ADCETRIS Powder for concentrate for solution Ref.[6593] Active ingredients: Brentuximab vedotin

Progressive multifocal leukoencephalopathy

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

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

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

Pancreatitis

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

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

Pulmonary toxicity

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

Serious infections and opportunistic infections

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

Infusion-related reactions

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

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

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

IRRs are more frequent and more severe in patients with antibodies to brentuximab vedotin (see section 4.8).

Tumour lysis syndrome

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

Peripheral neuropathy

ADCETRIS may cause peripheral neuropathy, both sensory and motor. ADCETRIS-induced peripheral neuropathy is typically an effect of cumulative exposure to this medicinal product and is reversible in most cases. In clinical trials, the majority of patients had resolution or improvement of their symptoms (see section 4.8). Patients should be monitored for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay and a dose reduction of ADCETRIS or discontinuation of treatment (see section 4.2).

Haematological toxicities

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

Febrile neutropenia

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

In combination therapy with AVD, advanced age was a risk factor for febrile neutropenia.When ADCETRIS is administered in combination with AVD, primary prophylaxis with G-CSF is recommended for all patients regardless of age beginning with the first dose.

Stevens-Johnson syndrome and toxic epidermal necrolysis

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

Gastrointestinal complications

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

Hepatotoxicity

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

Hyperglycaemia

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

Renal and hepatic impairment

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

CD30+ CTCL

The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes 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).

Sodium content in excipients

This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

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

Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73%, and did not alter the plasma exposure to brentuximab vedotin. Therefore, co-administration of brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of neutropenia. If neutropenia develops, refer to Table 1: Dosing recommendations for neutropenia (see section 4.2).

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

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

Doxorubicin, vinblastine and dacarbazine (AVD)

The serum and plasma pharmacokinetic characteristics of ADC and MMAE respectively following administration of brentuximab vedotin in combination with AVD were similar to that in monotherapy.

Co-administration of brentuximab vedotin did not affect the plasma exposure of AVD.

Bleomycin

There were no formal drug-drug interaction studies with brentuximab vedotin and bleomycin(B). In a phase 1 dose finding and safety study (SGN35-009), unacceptable pulmonary toxicity (including 2 fatal events) was noted in 11 of 25 patients (44%) treated with brentuximab vedotin plus ABVD. No pulmonary toxicity or fatal events were reported with brentuximab vedotin + AVD. Therefore, co-administration of ADCETRIS with bleomycin is contraindicated (see section 4.2).

Women of childbearing potential

Women of childbearing potential should be using two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment.

Pregnancy

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

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

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

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 (see section 5.3). Therefore, men being treated with this medicine are advised to have sperm samples frozen and stored before treatment. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.

ADCETRIS may have a moderate influence on the ability to drive and use machines (e.g. dizziness), see section 4.8.

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.

Monotherapy

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

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

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

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

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

Combination therapy

For safety information of chemotherapy agents given in combination with ADCETRIS (doxorubicin, vinblastine and dacarbazine) for newly diagnosed patients with HL, refer to their summary of product characteristics.

In the study of ADCETRIS as combination therapy with AVD in 662 patients with previously untreated advanced HL (C25003), the most common adverse reactions (≥ 10%) were: neutropenia, nausea, constipation, vomiting, fatigue, peripheral sensory neuropathy, diarrhoea, pyrexia, alopecia, peripheral motor neuropathy, decreased weight, abdominal pain, anaemia, stomatitis, febrile neutropenia, bone pain, insomnia, decreased appetite, cough, headache, arthralgia, back pain, dyspnoea, myalgia, upper respiratory tract infection, alanine aminotransferase increased.

In patients receiving ADCETRIS combination therapy, serious adverse reactions occurred in 36% of patients. Serious adverse reactions occurring in ≥3% of patients included febrile neutropenia (17%), pyrexia (6%), and neutropenia (3%).

Adverse events led to treatment discontinuation in 13% of patients. Adverse events that led to treatment discontinuation in ≥2% of patients included peripheral sensory neuropathy, peripheral neuropathy, and peripheral motor neuropathy.

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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3. Adverse reactions to ADCETRIS:

^a Represents pooling of preferred terms.
^b Toxic epidermal necrolysis was not reported in the combination therapy setting.

Description of selected adverse reactions

Neutropenia and febrile neutropenia

Monotherapy

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

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

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

Combination therapy

In the clinical trial of ADCETRIS as combination therapy, neutropenia led to dose delays in 24% of patients. Grade 3 neutropenia was reported in 18% and Grade 4 neutropenia was reported in 47% of patients. Two percent of patients required dose reduction and <1% discontinued one of more of the study drugs due to neutropenia.

Febrile neutropenia was reported in 21% of the patients who did not receive primary prophylaxis with G-CSF (see section 4.2). The frequency of febrile neutropenia was 11% in patients who received primary prophylaxis with G-CSF.

Serious infections and opportunistic infections

Monotherapy

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

Combination therapy

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

Peripheral neuropathy

Monotherapy

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

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

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

Combination therapy

In the clinical trial of ADCETRIS as combination therapy, treatment emergent neuropathy occurred in 67% of the population; peripheral motor neuropathy occurred in 11% of patients. Peripheral neuropathy led to treatment discontinuation in 7%, dose reductions in 21%, and dose delays in 1% of patients. For patients who experienced peripheral neuropathy the median time of onset of peripheral neuropathy was 8 weeks. Patients who discontinued due to peripheral neuropathy received a median of 8 doses of ADCETRIS+AVD (A+AVD) before discontinuation of one or more agents.

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

Infusion-related reactions

Monotherapy

IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus and cough were reported in 13% of patients. Anaphylactic reactions have been reported (see section 4.4). Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm. h4. Combination therapy

IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus, cough, infusion site pain and pyrexia were reported in 9% of patients. Anaphylactic reactions have been reported (see section 4.4). Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension and bronchospasm.

Immunogenicity

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

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

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 ½ 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.

Elderly

Monotherapy

The safety profile in elderly patients was consistent with that of adult patients.

Combination therapy

In older patients (≥60 years of age; n=83 [13%]), the incidence of adverse events was similar across treatment arms. More serious adverse events and dose modifications (including dose delays, reductions, and discontinuations) were reported in the older patients compared with the overall study population. Advanced age was a risk factor for febrile neutropenia in patients in both arms. Older patients who received G-CSF primary prophylaxis had lower incidence of neutropenia and febrile neutropenia than those who did not receive G-CSF primary prophylaxis.

Reporting of suspected adverse reactions

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

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