6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling. 3 )] ZYNYZ in Combination with Carboplatin and Paclitaxel In patients with SCAC, the most common (≥ 20%) adverse reactions are fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain.
1 ) ZYNYZ as a Single Agent In patients with SCAC, the most common (≥ 10%) adverse reactions are fatigue, musculoskeletal pain, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, nausea, decreased appetite, constipation, abdominal pain, dyspnea, pyrexia, vomiting, cough, pruritus, hypothyroidism, headache, and decreased weight.
1 ) In patients with MCC, the most common (≥ 10%) adverse reactions are musculoskeletal pain, fatigue, pruritus, diarrhea, rash, pyrexia, nausea, and constipation. gov/medwatch . 1 Clinical Trial 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 population described in Warnings and Precautions reflects exposure to ZYNYZ 500 mg as an intravenous infusion every 4 weeks in combination with carboplatin and paclitaxel in 154 patients with SCAC enrolled in the POD1UM-303 trial, and as a single agent in 94 patients with SCAC in the POD1UM-202 trial, 107 patients with MCC in the POD1UM-201 trial, and 251 patients with other solid tumors.
All patients received ZYNYZ until disease progression or unacceptable toxicity; those in the POD1UM-202 and POD1UM-201 trials received ZYNYZ for up to 24 months and those in the POD1UM-303 trial received ZYNYZ for up to 12 months. 4 months (range: 1 day to 27 months).
1 )] . Patients received ZYNYZ 500 mg or placebo intravenously every 4 weeks in combination with carboplatin and paclitaxel for 6 cycles followed by ZYNYZ 500 mg or placebo every 4 weeks until disease progression or unacceptable toxicity.
6 months). Serious adverse reactions occurred in 47% of patients receiving ZYNYZ in combination with carboplatin and paclitaxel. 6%). In patients receiving ZYNYZ in combination with carboplatin and paclitaxel, ZYNYZ was permanently discontinued due to an adverse reaction in 11% of patients.
Adverse reactions that resulted in permanent discontinuation of ZYNYZ included immune-mediated enterocolitis (2 patients), warm autoimmune hemolytic anemia, hepatitis, adrenal insufficiency, blood bilirubin increased, AST increased, blood alkaline phosphatase increased, arthritis, encephalopathy, peripheral sensorimotor neuropathy, hypothyroidism, immune‑mediated cholangitis, pruritus, malaise, and rash (1 patient each).
Dosage interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 55% of patients who received ZYNYZ in combination with carboplatin and paclitaxel. Adverse reactions that resulted in dosage interruptions in ≥ 2% of patients were neutropenia, anemia, thrombocytopenia, leukopenia, fatigue, COVID-19, and urinary tract infection.
The most common (≥ 20%) adverse reactions were fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain. Table 3 and Table 4 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-303.
Table 3:
Adverse Reactions in ≥ 10% of Patients with Inoperable Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in Combination with Carboplatin and Paclitaxel with a Difference Between Arms of ≥ 5% for All Grades or ≥ 2% for Grades 3 or 4 vs Placebo in Combination with Carboplatin and Paclitaxel in POD1UM-303 ZYNYZ in Combination with Carboplatin and Paclitaxel (N = 154) Placebo in Combination with Carboplatin and Paclitaxel (N = 152) Adverse Reaction All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal disorders Diarrhea Includes diarrhea, colitis, and frequent bowel movements.
49 5 41 7 Stomatitis Includes stomatitis, aphthous ulcer, cheilitis, mouth ulceration, and mucosal inflammation. 18 0 11 0 Nervous system disorders Peripheral neuropathy Includes peripheral neuropathy, paresthesia, peripheral sensory neuropathy, neuralgia, hypoesthesia, peripheral sensorimotor neuropathy, dysesthesia, peripheral motor neuropathy, and hyperesthesia.
6 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.
6 34 0 Vascular disorders Hemorrhage Includes hemorrhage, anal hemorrhage, anal ulcer hemorrhage, conjunctival hemorrhage, epistaxis, gastrointestinal hemorrhage, genital hemorrhage, hematuria, hemoptysis, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, lymph node hemorrhage, rectal hemorrhage, stoma site hemorrhage, tumor hemorrhage, urinary bladder hemorrhage, uterine hemorrhage, vaginal hemorrhage, and wound hemorrhage.
2 21 0 Skin and subcutaneous tissue disorders Rash Includes rash, eczema, dermatitis acneiform, dermatitis, rash erythematous, rash maculo-papular, rash papular, rash pustular, and rash pruritic. 0.
Table 4:
Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥ 1% of Patients with Inoperable Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in Combination with Carboplatin and Paclitaxel in POD1UM-303 ZYNYZ in Combination with Carboplatin and Paclitaxel The denominator used to calculate the rate varied from 142 to 153 based on the number of patients with a baseline value and at least one post-treatment value.
0. 1 )] . Patients received ZYNYZ 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. 1 months). Serious adverse reactions occurred in 40% of patients receiving ZYNYZ. The most frequent serious adverse reactions (≥ 2% of patients) were non-urinary tract infection, perineal pain, abdominal pain, anemia, hemorrhage, diarrhea, pyrexia, urinary tract infection, musculoskeletal pain, and dyspnea.
3% of patients. These adverse reactions included diarrhea, non-urinary tract infection, perineal pain, and rash. Dosage interruptions due to an adverse reaction occurred in 21% of patients who received ZYNYZ. Adverse reactions that resulted in dose delay in ≥ 2% of patients who received ZYNYZ were non-urinary tract infection, rash, diarrhea, abdominal pain, hemorrhage, musculoskeletal pain, pyrexia, and urinary tract infection.
The most common (≥ 10%) adverse reactions that occurred in patients receiving ZYNYZ were fatigue, musculoskeletal pain, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, nausea, decreased appetite, constipation, abdominal pain, dyspnea, pyrexia, vomiting, cough, pruritus, hypothyroidism, headache, and decreased weight.
Table 5 and Table 6 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-202.
Table 5:
Adverse Reactions in ≥ 10% of Patients with Platinum-Refractory Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in POD1UM-202 Adverse Reaction ZYNYZ (N = 94) All Grades (%) Grades 3-4 (%) General disorders and administration site conditions Fatigue Includes fatigue and asthenia.
1 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, bone pain, musculoskeletal chest pain, myalgia, non-cardiac chest pain, osteoarthritis, pain in extremity, and spinal pain. 1 Gastrointestinal disorders Diarrhea Includes diarrhea, gastroenteritis, and immune-mediated enterocolitis.
1 Nausea 16 0 Constipation 15 0 Abdominal pain Includes abdominal pain, abdominal discomfort, and abdominal pain upper. 1 Infections and infestations Non-urinary tract infections Includes anal abscess, cellulitis, cholangitis, cholecystitis, cholecystitis acute, device related infection, herpes zoster, Lyme disease, pelvic infection, peritonitis, Pneumocystis jirovecii pneumonia, pneumonia, postoperative wound infection, pseudomonas infection, sepsis, skin infection, stoma site infection, and wound infection bacterial.
21 12 Urinary tract infection Includes urinary tract infection, cystitis, escherichia urinary tract infection, and pyelonephritis. 1 Reproductive system and breast disorders Perineal pain Includes anorectal discomfort, pelvic pain, proctalgia, and vulvovaginal discomfort.
19 7 Vascular disorders Hemorrhage Includes epistaxis, hematochezia, hematuria, proctitis hemorrhagic, rectal hemorrhage, stoma site hemorrhage, and vaginal hemorrhage. 2 Skin and subcutaneous tissue disorders Rash Includes rash, dermatitis, dermatitis acneiform, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash erythematous, and rash maculo-papular.
1 Pruritus 12 0 Metabolism and nutrition disorders Decreased appetite Includes decreased appetite and hypophagia. 2 Cough Includes cough and productive cough. 0.
Table 6:
Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥ 1% of Patients with Platinum-Refractory Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in POD1UM-202 Laboratory abnormality ZYNYZ The denominator used to calculate the rate varied from 59 to 87 based on the number of patients with a baseline value and at least one post-treatment value.
0. 2)] . Patients received ZYNYZ 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. 3 months (range: 1 day to 25 months). Serious adverse reactions occurred in 26% of patients receiving ZYNYZ.
The most frequent serious adverse reactions (≥ 2% of patients) were fatigue, arrhythmia, and pneumonitis. Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 21% of patients. These included asthenia, colitis, demyelinating polyneuropathy, diarrhea, drug hypersensitivity, eosinophilic fasciitis, hepatitis, hypophysitis, increased transaminases, infusion-related reaction, pancreatitis, polyarthritis, radiculopathy, toxic epidermal necrolysis, and tubulointerstitial nephritis (1 patient each).
Dosage interruptions due to an adverse reaction occurred in 39% of patients who received ZYNYZ. Adverse reactions or laboratory abnormalities that required dosage interruption in > 2% of patients who received ZYNYZ were increased transaminases, increased lipase, increased amylase, and pyrexia.
The most common (≥ 10%) adverse reactions that occurred in patients receiving ZYNYZ were musculoskeletal pain, fatigue, pruritus, diarrhea, rash, pyrexia, nausea, and constipation. Table 7 and Table 8 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-201.
0. Adverse Reaction ZYNYZ (N = 107) All Grades (%) Grades 3-4 (%) Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, bone pain, pain in extremity, neck pain, myalgia, and musculoskeletal chest pain.
37 3 General disorders and administration site conditions Fatigue Includes fatigue and asthenia. 33 1 Pyrexia 12 0 Skin and subcutaneous tissue disorders Pruritus 22 0 Rash Includes rash, dermatitis, dermatitis bullous, rash erythematous, rash maculo-papular, rash papular, rash pruritic, psoriasis, and toxic epidermal necrolysis.
0. ZYNYZ The denominator used to calculate the rate varied from 96 to 101 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality All Grades (%) Grades 3-4 (%) Hematology Decreased lymphocytes 31 11 Decreased neutrophils 14 3 Chemistry Increased lipase 39 5 Increased aspartate aminotransferase 28 3 Decreased sodium 27 3 Increased alanine aminotransferase 26 4 Increased alkaline phosphatase 22 2 Decreased potassium 15 2