Adcetris

ADCETRIS 50 mg powder for concentrate for solution for infusion.

Each vial contains 50 mg of brentuximab vedotin.

After reconstitution , each ml contains 5 mg of brentuximab vedotin.

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

Excipients with known effect

Each vial contains approximately 13.2 mg of sodium.

Powder for concentrate for solution for infusion.

White to off-white cake or powder.

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL):

1. following autologous stem cell transplant (ASCT) or

2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option.

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

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

ADCETRIS is indicated for the treatment of adult patients with CD30+ cutaneous T-cell lymphoma (CTCL) after at least 1 prior systemic therapy.

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

Posology

The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.

The recommended starting dose for the retreatment of patients with relapsed or refractory HL or sALCL who have previously responded to treatment with ADCETRIS is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. Alternatively, treatment may be started at the last tolerated dose.

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.

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.

If the patient's weight is more than 100 kg, the dose calculation should use 100 kg.

Complete blood counts should be monitored prior to administration of each dose of this treatment.

Patients should be monitored during and after infusion.

Treatment should be continued until disease progression or unacceptable toxicity.

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).

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.

Patients with CTCL should receive up to 16 cycles.

Dose adjustments

Neutropenia

If neutropenia develops during treatment it should be managed by dose delays.).

Table 1: Dosing recommendations for neutropenia

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

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

Peripheral neuropathy

If peripheral sensory or motor neuropathy emerges or worsens during treatment see Table 2 below for appropriate dosing recommendations.

Table 2: Dosing recommendations for new or worsening peripheral sensory or motor neuropathy

^a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0; see neuropathy: motor; neuropathy: sensory; and neuropathic pain.

Elderly

Based upon population PK analyses and the safety profile in elderly patients, which are consistent with that of adult patients, the dosing recommendations for patients aged 65 and older are the same as for adults.

Paediatric population

The safety and efficacy of children less than 18 years have not yet been established.1 and 5.2 but no recommendation on a posology can be made.

In nonclinical studies, thymus depletion has been observed.

Method of administration

The recommended dose of ADCETRIS is infused over 30 minutes.

Brentuximab vedotin must not be administered as an intravenous push or bolus. Brentuximab vedotin should be administered through a dedicated intravenous line and it must not be mixed with other medicinal products.

Combined use of bleomycin and brentuximab vedotin causes pulmonary toxicity.

Progressive multifocal leukoencephalopathy

John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in brentuximab vedotin-treated patients. PML has been reported in patients who received this treatment after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.

Patients should be closely monitored for new or worsening neurological, cognitive, or behavioural signs or symptoms, which may be suggestive of PML. Brentuximab vedotin dosing should be held for any suspected case of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established. Brentuximab vedotin dosing should be permanently discontinued if a diagnosis of PML is confirmed.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).

Pancreatitis

Acute pancreatitis has been observed in patients treated with brentuximab vedotin. Fatal outcomes have been reported.

Patients should be closely monitored for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Brentuximab vedotin should be held for any suspected case of acute pancreatitis. Brentuximab vedotin should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Pulmonary Toxicity

Cases of pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported in patients receiving brentuximab vedotin. Although a causal association with brentuximab vedotin has not been established, the risk of pulmonary toxicity cannot be ruled out. In the event of new or worsening pulmonary symptoms (e.g. cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients should be treated appropriately. Consider holding brentuximab vedotin dosing during evaluation and until symptomatic improvement.

Serious infections and opportunistic infections

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

Infusion-related reactions

Immediate and delayed infusion-related reactions (IRR), as well as anaphylactic reactions, have been reported.

Patients should be carefully monitored during and after infusion. If an anaphylactic reaction occurs, administration of brentuximab vedotin should be immediately and permanently discontinued and appropriate medical therapy should be administered.

If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. Premedication may include paracetamol, an antihistamine and a corticosteroid.

IRRs are more frequent and more severe in patients with antibodies to brentuximab vedotin.

Tumour lysis syndrome

Tumour lysis syndrome (TLS) has been reported with brentuximab vedotin. Patients with rapidly proliferating tumour and high tumour burden are at risk of tumour lysis syndrome. These patients should be monitored closely and managed according to best medical practice. Management of TLS may include aggressive hydration, monitoring of renal function, correction of electrolyte abnormalities, anti-hyperuricaemic therapy, and supportive care.

Peripheral neuropathy

Brentuximab vedotin treatment may cause peripheral neuropathy, both sensory and motor. Brentuximab vedotin-induced peripheral neuropathy is typically an effect of cumulative exposure to this medicinal product and is reversible in most cases. In clinical trials, the majority of patients had improvement or resolution of their symptoms Patients should be monitored for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay and a dose reduction of brentuximab vedotin or discontinuation of treatment.

Haematological toxicities

Grade 3 or Grade 4 anaemia, thrombocytopenia, and prolonged (>1 week) Grade 3 or Grade 4 neutropenia can occur with brentuximab vedotin.

Febrile neutropenia

Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with an absolute neutrophil count <1.0 x 10⁹/L, fever >38.5°C; ref CTCAE v3) has been reported with treatment with brentuximab vedotin. Complete blood counts should be monitored prior to administration of each dose of this treatment. Patients should be monitored closely for fever and managed according to best medical practice if febrile neutropenia develops.

Stevens-Johnson syndrome and toxic epidermal necrolysis

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

Gastrointestinal Complications

Gastrointestinal (GI) complications including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorrhage, some with fatal outcomes, have been reported in patients treated with brentuximab vedotin. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.

Hepatotoxicity

Hepatotoxicity in the form of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) has been reported with brentuximab vedotin. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, and concomitant medications may also increase the risk. Liver function should be tested before initiating the treatment and routinely monitored in patients receiving brentuximab vedotin. Patients experiencing hepatotoxicity may require a delay, change in dose or discontinuation of brentuximab vedotin.

Hyperglycaemia

Hyperglycaemia has been reported during clinical trials in patients with an elevated Body Mass Index (BMI) with or without a history of diabetes mellitus. However, any patient who experiences an event of hyperglycaemia should have their serum glucose closely monitored. Anti-diabetic treatment should be administered as appropriate.

Renal and hepatic impairment

There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations.

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.

Sodium content in excipients

This medicinal product contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

Interaction with medicinal products metabolized through CYP3A4 route (CYP3A4 inhibitors/inducers)

Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73%, and did not alter the plasma exposure to brentuximab vedotin. Therefore, co-administration of brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of neutropenia. If neutropenia develops, refer to Table 1: Dosing recommendations for neutropenia.

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

Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter the metabolism of midazolam; therefore brentuximab vedotin is not expected to alter the exposure to medicines that are metabolized by CYP3A4 enzymes.

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.

Pregnancy

There are no data from the use of brentuximab vedotin in pregnant women. Studies in animals have shown reproductive toxicity.

Brentuximab vedotin should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the foetus. If a pregnant woman needs to be treated she should be clearly advised on the potential risk to the foetus.

See the fertility section below pertaining to advice for women whose male partners are being treated with brentuximab vedotin.

Breastfeeding

There are no data as to whether brentuximab vedotin or its metabolites are excreted in human milk.

A risk to the newborn/infant cannot be excluded.

A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from this therapy, taking into account a potential risk of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity, and may alter male fertility. MMAE has been shown to have aneugenic properties. Therefore, men being treated with this medicine are advised to have sperm samples frozen and stored before treatment. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.

Brentuximab vedotin may have a minor influence on the ability to drive and use machines.

Summary of the safety profile

The safety profile of ADCETRIS is based on available clinical trial data, the Named Patient Program (NPP), and post-marketing experience to date. Frequencies of adverse reactions described below and in Table 3 have been determined based on data generated from clinical studies.

In the pooled dataset of Adcetris as monotherapy across HL, sALCL and CTCL studies the most frequent adverse reactions (>10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain.

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

Adverse events led to treatment discontinuation in 24% of patients receiving brentuximab vedotin

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

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

Tabulated list of adverse reactions

Adverse reactions for ADCETRIS are listed by MedDRA System Organ Class and Preferred Term (see Table 3). Within each System Organ Class, adverse reactions are listed under frequency categories of: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 3: Adverse reactions to ADCETRIS

^a. Represents pooling of preferred terms.

Description of selected adverse reactions

Neutropenia

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

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

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

Serious infections and opportunistic infections

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

Peripheral neuropathy

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

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

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

Infusion-related reactions

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

Immunogenicity

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

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

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. In this study in 36 patients, no new safety concerns were reported.

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:

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no known antidote for overdose of brentuximab vedotin. In case of overdose, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents; monoclonal antibodies, ATC code: L01XC12

Mechanism of action

Brentuximab vedotin is an antibody drug conjugate (ADC) that delivers an antineoplastic agent that results in apoptotic cell death selectively in CD30-expressing tumour cells. Nonclinical data suggest that the biological activity of brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on the cell surface initiates internalisation of the ADC-CD30 complex, which then traffics to the lysosomal compartment. Within the cell, a single defined active species, MMAE, is released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest and results in apoptotic death of the CD30-expressing tumour cell.

Classical HL, 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, sALCL and CD30+ CTCL disease and therapeutic spectrums and clinical evidence in CD30-positive malignancies following multiple lines of treatment provide a biologic rationale for its use in patients with relapsed and refractory classical HL, sALCL with or without prior ASCT and CD30+ CTCL after at least 1 prior systemic therapy.

Contributions to the mechanism of action by other antibody associated functions have not been excluded.

Pharmacodynamic effects

Cardiac electrophysiology

Forty-six (46) patients with CD30-expressing hematologic malignancies were evaluable of the 52 patients who received 1.8 mg/kg of brentuximab vedotin every 3 weeks as part of a phase 1, single-arm, open-label, multicenter cardiac safety study. The primary objective was to evaluate the effect of brentuximab vedotin on cardiac ventricular re-polarization and the predefined primary analysis was the change in QTc from baseline to multiple time points in Cycle 1.

The upper 90% confidence interval (CI) around the mean effect on QTc was <10 msec at each of the Cycle 1 and Cycle 3 post-baseline time points. These data indicate the absence of clinically relevant QT prolongation due to brentuximab vedotin administered at a dose of 1.8 mg/kg every 3 weeks in patients with CD30-expressing malignancies.

Clinical efficacy

Hodgkin lymphoma

Study SG035-0003

The efficacy and safety of brentuximab vedotin as a single agent was evaluated in a pivotal open-label, single-arm, multicenter study in 102 patients with relapsed or refractory HL. See Table 4 below for a summary of baseline patient and disease characteristics.

Table 4: Summary of baseline patient and disease characteristics in the phase 2 relapsed or refractory HL study

^a. Primary refractory HL is defined as a failure to achieve a complete remission to, or progressed within 3 months of completing frontline therapy.

Eighteen (18) patients (18%) received 16 cycles of brentuximab vedotin; and the median number of cycles received was 9 (ranging from 1 to 16).

Response to treatment with brentuximab vedotin was assessed by Independent Review Facility (IRF) using the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was assessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Response assessments were performed at cycles 2, 4, 7, 10, 13, and 16 with PET at cycles 4 and 7.

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 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, 8 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

^a. The range of DOR was 1.2+ months to 43+ 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.

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.

Of the 35 patients (33%) who had B symptoms at baseline, 27 patients (77%) experienced resolution of all B symptoms at a median time of 0.7 months from initiation of brentuximab vedotin.

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 one 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.

Baseline patient characteristics showed failure from multiple prior chemotherapy regimens (median of 3 with a range of 1 to 7) before first administration with brentuximab vedotin. Fifty nine percent (59%) of patients had advanced stage disease (stage III or IV) at initial diagnosis.

Results from these phase 1 studies and from the NPP experience showed, that in patients with relapsed or refractory HL without prior ASCT, clinically meaningful responses can be achieved as evidenced by an investigator-assessed, objective response rate of 54% and a complete remission rate of 22% after a median of 5 cycles of brentuximab vedotin.

Study SGN35-005

The efficacy and safety of brentuximab vedotin were evaluated in a randomized, double-blind, placebo-controlled, 2-arm multicenter trial in 329 patients with HL at risk of relapse or progression following ASCT. Patients with known cerebral/meningeal disease, including history of PML were excluded from the study. See Table 6 for patient characteristics. Of the 329 patients, 165 patients were randomized to the treatment arm and 164 patients were randomized to the placebo arm. In the study, patients were to receive their first dose after recovery from ASCT (between days 30-45 following ASCT). Patients were treated with 1.8 mg/kg of ADCETRIS or matching placebo intravenously over 30 minutes every 3 weeks for up to 16 cycles.

Eligible patients were required to have at least one of the following risk factors:

- HL that was refractory to frontline treatment

- Relapsed or progressive HL that occurred <12 months from the end of frontline treatment

- Extranodal involvement at time of pre-ASCT relapse, including extranodal extension of nodal masses into adjacent vital organs

Table 6: Summary of Baseline Patient and Disease Characteristics in the Phase 3 HL post-ASCT Study

^a. For refractory disease, or upon progression or relapse after frontline therapy.

^b. Stratification factors at randomization.

The efficacy results are shown in Table 7. The primary endpoint of PFS was met and showed a difference in median PFS of 18.8 months in favour of the treatment arm.

Table 7: Efficacy Results in HL Patients at Increased Risk of Relapse or Progression Following ASCT Treated with 1.8 mg/kg of Brentuximab Vedotin Every 3 Weeks

^a. At the time of the primary analysis, the median follow-up time for both arms was 30 months [range, 0 to 50].

^b. Stratified log-rank test was not performed for PFS per Investigator.

Pre-specified subgroup analyses of PFS per IRF were performed by patients' best response to pre-ASCT salvage therapy, HL status after frontline therapy, age, gender, baseline weight, baseline ECOG performance status, number of treatments pre-ASCT, geographic region, pre-ASCT PET status, B symptom status after failure of frontline therapy, and pre-ASCT extranodal disease status. The analyses showed a consistent trend towards benefit for patients who received brentuximab vedotin compared with patients who received placebo with the exception of patients >65 years of age (n=8).

No differences were observed in quality of life between the treatment and placebo arms. Medical resource utilization (MRU) analysis showed that hospitalizations and outpatient visits, as well as working days/other activities missed by patients and caregivers were lower with brentuximab vedotin compared with placebo in patients with HL at increased risk of relapse.

An updated analysis conducted after 3 years of follow-up showed a sustained PFS improvement per IRF (HR = 0.58 [95% CI (0.41, 0.81)]).

Post-hoc Risk Factor Analyses

Post-hoc analyses were performed to evaluate the impact of increased risk (number of risk factors) on clinical benefit (Table 8). Representative risk factors for these analyses were:

- HL that occurred <12 months or HL that was refractory to frontline therapy

- Best response of PR or SD to most recent salvage therapy as determined by CT and/or PET scanning

- Extranodal disease at pre-ASCT relapse

- B symptoms at pre-ASCT relapse

- Two or more prior salvage therapies.

The results of these post-hoc analyses suggest increased clinical benefit for patients with two or more risk factors but no difference based on any of the individual risk factors. No benefit in terms of PFS or OS has been observed in patients with one risk factor for relapse or progression.

Table 8: Summary of PFS per IRF and OS by Number of Risk Factors in the Phase 3 HL post-ASCT Study

^a. Death without either prior progression or more than one missed assessment visit.

^b. Indicates results from non-stratified analysis.

^c. Events are death due to any cause.

At the time of the updated analysis (3 years of follow-up) for patients with 2 or more risk factors, the hazard ratio for PFS per IRF was 0.49 (95% CI [0.34, 0.71]) and the hazard ratio for PFS per investigator was 0.41 (95% CI [0.29, 0.58]) (see Figures 1 and 2).

Figure 1: Kaplan-Meier Plot of PFS per IRF in Patients with > 2 Risk Factors

Figure 2: Kaplan-Meier Plot of PFS per Investigator in Patients with > 2 Risk Factors

Study SGN35-006 (Retreatment Study)

The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with brentuximab vedotin was evaluated in a phase 2, open-label, multicenter trial. Twenty patients with relapsed or refractory HL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycles was 7 (range, 2 to 37 cycles). Of the 20 evaluable patients with HL, 6 patients (30%) achieved a CR and 6 patients (30%) achieved a PR with brentuximab vedotin retreatment, for an ORR of 60%. The median duration of response was 9.2 and 9.4 months in patients who achieved OR (CR+PR) and CR, respectively.

Systemic anaplastic large cell lymphoma

Study SG035-0004

The efficacy and safety of brentuximab vedotin as a single agent was evaluated in an open-label, single-arm, multicenter study in 58 patients with relapsed or refractory sALCL. See Table 9 below for a summary of baseline patient and disease characteristics.

Table 9: Summary of baseline patient and disease characteristics in the phase 2 relapsed or refractory sALCL study

a. One patient had a baseline ECOG status of 2, which was prohibited by protocol and is captured as Inclusion Criteria Not Met.

b. Primary refractory sALCL is defined as a failure to achieve a complete remission to, or progressed within 3 months of completing frontline therapy.

The median time from initial sALCL diagnosis to first dose with brentuximab vedotin was 16.8 months.

Ten (10) patients (17%) received 16 cycles of brentuximab vedotin; the median number

The pharmacokinetics of brentuximab vedotin were evaluated in phase 1 studies and in a population pharmacokinetic analysis of data from 314 patients. In all clinical trials, brentuximab vedotin was administered as an intravenous infusion.

Maximum concentrations of brentuximab vedotin ADC were typically observed at the end of infusion or the sampling timepoint closest to the end of infusion. A multiexponential decline in ADC serum concentrations was observed with a terminal half-life of approximately 4 to 6 days. Exposures were approximately dose proportional. Minimal to no accumulation of ADC was observed with multiple doses at the every 3-week schedule, consistent with the terminal half-life estimate. Typical C_max and AUC of ADC after a single 1.8 mg/kg in a phase 1 study was approximately 31.98 μg/ml and 79.41 μg/ml x day respectively.

MMAE is the major metabolite of brentuximab vedotin. Median C_max, AUC and T_max 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.

In the first cycle, higher MMAE exposure was associated with an absolute decrease in neutrophil count.

Distribution

In vitro, the binding of MMAE to human serum plasma proteins ranged from 68-82%. MMAE is not likely to displace or to be displaced by highly protein-bound medicines. In vitro, MMAE was a substrate of P-gp and was not an inhibitor of P-gp at clinical concentrations.

In humans, the mean steady state volume of distribution was approximately 6-10 l for ADC. Based on population PK estimation the typical apparent volume of distribution (VM and VMP) of MMAE were 7.37 l and 36.4 l respectively.

Metabolism

The ADC is expected to be catabolised as a protein with component amino acids recycled or eliminated.

In vivo data in animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. The levels of MMAE metabolites have not been measured in human plasma. At least one metabolite of MMAE has been shown to be active in vitro.

MMAE is a substrate of CYP3A4 and possibly CYP2D6. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits only CYP3A4/5 at concentrations much higher than was achieved during clinical application. MMAE does not inhibit other isoforms.

MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes.

Elimination

The ADC is eliminated by catabolism with a typical estimated CL and half life of 1.457 l/day and 4-6 days respectively.

The elimination of MMAE was limited by its rate of release from ADC, typical apparent CL and half life of MMAE was 19.99 l/day and 3-4 days respectively.

An excretion study was undertaken in patients who received a dose of 1.8 mg/kg of brentuximab vedotin. Approximately 24% of the total MMAE administered as part of the ADC during a brentuximab vedotin infusion was recovered in both urine and faeces over a 1-week period. Of the recovered MMAE, approximately 72% was recovered in the faeces. A lesser amount of MMAE (28%) was excreted in the urine.

Pharmacokinetics in special populations

Population PK analysis showed that baseline serum albumin concentration was a significant covariate of MMAE clearance. The analysis indicated that MMAE clearance was 2-fold lower in patients with low serum albumin concentrations <3.0 g/dl compared with patients with serum albumin concentrations within the normal range.

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

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.

Elderly

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.

Paediatric population

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). The C_max 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 C_max 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 C_max, AUC, and T_max 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.

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

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

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

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

Citric acid monohydrate

Sodium citrate dihydrate

α,α-Trehalose dihydrate

Polysorbate 80

4 years.

After reconstitution/dilution, from a microbiological point of view, the product should be used immediately. However, chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Keep the vial in the original carton in order to protect from light.

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

Pack of 1 vial.

General precautions

Procedures for proper handling and disposal of anticancer medicines should be considered.

Proper aseptic technique throughout the handling of this medicinal product should be followed.

Instructions for reconstitution

Each single use vial must be reconstituted with 10.5 ml of water for injections to a final concentration of 5 mg/ml. Each vial contains a 10% overfill giving 55 mg of ADCETRIS per vial and a total reconstituted volume of 11 ml.

1. Direct the stream toward the wall of the vial and not directly at the cake or powder.

2. Gently swirl the vial to aid dissolution. DO NOT SHAKE.

3. The reconstituted solution in the vial is a clear to slightly opalescent, colourless solution with a final pH of 6.6.

4. The reconstituted solution should be inspected visually for any foreign particulate matter and/or discoloration. In the event of either being observed, discard the medicinal product.

Preparation of infusion solution

The appropriate amount of reconstituted ADCETRIS must be withdrawn from the vial(s) and added to an infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection in order to achieve a final concentration of 0.4-1.2 mg/ml ADCETRIS. The recommended diluent volume is 150 ml. The already reconstituted ADCETRIS can also be diluted into 5% dextrose for injection or Lactated Ringer's for injection.

Gently invert the bag to mix the solution containing ADCETRIS. DO NOT SHAKE.

Any portion left in the vial, after withdrawal of the volume to be diluted, must be disposed of in accordance with local requirements.

Do not add other medicinal products to the prepared ADCETRIS infusion solution or intravenous infusion set. The infusion line should be flushed following administration with sodium chloride 9 mg/ml (0.9%) solution for injection, 5% dextrose for injection, or Lactated Ringer's for injection.

Following dilution, infuse the ADCETRIS solution immediately at the recommended infusion rate.

Total storage time of the solution from reconstitution to infusion should not exceed 24 hours.

Determining dosage amount:

Calculation to determine the total ADCETRIS dose (ml) to be further diluted :

Note: If patient's weight is more than 100 kg, the dose calculation should use 100 kg. The maximal recommended dose is 180 mg.

Calculation to determine the total number of ADCETRIS vials needed:

Table 11: Sample calculations for patients receiving the recommended dose of 1.8 mg/kg of ADCETRIS for weights ranging from 60 kg to 120 kg

a. For a reduced dose, use 1.2 mg/kg for the calculation.

b. To be diluted in 150 ml of diluent and administered by intravenous infusion over 30 minutes every 3 weeks.

c. If patient's weight is more than 100 kg, the dose calculation should use 100 kg.

d. The maximal recommended dose is 180 mg.

Disposal

ADCETRIS is for single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

Takeda Pharma A/S

Dybendal Alle 10

2630 Taastrup

Denmark

EU/1/12/794/001

Date of first authorization: 25 October 2012

Date of renewal: 10 November 2017

11 January 2018