PRODUCT MONOGRAPH Pr ADCETRIS Brentuximab vedotin Lyophilized powder for reconstitution with 10.5 ml of sterile Water for Injection, USP 50 mg Antineoplastic agent ADCETRIS, indicated for the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma (salcl) after failure of at least one multi-agent chemotherapy regimen, has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the nature of the authorization. For further information for ADCETRIS, please refer to Health Canada s Notice of Compliance with conditions drug products website: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/noticesavis/conditions/index-eng.php Seattle Genetics, Inc. 21823, 30 th Drive S.E. Bothell, WA 98021 Date of Approval: May 15, 2015 Date of Revision: February 11, 2015 Canadian importer/distributor: GMD Distribution Inc. 1215B North Service Road W Oakville, ON, L6M 2W2 Submission Control No: 176454 ADCETRIS Product Monograph Page 1 of 45
This product has been approved under the Notice of Compliance with Conditions (NOC/c) policy for one or all of its indicated uses. What is a Notice of Compliance with Conditions (NOC/c)? An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada. Products approved under Health Canada s NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame. What will be different about this Product Monograph? The following Product Monograph will contain boxed text at the beginning of each major section clearly stating the nature of the market authorization. Sections for which NOC/c status holds particular significance will be identified in the left margin by the symbol NOC/c. These sections may include, but are not limited to, the following: - Indications and Clinical Uses; - Action; - Warnings and Precautions; - Adverse Reactions; - Dosage and Administration; and - Clinical Trials. ADCETRIS Product Monograph Page 2 of 45
Adverse Drug Reaction Reporting and Re-Issuance of the Product Monograph Health care providers are encouraged to report Adverse Drug Reactions associated with normal use of these and all drug products to Health Canada s Health Product Safety Information Division at 1-866-234-2345. The Product Monograph will be re-issued in the event of serious safety concerns previously unidentified or at such time as the sponsor provides the additional data in support of the product s clinical benefit. Once the latter has occurred, and in accordance with the NOC/c policy, the conditions associated with market authorization will be removed. ADCETRIS Product Monograph Page 3 of 45
Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION... 5 SUMMARY PRODUCT INFORMATION... 5 DESCRIPTION... 5 INDICATIONS AND CLINICAL USE... 6 CONTRAINDICATIONS... 6 WARNINGS AND PRECAUTIONS... 7 ADVERSE REACTIONS... 12 DRUG INTERACTIONS... 24 DOSAGE AND ADMINISTRATION... 26 OVERDOSAGE... 28 ACTION AND CLINICAL PHARMACOLOGY... 28 STORAGE AND STABILITY... 31 SPECIAL HANDLING INSTRUCTIONS... 31 DOSAGE FORMS, COMPOSITION AND PACKAGING... 31 PART II: SCIENTIFIC INFORMATION... 32 PHARMACEUTICAL INFORMATION... 32 CLINICAL TRIALS... 33 DETAILED PHARMACOLOGY... 35 TOXICOLOGY... 38 REFERENCES... 41 PART III: CONSUMER INFORMATION... 42 ADCETRIS Product Monograph Page 4 of 45
Pr ADCETRIS Brentuximab vedotin ADCETRIS, indicated for the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma (salcl) after failure of at least one multi-agent chemotherapy regimen, has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the nature of the authorization. PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Intravenous infusion Pharmaceutical Form/Strength Lyophilized powder, 50 mg Clinically Relevant Nonmedicinal Ingredients None. For a complete listing see Dosage Forms, Composition and Packaging section. DESCRIPTION ADCETRIS (brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC) consisting of three components: 1) the chimeric IgG1 antibody cac10, specific for human CD30, 2) the potent microtubule-disrupting agent monomethyl auristatin E (MMAE), and 3) a protease-cleavable linker that covalently attaches MMAE to cac10. The biological activity of brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on the cell surface initiates internalization of the ADC-CD30 complex, which then traffics to the lysosomal compartment. Within the cell, 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 tumor cell. ADCETRIS Product Monograph Page 5 of 45
NOC/c INDICATIONS AND CLINICAL USE ADCETRIS (brentuximab vedotin) is a CD30-directed antibody-drug conjugate indicated for: The treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates; The treatment of patients with systemic anaplastic large cell lymphoma (salcl) after failure of at least one multi-agent chemotherapy regimen. The indications were authorized based on promising response rates demonstrated in single-arm trials (see CLINICAL TRIALS). No data demonstrate increased survival with ADCETRIS. ADCETRIS should only be administered by a qualified healthcare professional experienced in the use of antineoplastic therapy. Geriatrics ( 65 years of age): The safety and efficacy of ADCETRIS have not been established in the geriatric population. Pediatrics (<18 years of age): The safety and efficacy of ADCETRIS have not been established in the pediatric population. NOC/c CONTRAINDICATIONS Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. ADCETRIS is contraindicated for patients who have or have had progressive multifocal leukoencephalopathy (PML) (See WARNINGS AND PRECAUTIONS, Progressive Multifocal Leukoencephalopathy). ADCETRIS Product Monograph Page 6 of 45
Serious Warnings and Precautions Clinically significant and/or life-threatening adverse events include: JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death (see WARNINGS AND PRECAUTIONS, Progressive Multifocal Leukoencephalopathy) Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS AND PRECAUTIONS, Dermatologic) Serious and opportunistic infections (see WARNINGS AND PRECAUTIONS, Infections) Acute pancreatitis (see WARNINGS AND PRECAUTIONS, Gastrointestinal) NOC/c WARNINGS AND PRECAUTIONS General Infusion reactions Immediate and delayed infusion-related reactions, as well as anaphylaxis, have been reported. Monitor patients during infusion. Symptoms of an infusion reaction include chills, nausea, cough, and itching within 2 days after a dose. Symptoms of a severe infusion reaction include wheezing, difficulty breathing, hives, itching, and swelling. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid. Cardiac Ventricular Repolarization QT shortening was observed in CD30-positive patients treated with brentuximab vedotin. The clinical significance of QT shortening is unknown. Dermatologic Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. The symptoms of SJS and TEN include unexplained widespread skin pain, blisters on the skin and mucous membranes, hives, tongue swelling, a red or purple skin rash that spreads, or unexplained shedding of the skin. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy. ADCETRIS Product Monograph Page 7 of 45
Gastrointestinal Acute pancreatitis, including fatal outcomes, has been reported in patients treated with ADCETRIS. Consider the diagnosis of acute pancreatitis for patients presenting with new or worsening abdominal pain. Hold ADCETRIS for any suspected case of acute pancreatitis and discontinue if a diagnosis of acute pancreatitis is confirmed. Hematologic Anemia: Grade 3 or 4 anemia can occur with ADCETRIS. Neutropenia: Neutropenia was very common in the pivotal trials for HL and salcl occurring in 55 (54%) and 37 (64%) patients, respectively. Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged ( 1 week) severe neutropenia and febrile neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by growth factor support, dose delays, reductions or discontinuations (see DOSAGE AND ADMINISTRATION). Thrombocytopenia: Prolonged ( 1 week) severe thrombocytopenia can occur with ADCETRIS. If Grade 3 or 4 thrombocytopenia develops, monitor closely and consider platelet transfusions or dose delays. Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, mild to moderate transient elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), has been reported in patients receiving ADCETRIS. Hyperglycemia Hyperglycemia has been reported during clinical trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. If hyperglycemia develops, monitor the patient s serum glucose and administer anti-diabetic treatment as appropriate. Immune The efficacy and safety of, and ability to generate a primary or anamnestic response to immunization with live attenuated or inactivated vaccines during or following ADCETRIS treatment have not been established; therefore, patients should be observed for failure to respond to a vaccine. The risks and benefits of vaccinating patients with live attenuated, or inactivated, vaccines during or following ADCETRIS therapy should be considered. ADCETRIS Product Monograph Page 8 of 45
A higher incidence of infusion-related reactions was observed in patients who developed persistently positive antibodies than in those who did not. The effect of anti-brentuximab vedotin antibodies on efficacy and safety has not been established. Infections Serious and opportunistic infections such as pneumonia, bacteremia, sepsis/septic shock (including fatal outcomes), herpes zoster, Pneumocystis jiroveci pneumonia, and oral candidiasis have been reported in patients treated with ADCETRIS. Symptoms of infection include fever ( 38 C), sore throat, difficulty breathing, painful sores (ulcers) around the mouth and/or anus, or pain on urination. Patients should be carefully monitored during treatment for the emergence of possible bacterial, fungal, or viral infections. Neurologic Peripheral Neuropathy ADCETRIS treatment can cause a peripheral neuropathy that may be sensory or motor in nature. ADCETRIS-induced peripheral neuropathy is typically cumulative. In the pivotal HL and salcl clinical trials, 56 (55%) and 33 (59%) patients, respectively, experienced peripheral neuropathy (any grade). Of these, 34/56 (61%) HL patients and 16/33 (48%) salcl patients had complete resolution and 14/56 (25%) HL patients and 10/33 (30%) salcl patients showed some resolution or improvement. The remainder continued to have symptoms of peripheral neuropathy at the end of the treatment or during the follow-up period. Symptoms of peripheral sensory neuropathy include burning sensation, pain, numbness and tingling (feeling of pins and needles) of hands and/or feet. Symptoms of motor neuropathy include weakness and difficulty walking. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS (see DOSAGE AND ADMINISTRATION). Progressive multifocal leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death has occurred in patients treated with ADCETRIS. Contributing factors may include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. These symptoms include confusion or problems thinking, loss of balance or problems walking, difficulty speaking, decreased strength or weakness on one side of the body, blurred vision or loss of vision. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed. ADCETRIS Product Monograph Page 9 of 45
Pulmonary Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids. One patient in the clinical trial experienced fatal lung toxicity. Cases of pulmonary toxicity have been reported in patients receiving single-agent ADCETRIS. Although a causal association with single-agent 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, dyspnea), a prompt diagnostic evaluation should be performed and patients should be treated appropriately. Tumor Lysis Syndrome Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Symptoms of tumor lysis syndrome include nausea, vomiting, edema (swelling), shortness of breath, heart rhythm disturbances, and acute renal failure. Monitor closely and take appropriate measures. Special Populations Pregnant Women There are no adequate and well-controlled studies performed with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryofetal toxicities including increased early resorption, post-implantation loss, decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs) in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and salcl. Brentuximab vedotin and MMAE were both shown to cross the placenta in this study (see Part II, Developmental and Reproductive Toxicity). For women of childbearing potential, precautions should be taken to avoid pregnancy and at least two contraceptive methods should be used while taking ADCETRIS and for 6 months after completing therapy. If pregnancy occurs, the physician should be immediately informed. ADCETRIS should not be administered to pregnant women unless the possible benefits to the mother outweigh the risks to the fetus. If this drug is used during pregnancy, or if the patient ADCETRIS Product Monograph Page 10 of 45
becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. See the fertility section below pertaining to advice for women whose male partners are being treated with ADCETRIS. Nursing Women It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Fertility It is not known if ADCETRIS will affect human spermatogenesis. In non-clinical studies, brentuximab vedotin resulted in testicular toxicity which was partially resolved 16-weeks post last dose administration. Therefore, due to this potential risk, men should be advised not to impregnate their partner during treatment with ADCETRIS. Men of reproductive potential should use an appropriate method of barrier contraception throughout treatment with ADCETRIS and for at least 6 months after completing therapy (see Developmental and Reproductive Toxicity: Impairment of Fertility). Pediatrics (<18 years of age) The safety and efficacy of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients (see ACTION AND CLINICAL PHARMACOLOGY). Geriatrics ( 65 years of age) The safety and efficacy of ADCETRIS have not been established in the geriatric population. Clinical trials of ADCETRIS included 17 geriatric patients and this number is not sufficient to determine whether they respond differently than younger patients (see ACTION AND CLINICAL PHARMACOLOGY). Renal impairment The kidney is a route of excretion for MMAE. MMAE exposure is increased in patients with severe renal impairment (creatinine clearance <30 ml/min) (see ACTION AND CLINICAL PHARMACOLOGY). Hepatic impairment The liver is a route of clearance for MMAE. MMAE exposure is increased in patients with hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY). ADCETRIS Product Monograph Page 11 of 45
Monitoring and Laboratory Tests Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia or thrombocytopenia. NOC/c ADVERSE REACTIONS Adverse Drug Reaction Overview ADCETRIS was studied as monotherapy in 160 patients in two phase II trials. Across both trials, the most common adverse reactions ( 20%), regardless of causality, were peripheral sensory neuropathy, fatigue, nausea, diarrhea, anemia, pyrexia, upper respiratory tract infection, neutropenia, vomiting and cough. The most common adverse reactions occurring in at least 2 patients in either trial, regardless of causality, using the NCI Common Toxicity Criteria Version 3.0, are shown in Table 1. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. ADCETRIS was studied in 102 patients with HL and 58 patients with salcl in single arm pivotal, phase II trials in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks for a maximum of 16 cycles. Median durations of treatment were 27 weeks (range, 3 to 56 weeks) and 23.5 weeks (range, 3 to 75 weeks) for the HL and salcl studies, respectively (see Clinical Trials section). The treatment-emergent adverse reactions that occurred in 20% of HL patients were: leukopenia (61%), neutropenia (54%), peripheral sensory neuropathy (52%), upper respiratory tract infection (47%), fatigue (46%), nausea (42%), diarrhea (36%), anemia (33%), pyrexia (29%), thrombocytopenia (28%), lymphopenia (24%), vomiting (22%), and cough (21%). Grade 3 treatment-emergent adverse reactions that occurred in more than 2% of patients included neutropenia (15%), peripheral sensory neuropathy (9%), anemia (8%), thrombocytopenia (7%), lymphopenia (7%), leukopenia (6%), and peripheral motor neuropathy (4%). Grade 4 treatmentemergent adverse reactions included neutropenia (6%), thrombocytopenia (2%), anemia (2%), abdominal pain (1%) and lymphopenia (1%). ADCETRIS Product Monograph Page 12 of 45
The treatment-emergent adverse reactions that occurred in 20% of systemic ALCL patients were: neutropenia (64%), leukopenia (52%), peripheral sensory neuropathy (52%), nausea (40%), fatigue (38%), pyrexia (34%), anemia (33%), diarrhea (29%), upper respiratory tract infection (28%), lymphopenia (26%), rash (24%), thrombocytopenia (24%), and constipation (22%). Grade 3 treatment-emergent adverse reactions that occurred in more than 3% of patients included neutropenia (16%), peripheral sensory neuropathy (16%), lymphopenia (10%), thrombocytopenia (9%), anemia (7%) and peripheral motor neuropathy (7%). Grade 4 treatmentemergent adverse reactions included neutropenia (9%), thrombocytopenia (5%), fatigue, leukopenia, lymphopenia, pain in extremity, and pain (1 patient, 2% each). Table 1: Commonly Reported (at least 2 patients in either trial) Adverse Reactions System Organ Class Preferred Term HL Total N = 102 n (%) of patients Any Grade 3 Grade 4 Grade salcl Total N = 58 n (%) of patients Any Grade 3 Grade 4 Grade Blood and lymphatic system disorders a Leukopenia 62 (61) 6 (6) - 30 (52) 2 (3) 1 (2) Neutropenia 55 (54) 15 (15) 6 (6) 37 (64) 9 (16) 5 (9) Anemia 34 (33) 8 (8) 2 (2) 19 (33) 4 (7) - Thrombocytopenia 29 (28) 7 (7) 2 (2) 14 (24) 5 (9) 3 (5) Lymphopenia 24 (24) 7 (7) 1 (1) 15 (26) 6 (10) 1 (2) Lymphadenopathy 11 (11) - - 6 (10) - - Nervous system disorders Peripheral sensory neuropathy b 53 (52) 9 (9) - 30 (52) 9 (16) - Headache 19 (19) - - 11 (19) 1 (2) - Peripheral motor neuropathy c 16 (16) 4 (4) - 5 (9) 4 (7) - Dizziness 11 (11) - - 9 (16) - - Memory impairment 1 (1) - - 3 (5) - - Dysgeusia 2 (2) - - 1 (2) - - Restless legs syndrome 3 (3) - - - - - Syncope 2 (2) 2 (2) - 1 (2) - 1 (2) Lethargy - - - 2 (3) - - Somnolence - - - 2 (3) - - General disorders and administration site conditions Fatigue 47 (46) 2 (2) - 22 (38) 2 (3) 1 (2) Pyrexia 30 (29) 2 (2) - 20 (34) 1 (2) - Chills 13 (13) - - 8 (14) - - Pain 7 (7) - - 6 (10) - 1 (2) Edema peripheral 4 (4) - - 8 (14) - - ADCETRIS Product Monograph Page 13 of 45
System Organ Class Preferred Term HL Total N = 102 n (%) of patients Any Grade 3 Grade 4 Grade salcl Total N = 58 n (%) of patients Any Grade 3 Grade 4 Grade Asthenia 4 (4) 1 (1) - 5 (9) - - Chest discomfort 3 (3) - - - - - Influenza like illness 2 (2) - - 1 (2) - - Non-cardiac chest pain 3 (3) 1 (1) - - - - Edema 2 (2) - - 1 (2) - - Malaise 2 (2) - - - - - Gastrointestinal disorders Nausea 43 (42) - - 23 (40) 1 (2) - Diarrhea 37 (36) 1 (1) - 17 (29) 2 (3) - Vomiting 22 (22) - - 10 (17) 2 (3) - Abdominal pain 17 (17) 1 (1) 1 (1) 5 (9) 1 (2) - Constipation 16 (16) - - 13 (22) 1 (2) - Dyspepsia 5 (5) - - 5 (9) - - Abdominal pain upper 6 (6) 1 (1) - 2 (3) - - Abdominal distension 4 (4) - - 3 (5) - - Stomatitis 4 (4) - - 2 (3) - - Dry mouth 4 (4) - - 1 (2) - - Oral pain - - - 5 (9) - - Flatulence 3 (3) - - 1 (2) - - Gastroesophageal reflux disease 1 (1) - - 3 (5) - - Hemorrhoids 1 (1) - - 3 (5) - - Toothache 2 (2) - - 2 (3) - - Dysphagia 1 (1) - - 2 (3) 1 (2) - Epigastric discomfort 3 (3) - - - - - Gastritis 3 (3) - - - - - Hematemesis 3 (3) 1 (1) - - - - Hiatus hernia 3 (3) - - - - - Infections and infestations Upper respiratory tract 48 (47) - - 16 (28) - - infection d Bronchitis 9 (9) - - 3 (5) - - Urinary tract infection 6 (6) 1 (1) - 3 (5) 2 (3) - Herpes zoster 7 (7) - - 1 (2) - - ADCETRIS Product Monograph Page 14 of 45
System Organ Class Preferred Term HL Total N = 102 n (%) of patients Any Grade 3 Grade 4 Grade salcl Total N = 58 n (%) of patients Any Grade 3 Grade 4 Grade Folliculitis - - - 5 (9) - - Influenza 5 (5) - - - - - Pneumonia 4 (4) 1 (1) - 1 (2) 1 (2) - Herpes simplex 3 (3) - - 1 (2) - - Candidiasis 3 (3) - - - - - Cellulitis 1 (1) - - 2 (3) 1 (2) - Ear infection 1 (1) - - 2 (3) - - Fungal infection 3 (3) - - - - - Fungal skin infection 2 (2) - - 1 (2) - - Septic shock 1 (1) - 1 (1) 2 (3) 1 (2) - Oral candidiasis - - - 2 (3) - - Paronychia 2 (2) - - - - - Pyelonephritis 2 (2) 2 (2) - - - - Respiratory, thoracic and mediastinal disorders Cough 21 (21) - - 10 (17) - - Dyspnea 13 (13) 1 (1) - 11 (19) 1 (2) - Oropharyngeal pain 11 (11) - - 4 (7) - - Productive cough 6 (6) - - 3 (5) - - Nasal congestion 6 (6) - - 1 (2) - - Epistaxis 2 (2) - - 2 (3) - - Dyspnea exertional 2 (2) - - 1 (2) - - Pneumonitis 3 (3) 1 (1) 1 (1) - - - Pulmonary embolism 2 (2) - 2 (2) 1 (2) 1 (2) - Rhinorrhoea 1 (1) - - 2 (3) - - Dysphonia 2 (2) - - - - - Hemoptysis 2 (2) 1 (1) - - - - Lung disorder 2 (2) - - - - - Pneumothorax 2 (2) 1 (1) - - - - Throat tightness 2 (2) - - - - - Skin and subcutaneous tissue disorders Rash 14 (14) - - 14 (24) - - ADCETRIS Product Monograph Page 15 of 45
System Organ Class Preferred Term HL Total N = 102 n (%) of patients Any Grade 3 Grade 4 Grade salcl Total N = 58 n (%) of patients Any Grade 3 Grade 4 Grade Pruritus 16 (16) - - 11 (19) - - Alopecia 13 (13) - - 8 (14) - - Night sweats 12 (12) - - 4 (7) - - Dry skin 4 (4) - - 6 (10) - - Hyperhidrosis 6 (6) - - 1 (2) - - Rash pruritic 3 (3) - - 4 (7) - - Rash erythematous 4 (4) - - 2 (3) - - Erythema 4 (4) - - 1 (2) - - Rash maculo-papular 4 (4) - - 1 (2) - - Dermatitis - - - 4 (7) 1 (2) - Ecchymosis 2 (2) - - 1 (2) - - Rash papular 2 (2) - - 1 (2) 1 (2) - Skin lesion 1 (1) - - 2 (3) - - Urticaria 2 (2) - - 1 (2) - - Rash macular 2 (2) - - - - - Skin exfoliation - - - 2 (3) - - Musculoskeletal and connective tissue disorders Myalgia 17 (17) - - 9 (16) 1 (2) - Arthralgia 19 (19) - - 5 (9) - - Back pain 14 (14) - - 5 (9) 1 (2) - Pain in extremity 10 (10) - - 8 (14) 1 (2) 1 (2) Muscle spasms 9 (9) - - 8 (14) 1 (2) - Neck pain 6 (6) - - 5 (9) 1 (2) - Bone pain 8 (8) 1 (1) - 2 (3) - - Groin pain 4 (4) - - 5 (9) - - Musculoskeletal pain 5 (5) - - 4 (7) 1 (2) - Musculoskeletal chest pain 3 (3) - - 1 (2) - - Flank pain 2 (2) - - - - - Psychiatric disorders Insomnia 14 (14) - - 9 (16) - - Anxiety 11 (11) 2 (2) - 4 (7) - - Depression 8 (8) - - 4 (7) 1 (2) - Confusional state 1 (1) - - 3 (5) 1 (2) - ADCETRIS Product Monograph Page 16 of 45
System Organ Class Preferred Term HL Total N = 102 n (%) of patients Any Grade 3 Grade 4 Grade salcl Total N = 58 n (%) of patients Any Grade 3 Grade 4 Grade Mental status changes 1 (1) - - 2 (3) - 1 (2) Panic attack 2 (2) - - - - - Metabolism and nutrition disorders Decreased appetite 11 (11) - - 9 (16) 1 (2) - Hyperglycemia 6 (6) 4 (4) - 3 (5) 1 (2) - Hypokalemia 2 (2) 1 (1) - 5 (9) 2 (3) - Dehydration 3 (3) - - 3 (5) 1 (2) - Hypomagnesemia 2 (2) - - 3 (5) - - Fluid overload - - - 2 (3) 1 (2) - Hypophosphatemia - - - 2 (3) 1 (2) - Investigations Weight decreased 6 (6) - - 8 (14) 2 (3) - Weight increased 2 (2) - - 2 (3) - - Alanine aminotransferase increased 2 (2) 1 (1) - 1 (2) - 1 (2) Transaminases increased 1 (1) 1 (1) - 2 (3) 1 (2) - Vascular disorders Hot flush 5 (5) - - 3 (5) - - Hypotension 2 (2) - - 2 (3) - - Flushing 2 (2) - - 1 (2) - - Hypertension 2 (2) 1 (1) - 1 (2) 1 (2) - Deep vein thrombosis - - - 2 (3) 2 (3) - Neoplasms benign, malignant and unspecified (including cysts and polyps) Hodgkin's disease recurrent 7 (7) 1 (1) - - - - Tumor flare 1 (1) - - 5 (9) - 1 (2) Anaplastic large cell lymphoma t- and null-cell types recurrent - - - 3 (5) - - Diffuse large b-cell lymphoma 2 (2) - - - - - Mycosis fungoides - - - 2 (3) 2 (3) - Cardiac disorders Tachycardia 2 (2) - - 3 (5) - - Bradycardia 1 (1) - - 2 (3) - 1 (2) Eye disorders Cataract 2 (2) - - 1 (2) - - Dry eye 2 (2) - - 1 (2) - - ADCETRIS Product Monograph Page 17 of 45
System Organ Class Preferred Term HL Total N = 102 n (%) of patients Any Grade 3 Grade 4 Grade salcl Total N = 58 n (%) of patients Any Grade 3 Grade 4 Grade Vision blurred 1 (1) - - 2 (3) 1 (2) - Ocular hyperemia - - - 2 (3) - - Injury, poisoning and procedural complications Contusion 2 (2) - - 1 (2) - - Excoriation - - - 3 (5) - - Arthropod bite 2 (2) - - - - - Ear and labyrinth disorders Deafness - - - 2 (3) - - Ear congestion - - - 2 (3) - - Renal and urinary disorders Dysuria - - - 2 (3) - - Reproductive system and breast disorders Erectile dysfunction 2 (2) - - - - - Vaginal hemorrhage 2 (2) - - - - - a includes adverse reactions and laboratory abnormalities b includes peripheral sensory neuropathy, paresthesia, neuralgia, hyperesthesia, hypoesthesia, and burning sensation c includes peripheral motor neuropathy, demyelinating polyneuropathy, muscular weakness, and polyneuropathy d includes terms upper respiratory tract infection, sinusitis, nasopharyngitis, rhinitis, viral upper respiratory tract infection, and acute sinusitis Infusion reactions Two cases of anaphylaxis were reported in phase 1 trials. There were no Grade 3 or 4 infusionrelated reactions reported in the pivotal trials, however, Grade 1 or 2 infusion-related reactions were reported for 12 HL patients (12%) and 5 salcl patients (9%). The adverse reactions that were associated with infusion-related reactions in HL patients were chills (5%), nausea (4%), dyspnoea (4%), pruritus (4%), cough (3%), erythema (2%), flushing (2%), throat tightness (2%) and in 1 patient each, dizziness, pyrexia, rash, vomiting, back pain, dyspepsia, dysphagia, hypoaesthesia facial, oropharyngeal pain, and urticaria. The adverse reactions that were associated with infusion-related reactions in salcl patients were chills, nausea, dizziness, pyrexia, rash, vomiting, diarrhea and local neck swelling each of which occurred in 1 patient. ADCETRIS Product Monograph Page 18 of 45
Cardiac Adverse Reactions In the phase 2 salcl trial, four patients experienced serious cardiac adverse events. Of these, one patient with a history of severe cardiac disease experienced a myocardial infarction while on study therapy. The potential cardiac toxicity of ADCETRIS is unknown, and patients with significant pre-existing cardiac conditions should be monitored closely. Serious adverse reactions In the HL pivotal trial, serious adverse reactions, regardless of causality, were reported in 25 (25%) of patients receiving ADCETRIS. In the salcl pivotal trial, serious adverse reactions, regardless of causality, were reported in 25 (43%) of patients receiving ADCETRIS. The serious adverse reactions experienced by 2 HL patients were abdominal pain, pulmonary embolism, demyelinating polyneuropathy, pneumonitis, pneumothorax, pyelonephritis, and pyrexia. The serious adverse reactions experienced by at least 2 salcl patients were ALCL recurrent in 3 patients, and septic shock, supraventricular arrhythmia, pain in extremity, and urinary tract infection each in 2 patients. Other important serious adverse reactions reported in patients receiving ADCETRIS included one case of Stevens-Johnson syndrome in an HL patient and one case of tumor lysis syndrome in an salcl patient. Dose modifications Adverse reactions that led to dose reductions in at least 2 HL patients included peripheral sensory neuropathy (10%). Adverse reactions that led to dose delays in at least 2 HL patients included neutropenia (16%), peripheral sensory neuropathy (13%), thrombocytopenia (4%), upper respiratory tract infection, alanine aminotransferase increased, herpes zoster, influenza, lymphadenopathy and pyelonephritis (2%). Adverse reactions that led to dose reductions in at least 2 salcl patients included peripheral sensory neuropathy (10%). Adverse reactions that led to dose delays in at least 2 salcl patients included peripheral sensory neuropathy (14%), neutropenia (12%), and thrombocytopenia (5%). Discontinuations Adverse reactions that led to treatment discontinuation in at least 2 patients with HL were peripheral sensory neuropathy (6%), peripheral motor neuropathy (3%) and Hodgkin s disease recurrent (2%). The adverse reaction that led to treatment discontinuation in patients with salcl was peripheral sensory neuropathy (12%). ADCETRIS Product Monograph Page 19 of 45
Deaths In the HL pivotal trial, there were no deaths within 30 days of the last study treatment. In the salcl pivotal trial, 6 deaths occurred within 30 days of the last study treatment and were due to ALCL recurrent (3 patients), acute myocardial infarction and acute renal failure not related to disease (both in 1 patient), respiratory failure secondary to progressive salcl (1 patient) and sudden death (1 patient). Immunogenicity Patients with HL and salcl in the pivotal trials (see Clinical Trials section) were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent immunoassay. Seven (7) % of patients in these trials developed persistently positive antibodies (positive test at more than 2 timepoints) and 27% of patients developed transiently positive antibodies (positive test at one or two timepoints). One additional patient who tested positive at baseline had persistently positive antibodies. Two patients with persistently positive antibodies experienced adverse events consistent with infusion reactions that led to discontinuation of treatment. Of 59 patients with ATA-positive samples, 31% were negative for the presence of neutralizing antibodies, 63% had at least one sample that was positive for the presence of neutralizing antibodies, and the remainder were of unknown status. A higher incidence of infusion-related reactions was associated with patients who had positive antibodies than those who did not. The effect of anti-brentuximab vedotin antibodies on efficacy and safety has not been established. Less Common Clinical Trial Adverse Drug Reactions (1 patient in either trial) Blood and lymphatic system disorders: anemia of chronic disease, coagulopathy, idiopathic thrombocytopenic purpura, lymph node pain, macrocytosis Cardiac disorders: acute myocardial infarction, arrhythmia supraventricular, atrial fibrillation, atrioventricular block complete, cyanosis Ear and labyrinth disorders: ear discomfort, ear pain, otorrhoea, tinnitus, vertigo, vestibular disorder Endocrine disorders: Addison s disease, hypogonadism, hypothyroidism ADCETRIS Product Monograph Page 20 of 45