6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

Ocular Adverse Reactions [see Boxed Warning, Warnings and Precautions (5.1)]
Peripheral Neuropathy [see Warnings and Precautions (5.2)]
Hemorrhage [see Warnings and Precautions (5.3)]
Pneumonitis [see Warnings and Precautions (5.4)]
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

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 data in the WARNINGS AND PRECAUTIONS section reflect exposure to TIVDAK in 425 patients with recurrent or metastatic cervical cancer who received at least one dose of TIVDAK at 2 mg/kg intravenously every 3 weeks in innovaTV 301, innovaTV 204, innovaTV 201 (NCT02001623), innovaTV 202 (NCT02552121), innovaTV 203 (NCT03245736), and innovaTV 206 (NCT03913741). The median duration of treatment with TIVDAK was 3.7 months (range: 0.4-40.2). In this pooled safety population, the most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (45%), peripheral neuropathy (39%), conjunctival adverse reactions (38%), nausea (37%), fatigue (36%), aspartate aminotransferase increased (33%), epistaxis (33%), alopecia (31%), alanine aminotransferase increased (30%), and hemorrhage (28%).

The data described in this section reflect exposure to TIVDAK from innovaTV 301 and innovaTV 204.

innovaTV 301

The safety of TIVDAK was evaluated in an open-label, randomized study in patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy [see Clinical Studies (14.1)]. A total of 250 patients received TIVDAK 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment with TIVDAK was 3.7 months (range: 0.4-19).

Serious adverse reactions occurred in 33% of patients receiving TIVDAK. The most common (≥2%) serious adverse reactions were urinary tract infection (4.8%), small intestinal obstruction (2.4%), sepsis (2%), abdominal pain (2%), and hemorrhage (2%). Fatal adverse reactions occurred in 1.6% of patients who received TIVDAK, including acute kidney injury (0.4%), pneumonia (0.4%), sepsis (0.4%) and Stevens-Johnson syndrome (0.4%).

Adverse reactions leading to permanent discontinuation occurred in 15% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to permanent discontinuation were peripheral neuropathy (6%) and ocular adverse reactions (6%).

Adverse reactions leading to dose interruption occurred in 39% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to dose interruption were ocular adverse reactions (16%) and peripheral neuropathy (6%).

Adverse reactions leading to dose reduction occurred in 30% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to dose reduction were peripheral neuropathy (10%) and ocular adverse reactions (10%). The ocular adverse reactions included conjunctival disorders (4.8%), keratopathy (4%), and dry eye (0.8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, in patients receiving TIVDAK were hemoglobin decreased, peripheral neuropathy, conjunctival adverse reactions, aspartate aminotransferase increased, nausea, alanine aminotransferase increased, fatigue, sodium decreased, epistaxis, and constipation.

Table 4 summarizes the all grade and Grade 3-4 adverse reactions from innovaTV 301.

Table 4: Adverse Reactions (≥10%) in Patients Who Received TIVDAK in innovaTV 301
* Peripheral neuropathy includes peripheral sensory neuropathy, paresthesia, muscular weakness, peripheral sensorimotor neuropathy, peripheral motor neuropathy, neurotoxicity, gait disturbance, neuralgia, hypoaesthesia, neuropathy peripheral, and skin burning sensation † Conjunctival adverse reactions includes conjunctivitis, conjunctivitis bacterial, conjunctivitis viral, episcleritis, ocular hyperemia, conjunctival hemorrhage, conjunctival hyperemia, conjunctival ulcer, conjunctivitis allergic, conjunctival disorder, symblepharon, conjunctival erosion, conjunctival oedema, conjunctivochalasis, and conjunctival scar ‡ Corneal adverse reactions includes keratitis, punctate keratitis, corneal erosion, ulcerative keratitis, corneal degeneration, corneal opacity, and keratopathy § Dry eye includes dry eye, eye discharge, eye pruritus, eye pain, eye irritation, and lacrimation increased ¶ Nausea includes nausea and retching # Diarrhea includes diarrhea and gastroenteritis Þ Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower ß Fatigue includes fatigue and asthenia à Hemorrhage includes hematuria, vaginal hemorrhage, rectal hemorrhage, hemoptysis, anal hemorrhage, hemorrhage, gastrointestinal hemorrhage, hemorrhagic shock, lower gastrointestinal hemorrhage, gingival bleeding, tumor hemorrhage, intra-abdominal hemorrhage, gastric hemorrhage, genital hemorrhage, uterine hemorrhage, urinary tract hemorrhage, hemorrhoidal hemorrhage è Rash includes rash maculo-papular, eczema, rash macular, rash pustular, dermatitis acneiform, erythema, rash, urticaria, dermatitis, and rash erythematous ð Urinary tract infection includes urinary tract infection, pyelonephritis acute, cystitis, and urinary tract infection bacterial
Adverse Reaction	TIVDAK N=250		Chemotherapy N=239
	All Grades	Grade 3-4	All Grades	Grade 3-4
	%	%	%	%
Nervous system disorders
Peripheral neuropathy*	38	6	4.2	0.4
Eye disorders
Conjunctival adverse reactions†	37	0	1.7	0
Corneal adverse reactions‡	21	3.2	0	0
Dry eye§	21	0	1.7	0
Gastrointestinal disorders
Nausea¶	33	0.4	40	2.1
Constipation	25	1.2	16	0
Diarrhea#	22	1.6	15	1.3
Abdominal PainÞ	18	4	15	2.5
Vomiting	18	1.6	18	1.3
General
Fatigueß	28	6	32	6
Pyrexia	17	0.4	21	0.8
Pruritus	10	0.4	2.9	0
Vascular disorders
Epistaxis	26	0	2.5	0
Hemorrhageà	21	2	11	2.5
Metabolism and nutrition disorders
Decreased appetite	24	0.8	18	0.4
Decreased weight	10	0.4	5	0
Skin and subcutaneous tissue disorders
Alopecia	24	0	2.9	0
Rashè	17	1.6	16	1.3
Infections
Urinary tract infectionð	16	5	18	8

Clinically relevant adverse reactions in <10% of patients who received TIVDAK in innovaTV 301 include periorbital adverse reactions (9%) and intestinal obstruction (4.4%, including small bowel, large bowel, and malignant gastrointestinal obstruction).

Table 5 summarizes the laboratory abnormalities in innovaTV 301.

Table 5: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline In Patients Who Received TIVDAK in innovaTV 301
* The denominator used to calculate the rate varied from 206 to 244 based on the number of patients with a baseline value and at least one post-treatment value.
	TIVDAK*		Chemotherapy*
	All Grades (%)	Grades 3 or 4 (%)	All Grades (%)	Grades 3-4 (%)
Hematology
Hemoglobin decreased	41	7	70	23
Neutrophils decreased	16	3.3	39	17
Chemistry
Aspartate aminotransferase increased	34	2.5	32	0.4
Alanine aminotransferase increased	30	3.3	35	2.6
Sodium decreased	27	0.4	27	0.4
Creatinine increased	23	2	26	2.2
Coagulation
Activated partial thromboplastin time prolonged	16	1.9	17	0.5

innovaTV 204

The safety of TIVDAK was evaluated in a single arm study in patients (n=101) with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy [see Clinical Studies (14.1)]. Patients received TIVDAK 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7-16).

Serious adverse reactions occurred in 43% of patients. The most common (≥3%) serious adverse reactions were ileus (6%), hemorrhage (5%), pneumonia (4%), peripheral neuropathy, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock (1%), pneumonitis (1%), sudden death (1%), and multisystem organ failure (1%).

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) adverse reactions leading to permanent discontinuation were peripheral neuropathy (5%) and corneal adverse reactions (4%).

Adverse reactions leading to dose interruption occurred in 47% of patients; the most (≥3%) common adverse reactions leading to dose interruption were peripheral neuropathy (8%), conjunctival adverse reactions (4%), and hemorrhage (4%).

Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) adverse reactions leading to dose reduction were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash.

Table 6 summarizes the all grade and Grade 3-4 adverse reactions from innovaTV 204.

Table 6: Adverse Reactions (≥10%) in Patients Who Received TIVDAK in innovaTV 204
* Fatigue includes fatigue and asthenia † Nausea includes nausea and retching ‡ Diarrhea includes diarrhea, gastroenteritis, and colitis § Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal distention and abdominal discomfort ¶ Peripheral neuropathy includes neuropathy peripheral, peripheral sensorimotor neuropathy, polyneuropathy, peripheral sensory neuropathy, paresthesia, hypoesthesia, burning sensation, neuralgia, sensory loss, peripheral motor neuropathy, muscular weakness, gait disturbance, and hyperesthesia # Rash includes rash, rash maculo-papular, rash macular, dermatitis acneiform, dermatitis allergic, and erythema Þ Hemorrhage includes vaginal hemorrhage, hematuria, rectal hemorrhage, cystitis hemorrhagic, lower gastrointestinal hemorrhage, urinary bladder hemorrhage, hematochezia, anal hemorrhage, gingival bleeding, post procedural hemorrhage, radiation associated with hemorrhage, metrorrhagia, large intestinal hemorrhage, paranasal sinus hemorrhage, and hemoptysis ß Conjunctival adverse reactions includes conjunctivitis, conjunctival abrasion, conjunctival erosion, conjunctival hyperemia, conjunctival scar, noninfective conjunctivitis, ocular hyperemia, and conjunctival hemorrhage à Dry eye includes dry eye and lacrimation increased è Corneal adverse reactions includes keratitis, punctate keratitis, ulcerative keratitis, corneal erosion, corneal scar, keratopathy, and corneal bleeding ð Periorbital adverse reactions includes blepharitis, meibomianitis, eye pruritus, entropion, trichiasis, chalazion, and meibomian gland dysfunction ø Myalgia includes myalgia, musculoskeletal discomfort, and musculoskeletal pain ý Pain in extremity includes pain in extremity and limb discomfort £ Urinary tract infection includes urinary tract infection, urinary tract infection bacterial, and cystitis
Adverse Reaction	TIVDAK N=101
	All Grades	Grade 3-4
	%	%
General
Fatigue*	50	7
Pyrexia	16	1
Pruritus	13	1
Gastrointestinal disorders
Nausea†	41	0
Diarrhea‡	25	2
Constipation	23	2
Abdominal pain§	23	1
Vomiting	17	2
Nervous system disorders
Peripheral neuropathy¶	39	7
Skin and subcutaneous tissue disorders
Alopecia	39	0
Rash#	25	0
Vascular disorders
Epistaxis	39	0
HemorrhageÞ	32	6
Eye disorders
Conjunctival adverse reactionsß	37	0
Dry eyeà	29	0
Corneal adverse reactionsè	21	3
Periorbital adverse reactionsð	16	0
Musculoskeletal and connective tissue disorders
Myalgiaø	21	0
Arthralgia	16	0
Pain in extremityý	13	1
Metabolism and nutrition disorders
Decreased appetite	16	1
Infections
Urinary tract infection£	14	2
Investigations
Weight decreased	12	0

Clinically relevant adverse reactions in <10% of patients who received TIVDAK in innovaTV 204 included venous thrombosis (3%), pulmonary embolism (3%), and pneumonitis (2%).

Table 7 summarizes the laboratory abnormalities in innovaTV 204.

Table 7: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline In Patients Who Received TIVDAK in innovaTV 204
* 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	TIVDAK*
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)
Hematology
Hemoglobin decreased	52	7
Neutrophils decreased	21	3
Chemistry
Creatinine increased	29	4.1
Alanine aminotransferase increased	24	0
Aspartate aminotransferase increased	18	0
Sodium decreased	20	0
Alkaline phosphatase increased	17	0
Creatinine kinase increased	16	2.1
Magnesium decreased	17	2.1
Coagulation
Prothrombin international normalized ratio increased	26	0
Activated partial thromboplastin time prolonged	26	2