Adverse reactions

innovaTV 204 Clinical Trial: Adverse reactions reported in ≥10% of patients treated with Tivdak

The majority of these adverse reactions were Grade 1-2

  • Tivdak has a BOXED WARNING for Ocular Toxicity, WARNINGS & PRECAUTIONS, and ADVERSE REACTIONS, which may require discontinuation of Tivdak

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Adverse ReactionTivdak (2 mg/kg)
N=101
All Grades
(%)
Grade 3-4
(%)
General
Fatiguea507
Pyrexia161
Pruritus131
Gastrointestinal Disorders
Nauseab410
Diarrheac252
Constipation232
Abdominal paind231
Vomiting172
Nervous System Disorders
Peripheral neuropathye397
Skin and Subcutaneous Tissue Disorders
Alopecia390
Rashf250
Vascular Disorders
Epistaxis390
Hemorrhageg326
Eye Disorders
Conjunctival adverse reactionsh370
Dry eyei290
Corneal adverse reactionsj213
Periorbital adverse reactionsk160
Musculoskeletal and Connective Tissue Disorders
Myalgial210
Arthralgia160
Pain in extremitym131
Metabolism and Nutrition Disorders
Decreased appetite161
Infections
Urinary tract infectionn142
Investigations
Weight decreased120

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Clinically Relevant Adverse Reactions

  • 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%)
  • The permanent discontinuation rate due to adverse reactions was low (13%). The most common (≥3%) adverse reactions leading to permanent treatment discontinuation were peripheral neuropathy (5%) and corneal adverse reactions (4%)
  • Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) 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 (9%) and corneal adverse reactions (8%)
  • Clinically relevant adverse reactions in <10% of patients who received Tivdak in innovaTV 204 included venous thrombosis (3%), pulmonary embolism (3%), and pneumonitis (2%)

aFatigue includes fatigue and asthenia.

bNausea includes nausea and retching.

cDiarrhea includes diarrhea, gastroenteritis, and colitis.

dAbdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal distention, and abdominal discomfort.

ePeripheral 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.

fRash includes rash, rash maculo-papular, rash macular, dermatitis acneiform, dermatitis allergic, and erythema.

gHemorrhage 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.

hConjunctival adverse reactions includes conjunctivitis, conjunctival abrasion, conjunctival erosion, conjunctival hyperemia, conjunctival scar, noninfective conjunctivitis, ocular hyperemia, and conjunctival hemorrhage.

iDry eye includes dry eye and lacrimation increased.

jCorneal adverse reactions includes keratitis, punctate keratitis, ulcerative keratitis, corneal erosion, corneal scar, keratopathy, and corneal bleeding.

kPeriorbital adverse reactions includes blepharitis, meibomianitis, eye pruritus, entropion, trichiasis, chalazion, and meibomian gland dysfunction.

lMyalgia includes myalgia, musculoskeletal discomfort, and musculoskeletal pain.

mPain in extremity includes pain in extremity and limb discomfort.

nUrinary tract infection includes urinary tract infection, urinary tract infection bacterial, and cystitis.

Ocular adverse reactions

Most ocular adverse reactions were Grade 1-2

Tivdak has a BOXED WARNING for ocular toxicity and caused changes in the corneal epithelium and conjunctiva, resulting in changes in vision, including severe vision loss and corneal ulceration.

A summary of ocular adverse reactions associated with tivdak

Tivdak has a BOXED WARNING for ocular toxicity and caused changes in the corneal epithelium and conjunctiva, resulting in changes in vision, including severe vision loss and corneal ulceration.

  • Ocular adverse reactions occurred in 60% of cervical cancer patients treated with Tivdak across clinical trials. The most common ocular adverse reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reaction (21%), and blepharitis (8%)a
  • Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patientsa
  • The median time to onset of the first ocular adverse reaction was 1.2 months (range: 0-6.5)a
  • Ocular adverse reactions led to discontinuation of Tivdak in 6% of patients with cervical cancera
  • 1 patient experienced ulcerative keratitis with perforation requiring corneal transplantationa
  • Cases of symblepharon were reported in patients with other tumor types treated with Tivdak at the recommended dosea
  • 4% of patients experienced visual acuity changes to 20/50 or worse, including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200b
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Tivdak Dosing, Administration, and Eye Care Guide

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aThese data reflect exposure to Tivdak in 158 patients with recurrent or metastatic cervical cancer who received at least one dose of Tivdak at 2 mg/kg intravenously every 3 weeks in 4 clinical trials.

bThese data reflect exposure to Tivdak in 101 patients with recurrent or metastatic cervical cancer who received Tivdak 2 mg/kg intravenously every 3 weeks in the innovaTV 204 clinical trial.

Resolution of ocular adverse reactionsa

At last follow-up, 85% of patients who experienced ocular adverse reactions had either

COMPLETE
RESOLUTION

55%

OR

PARTIAL
IMPROVEMENT

30%

Partial improvement was defined as a decrease in severity by 1 or more grades from the worst grade.

aThese data reflect exposure to Tivdak in 158 patients with recurrent or metastatic cervical cancer who received at least one dose of Tivdak at 2 mg/kg intravenously every 3 weeks in 4 clinical trials.

Important Safety Information
BOXED WARNING: OCULAR TOXICITY

TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

Warnings and Precautions

Ocular Adverse Reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose.

In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.

Peripheral Neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain-Barre syndrome. Monitor patients for signs and symptoms of neuropathy. For new or worsening PN, withhold, dose reduce, or permanently discontinue TIVDAK based on the severity of PN.

Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.

Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.

Pneumonitis: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.

Embryo-Fetal Toxicity: TIVDAK can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Adverse Reactions

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

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

Drug interactions

Strong CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.

Use in Specific Populations

Moderate or Severe Hepatic Impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.

Please see full prescribing information, including BOXED WARNING for TIVDAK.

Indication

TIVDAK is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Reference:
  1. TIVDAK [Prescribing Information]. Bothell, WA: Seagen Inc. January 2022.
Important Safety Information

BOXED WARNING: OCULAR TOXICITY

TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct anophthalmic examat baseline, prior to each dose, andas clinically indicated.

Important Safety Information
BOXED WARNING: OCULAR TOXICITY

TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

Warnings and Precautions

Ocular Adverse Reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose.

In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.

Peripheral Neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain-Barre syndrome. Monitor patients for signs and symptoms of neuropathy. For new or worsening PN, withhold, dose reduce, or permanently discontinue TIVDAK based on the severity of PN.

Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.

Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.

Pneumonitis: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.

Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.

Embryo-Fetal Toxicity: TIVDAK can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Adverse Reactions

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

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

Drug interactions

Strong CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.

Use in Specific Populations

Moderate or Severe Hepatic Impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.

Please see full prescribing information, including BOXED WARNING for TIVDAK.

Indication

TIVDAK is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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