Last Updated on eMC 31-07-2017 View medicine  | Takeda UK Ltd Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

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

Date of revision of text on the SPC:20-07-2017

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Please find below a summary of the changes to the Adcetris (brentuximab vedotin) SmPC:

 

Section

Details of change

5.1 Pharmacodynamic Properties

Within the “Pharmacodynamic effects” section an additional sub-section has been added to the Hodgkin’s Lymphoma clinical efficacy section. Additional text in red.

 

Data in HL Patients Who Are Not Stem Cell Transplant (SCT) Candidates

Study C25007

A phase 4 single-arm study was conducted in patients with relapsed or refractory HL (n=60) who had received at least 1 prior chemotherapeutic regimen and at the time of treatment initiation with brentuximab vedotin were not considered candidates for SCT or multiagent chemotherapy.

The median number of cycles was 7 (range, 1 to 16 cycles). Patients were treated with 1.8 mg/kg of brentuximab 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 of CR was reported for 7 patients (12%); PR was reported for 23 patients (38%). Among these 30 patients, the median time to response, defined as the time from first dose to the soonest of PR or CR, was 6 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 or PR, was 11 weeks (range, 5 to 60 weeks). Twenty-eight patients (47%) went on to receive SCT after a median of 7 cycles (range, 4 to 16 cycles) of brentuximab vedotin treatment. The 32 patients (53%) who did not receive subsequent SCT also received brentuximab vedotin for a median of 7 cycles (range, 1 to 16 cycles).

 

Of the study’s 60 patients, 49 patients (82%) received >1 prior cancer-related treatment and 11 patients (18%) received 1 prior cancer-related treatment. Per IRF, the ORR was 51% (95% CI [36%, 66%]) for the patients who had received >1 prior cancer-related treatment and 45% (95% CI [17%, 77%]) for the patients who had received 1 prior cancer-related treatment. For the patients who received >1 prior cancer-related treatment, a best overall response of CR was reported for 6 patients (12%); PR was reported for 19 patients (39%). For the patients who received 1 prior cancer-related treatment, CR was reported for 1 patient (9%) and PR was reported for 4 patients (36%). Out of the 49 patients receiving >1 line of prior treatment, 22 patients (45%) received subsequent SCT; of the 11 patients who had received 1 prior treatment, 6 patients (55%) received subsequent SCT.

 

Data were also collected from patients (n=15) in phase 1 dose escalation and clinical pharmacology studies, and from patients (n=26) in a NPP, with relapsed or refractory HL who had not received an ASCT, and who were treated with 1.8 mg/kg of brentuximab vedotin every 3 weeks.

10. DATE OF REVISION OF THE TEXT

 

Updated as follows:

20th July 2017


Reasons for adding or updating:

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

Date of revision of text on the SPC:05-07-2017

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Please find below a summary of the main changes to the SmPC:

 

 

Section

Details of change

4.4 Special warnings and precautions for use

In the section ‘Serious infections and opportunistic infections’ the following text in red has been added:

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

4.8 Undesirable effects

In the section ‘Tabulated list of adverse reactions’ the following text in red has been added:

Table 3: Adverse reactions to ADCETRIS

System organ class

Adverse reactions

Infections and infestations

Very common:

Infectiona, upper respiratory tract infection

Common:

Sepsis/septic shock, herpes zoster, pneumonia, herpes simplex

Uncommon:

Oral candidiasis, Pneumocystis jiroveci pneumonia, staphylococcal bacteraemia, cytomegalovirus infection or reactivation

Frequency not known:

Progressive multifocal leukoencephalopathy

Blood and lymphatic system disorders

Very common:

Neutropenia

Common:

Anaemia, thrombocytopenia

Frequency not known:

Febrile neutropenia

Immune system disorders

Frequency not known:

Anaphylactic reaction

Metabolism and nutrition disorders

Common

Hyperglycaemia

Uncommon:

Tumour lysis syndrome

Nervous system disorders

Very common:

Peripheral sensory neuropathy, peripheral motor neuropathy

Common:

Dizziness, demyelinating polyneuropathy

Respiratory, thoracic and mediastinal disorders

Very Common:

Cough, dyspnoea

Gastro-intestinal disorders

Very common:

Diarrhoea, nausea, vomiting, constipation, abdominal pain

Uncommon:

Pancreatitis acute

Hepatobiliary disorders

Common:

Alanine aminotransferase/aspartate

aminotransferase (ALT/AST) increased

Skin and subcutaneous tissue disorders

Very common:

Alopecia, pruritus

Common:

Rash

Rare:

Stevens-Johnson syndrome/toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Very common:

Myalgia, arthralgia

Common:

Back pain

General disorders and administration site conditions

Very common:

Fatigue, chills, pyrexia, infusion-related reactionsb

Investigations

Very common:

Weight decreased

a. Preferred terms that were reported under the Infections and Infestations SOC include sepsis/septic shock, upper respiratory tract infection, herpes zoster, and pneumonia.

b. Preferred terms associated with IRRs were headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus and cough.

 

10. DATE OF REVISION OF THE TEXT

 

Updated as follows:

05th July 2017

 


Reasons for adding or updating:

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

Date of revision of text on the SPC:22-06-2017

Legal Category:POM

Black Triangle (CHM): YES

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Section

Details of change

5.1 Pharmacodynamic properties

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

 

The ORR per IRF assessment was 86% (50 of 58patients in the ITT set). CR was 59% (34 of 58patients in the ITT set) and tumour reduction (of any degree) was achieved in 97% of patients. The estimated 36month 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 79 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 11.815.5months.

b. Not estimable.

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

 

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


Reasons for adding or updating:

  • Change to section 6.3 - Shelf life

Date of revision of text on the SPC:28-06-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



Dear Sir/Madam,

 

Takeda UK would like to advise that the Summary of Product Characteristics (SmPC) for Adcetris (brentuximab vedotin) has been updated.

 

Please find below summary of the main changes to the Adcetris SmPC;

 

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

 

 

Reasons for adding or 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

Date of revision of text on the SPC:24-06-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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

Reasons for adding or 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

Date of revision of text on the SPC:28-04-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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

Reasons for adding or updating:

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

Date of revision of text on the SPC:01-04-2016

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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

Reasons for adding or 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

Date of revision of text on the SPC:19-11-2015

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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 on retreatment added.
5.1 Pharmacodynamic properties has information on Study SGN35-006 (Retreatment Study) added.
10. Date of revision of the text has been updated to 19 November 2015.

Reasons for adding or updating:

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

Date of revision of text on the SPC:02-03-2015

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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

Reasons for adding or 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 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:22-08-2014

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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.

 

 

 

 

 

 

Reasons for adding or updating:

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

Date of revision of text on the SPC:20-03-2014

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

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.

Reasons for adding or updating:

  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC:23-01-2014

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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.

Reasons for adding or updating:

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

Date of revision of text on the SPC:21-11-2013

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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

Reasons for adding or updating:

  • Change to section 7 - Marketing authorisation holder

Date of revision of text on the SPC:24-10-2013

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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

Reasons for adding or updating:

  • 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

Date of revision of text on the SPC:26-08-2013

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Change of wording elderly to older in section 4.2 and 5.2

Reasons for adding or updating:

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

Date of revision of text on the SPC:21-02-2013

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



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*

Reasons for adding or updating:

  • New SPC for new product

Date of revision of text on the SPC:01-01-0001

Legal Category:POM

Black Triangle (CHM): YES