) in which 160 patients with relapsed or refractory HL or sALCL received at least one dose of brentuximab vedotin at the recommended dose of 1.8 mg/kg every 3 weeks.


Addition of :
Sepsis/ septic shock and alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased added to table 3.

Updated on 4 February 2014 PIL

Reasons for updating

  • Change to information about pregnancy or lactation

Updated on 4 February 2014 SmPC

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties

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The following information has been added/ updated in the sections listed below;

 

Section 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 brentuximab vedotin and until 6 months after treatment.

 

5.1 Pharmacodynamic properties:

 

Hodgkin lymphoma

The objective response rate (ORR) per IRF assessment was 75% (76 of 102 patients in the intent-to-treat [ITT] set) and tumour reduction was achieved in 94% of patients. Complete remission (CR) was 33% (34 of 102 patients in the ITT set). The median overall survival (OS) is 40.5 months (the median follow-up time from first dose was 32.7 months).

 

Overall survival

Median

95% CI

Median

40.5 months
 

28.7, NE

 

An exploratory intra-patient analysis showed that approximately 64% of the HL patients treated with brentuximab vedotin as part of the SG035-0003 clinical study experienced an improvement in clinical benefit as measured by longer progression free survival (PFS) compared with their most recent prior line of therapy.

 

Systemic anaplastic large cell lymphoma

 

The ORR per IRF assessment was 86% (50 of 58 patients in the ITT set). CR was 59% (34 of 58 patients in the ITT set) and tumour reduction was achieved in 97% of patients. The estimated 36 month overall survival was 63% (the median follow-up time from first dose was 33.4 months).

 

Overall survival

Median

95% CI

Median

Not reached c

21.3, NE

c. The estimated 36 month overall survival was 63% (the median follow-up time from first dose was 33.4 months).

 

An exploratory intra-patient analysis showed that approximately 69% of the sALCL patients treated with brentuximab vedotin as part of the SG035-0004 clinical study experienced an improvement in clinical benefit as measured by longer progression free survival (PFS) compared with their most recent prior line of therapy.

Updated on 10 December 2013 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

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In section 4.4:

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 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.

In section 4.8
Uncommon: pancreatitis acute

Updated on 10 December 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects

Updated on 1 November 2013 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder

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The updated Adcetris (brentuximab) SmPC contains a change to the following section:

 

Section 7. Marketing authorisation holder:          

           

Takeda Pharma A/S

Langebjerg 1

DK-4000 Roskilde

Denmark

Updated on 1 November 2013 PIL

Reasons for updating

  • Change to marketing authorisation holder

Updated on 12 September 2013 PIL

Reasons for updating

  • Addition of black triangle

Updated on 12 September 2013 SmPC

Reasons for updating

  • Addition of black triangle
  • Change to section 4.2 - Posology and method of administration
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.2 - Pharmacokinetic properties

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Additional wording to SmPC:

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

 


 

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 to Pharmacovigilance Section, Irish Medicines Board, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, IRL – Dublin 2. Tel: +353 1 6764971, Fax: +353 1 6767836, Website: www.imb.ie.

 

 e-mail: imbpharmacovigilance@imb.ie.

Change of wording elderly to older in section 4.2 and 5.2

 

Updated on 3 June 2013 PIL

Reasons for updating

  • Change of manufacturer

Updated on 7 March 2013 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may not be renewed (A)

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Section 4.4

Under the infusion-related reactions heading, anaphylaxis is now referred to as anaphylactic reactions.

 

Section 4.8

Rewording and additional wording has been added to section 4.8 (undesirable effects) to clarify where the safety data has originated:

               

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 3 have been determined based on data generated from two pivotal phase 2 studies (SG035-0003 and SG035-0004; see section 5.1) in which 160 patients with relapsed or refractory HL or sALCL received at least one dose of brentuximab vedotin at the recommended dose of 1.8 mg/kg every 3 weeks. Adverse drug reactions solely reported outside of the phase 2 population are also included in the table under the frequency category “not known” (cannot be estimated from the available data).

 

Serious adverse drug reactions in the phase 2 population were: neutropenia, thrombocytopenia, constipation, diarrhoea, vomiting, pyrexia, peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycaemia, demyelinating polyneuropathy, tumour lysis syndrome and Stevens-Johnson syndrome.

 

The most frequently observed adverse reactions in the phase 2 population were: peripheral sensory neuropathy, fatigue, nausea, diarrhoea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection.

 

In the phase 2 population, adverse reactions led to treatment discontinuation in 19% of patients receiving brentuximab vedotin. Serious adverse reactions that led to treatment discontinuation in two or more HL or sALCL patients were peripheral sensory neuropathy (6%) and peripheral motor neuropathy (2%).

 

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 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.

 

Adverse drug reactions solely reported outside of the phase 2 population are also included in the table under the frequency category “not known” (cannot be estimated from the available data):

·         Progressive multifocal leukoencephalopathy*

·         Febrile neutropenia*

·         Anaphylactic reaction*

Updated on 4 March 2013 PIL

Reasons for updating

  • Change to side-effects

Updated on 15 November 2012 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

None provided

Updated on 14 November 2012 PIL

Reasons for updating

  • New PIL for new product