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warnings and cautions
5 WARNINGS AND PRECAUTIONS Accidental exposure to TUDRIQEV: Healthcare providers, caregivers, close contacts, pregnant women, newborns, and patients should avoid direct contact with injected tumors, dressings, or bodily fluids of patients. Should accidental exposure occur, clean the affected area. ( 5.1 ) Herpetic infection or reactivation: Assess and treat suspected herpetic lesions as clinically warranted. ( 5.2 ) Injection procedure complications, including but not limited to hemorrhage, infection, and visceral injury. Monitor patients for signs and symptoms of visceral injury during and after TUDRIQEV administration and manage according to clinical practice. ( 5.3 ) Immune-mediated events: TUDRIQEV in combination with nivolumab may result in immune-mediated events. In clinical studies, immune-mediated events, including colitis, hepatitis, myocarditis, neuropathy, capillary leak syndrome, dermatitis, and vitiligo have been reported in patients treated with TUDRIQEV and nivolumab. ( 5.4 ) 5.1 Accidental Exposure Accidental exposure of TUDRIQEV to close contacts may lead to transmission of herpetic infection. Healthcare providers, caregivers, close contacts, pregnant women, newborns, and patients should avoid direct contact with injected tumors, dressings, or bodily fluids of patients [see Use in Specific Populations (8.1) ]. Healthcare providers and caregivers must wear protective gloves when applying or changing dressings and dispose of used dressings, gloves, and cleaning materials as biohazardous waste [see Dosage and Administration (2.2) ] . If an accidental exposure to TUDRIQEV occurs (e.g. touching or scratching the unprotected injection site or dressings), exposed individuals should clean the affected area with soap and water. If signs and symptoms of herpetic infection develop, exposed individuals should contact their healthcare provider for assessment and treatment as clinically warranted. 5.2 Herpetic Infection or Reactivation There is a potential risk for herpetic infection or reactivation after TUDRIQEV administration. Patients with suspected herpetic infections should contact their healthcare provider for assessment and antiviral treatment of the suspected herpetic infection as clinically warranted. 5.3 Injection Procedure Complications Complications related to injection procedure have occurred, including but not limited to hemorrhage, infection, and visceral injury (for example: pneumothorax). [see Adverse Reaction (6.1) ]. Monitor patients for signs and symptoms of visceral injury during and after TUDRIQEV administration and manage according to clinical practice. 5.4 Immune-Mediated Events TUDRIQEV in combination with nivolumab may result in immune-mediated events. In clinical studies, immune-mediated events, including colitis, hepatitis, myocarditis, neuropathy, capillary leak syndrome, dermatitis, and vitiligo have been reported in patients treated with TUDRIQEV and nivolumab [see Adverse Reaction (6.1) ].
6 ADVERSE REACTIONS Most common non-laboratory adverse reactions (incidence > 10%) are fatigue, pyrexia, infections, chills, musculoskeletal pain, nausea, diarrhea, injection site reaction, headache, cough, influenza like illness, rash, vomiting, pruritus, arthralgia, constipation, decreased appetite, dizziness, dyspnea, hemorrhage, edema, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Replimune, Inc. at 1-877-375-0095 or medinfo@replimune.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflect exposure of TUDRIQEV administered with nivolumab in 140 patients evaluated in the IGNYTE Study [ see Clinical Studies (14) ]. Patients received a median of 8 doses (range 1 to 32) of TUDRIQEV, and 7 (range 0 to 29) doses of nivolumab during the study. The median duration of the first course of TUDRIQEV and nivolumab exposure was 3.3 months (range 0.5 to 5.1 months) and 3.2 months (range 0 to 24.4 months), respectively. Serious adverse reactions occurring in >1% patients include pleural effusion (n=3), acute kidney injury (n=2), arthralgia (n=2), atrial fibrillation (n=2), atrial flutter (n=2), cancer pain (n=2), hypophysitis (n=2), immune-mediated enterocolitis (n=2), pyrexia (n=2), sepsis (n=2), urinary tract infection (n=2), and myocardial infarction (n=2). Serious adverse reactions leading to death include myocardial infarction (n=1) and multiple organ dysfunction (n=1). Adverse reactions leading to discontinuation of treatment occurred in 22 (16%) patients. Table 1 summarizes the most common adverse reactions that occurred in ≥10% patients in the IGNYTE Study. Table 1: Adverse Reactions Occurring in ≥10% of Patients in IGNYTE Study (N=140) Adverse Reactions Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. None of the common adverse reactions were Grade 4 or 5 All Grades n (%) Grade ≥ 3 n (%) Gastrointestinal - - Nausea 40 (29) 0 (0) Diarrhea a composite that includes multiple related terms 41 (29) 3 (2) Vomiting 24 (17) 0 (0) Constipation 22 (16) 0 (0) Decreased appetite 18 (13) 2 (1) Abdominal pain 14 (10) 3 (2) General disorders and administration site conditions - - Fatigue 82 (59) 4 (3) Pyrexia 54 (39) 0 (0) Chills 45 (32) 0 (0) Injection site reaction 37 (26) 0 (0) Influenza like illness 25 (18) 0 (0) Edema 14 (10) 4 (3) Infections and Infestations - - Infections 47 (34) 8 (6) Musculoskeletal and connective tissue disorders - - Musculoskeletal pain 45 (32) 4 (3) Arthralgia 23 (16) 2 (1) Nervous system disorders - - Headache 26 (19) 0 (0) Dizziness 21 (15) 1 (1) Respiratory, thoracic and mediastinal disorders - - Cough 25 (18) 0 (0.0) Dyspnea 16 (11) 1 (1) Skin and subcutaneous tissue disorders - - Rash 25 (18) 2 (1) Pruritus 24 (17) 0 (0.0) Vascular disorders Hemorrhage 15 (11) 2 (1) Other clinically significant adverse reactions occurring less than 10% include visceral injury including pneumothorax (n= 3), oral herpes (n=2), herpes simplex (n=1), and herpes simplex reactivation (n=1). Table 2 presents the most common laboratory abnormalities that worsened from baseline in ≥10% of patients in the IGNYTE Study. Table 2: Laboratory Values Worsening from Baseline in ≥10% in IGNYTE (N=140) Laboratory Abnormalities Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All Grades (%) Grades 3-4 (%) Anemia 57 (41) 7 (5) Lymphocyte count decreased 40 (29) 7 (5) Lipase increased 36 (26) 13 (9) Hyponatremia 34 (24) 3 (2) Hypophosphatemia 33 (24) 3 (2) Alkaline phosphatase (ALP) increased 30 (21) 1 (1) Hypoalbuminemia 28 (20) 1 (1) Aspartate aminotransferase (AST) increased 26 (19) 2 (1) Alanine aminotransferase (ALT) increased 23 (16) 3 (2) Hypokalemia 23 (16) 1(1) Hyperkalemia 22 (16) 0 Creatinine increased 21 (15) 0 Hypoglycemia 17 (12) 1 (1) Serum amylase increased 16 (11) 3 (2)