Adcetris · 4.4 Special warnings and precautions for use · 1

HOS-096216 · has-adverse-reaction-information · PDF-Seite 14

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 7 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, C25006 and C25007, see section 5.1) the most frequent adverse reactions (≥ 10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, neutropenia, upper respiratory tract infection, arthralgia, rash, cough, vomiting, pruritus, peripheral motor neuropathy, infusion-related reactions, constipation, dyspnoea, myalgia, weight decreased, 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. 14 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 (AVD/CHP) For safety information of chemotherapy agents given in combination with ADCETRIS (doxorubicin, vinblastine and dacarbazine (AVD) or cyclophosphamide, doxorubicin and prednisone (CHP)), refer to their summary of product characteristics. In the studies of ADCETRIS as combination therapy in 662 patients with previously untreated advanced HL (C25003) and 223 patients with previously untreated CD30+ peripheral T-cell lymphoma (PTCL) (SGN35-014), the mo

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HOS-096212 · has-contraindication-information · PDF-Seite 9

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Combined use of bleomycin and ADCETRIS causes pulmonary toxicity (see section 4.5).

HOS-096211 · has-indication-information · PDF-Seite 2

Hodgkin lymphoma ADCETRIS is indicated for adult patients with previously untreated CD30+ Stage III or IV Hodgkin lymphoma (HL) in combination with doxorubicin, vinblastine and dacarbazine (AVD) (see sections 4.2 and 5.1). ADCETRIS is indicated for adult patients with previously untreated CD30+ Stage IIB with risk factors, Stage III or Stage IV HL in combination with etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone (BrECADD) (see sections 4.2 and 5.1). ADCETRIS is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT) (see section 5.1). ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL): 1. following ASCT, or 2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. 2 Systemic anaplastic large cell lymphoma ADCETRIS in combination with cyclophosphamide, doxorubicin and prednisone (CHP) is indicated for adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) (see section 5.1). ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory sALCL. Cutaneous T-cell lymphoma ADCETRIS is indicated for the treatment of adult patients with CD30+ cutaneous T-cell lymphoma (CTCL) after at least 1 prior systemic therapy (see section 5.1).

HOS-096214 · has-interaction-information · PDF-Seite 13

Interaction with medicinal products metabolised through CYP3A4 route (CYP3A4 inhibitors/inducers) Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased the exposure to the antimicrotubule agent MMAE by approximately 73%, and did not alter the plasma exposure to brentuximab vedotin. Therefore, co-administration of brentuximab vedotin with strong CYP3A4 and P-gp inhibitors may increase the incidence of neutropenia. If neutropenia develops, refer to Tables 1 and 2 for dosing recommendations for neutropenia (see section 4.2). Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter the plasma exposure to brentuximab vedotin. Though PK data are limited, co-administration of rifampicin appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter the metabolism of midazolam; therefore brentuximab vedotin is not expected to alter the exposure to medicines that are metabolised by CYP3A4 enzymes. Doxorubicin, vinblastine and dacarbazine (AVD) The serum and plasma pharmacokinetic characteristics of antibody drug conjugate (ADC) and MMAE respectively following administration of brentuximab vedotin in combination with AVD were similar to that in monotherapy. Co-administration of brentuximab vedotin did not affect the plasma exposure of AVD. Cyclophosphamide, doxorubicin and prednisone (CHP) The serum and plasma pharmacokinetic characteristics of ADC and MMAE, respectively, following administration of brentuximab vedotin in combination with CHP were similar to that in monotherapy. Co-administration of brentuximab vedotin is not expected to affect the exposure of CHP. Bleomycin There were no formal drug-drug interaction studies with brentuximab vedotin and bleomycin (B). In a phase 1 dose finding and safety study (SGN35-009), unacceptable pulmonary toxicity (including 2 fatal events) was noted in 11 of 25 patients (44%) treated with brentuximab vedotin plus ABVD. No pulmonary toxicity or fatal events were reported with brentuximab vedotin + AVD. Therefore, co-administration of ADCETRIS with bleomycin is contraindicated (see section 4.3). Etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone (BrECADD regimen) The pharmacokinetics of ADC and MMAE have not been characterized in the setting of BrECADD. Exposures of brentuximab vedotin and concur

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HOS-096215 · has-pregnancy-information · PDF-Seite 13

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. 13 Pregnancy There are no data from the use of ADCETRIS in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the foetus. If a pregnant woman needs to be treated she should be clearly advised on the potential risk to the foetus. See the fertility section below pertaining to advice for women whose male partners are being treated with ADCETRIS. Breast-feeding There are no data as to whether brentuximab vedotin or its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from this therapy, taking into account a potential risk of breast-feeding for the child and the benefit of therapy for the woman. Fertility In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity, and may alter male fertility. MMAE has been shown to have aneugenic properties (see section 5.3). Therefore, men being treated with this medicine are advised to have sperm samples frozen and stored before treatment. Men being treated with this medicine are advised not to father a child during treatment and for up to 6 months following the last dose.

HOS-096213 · has-warning-information · PDF-Seite 9

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. 9 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

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