TIVDAK Solution for injection Ref.[109850] Active ingredients: Tisotumab vedotin

5.1 Ocular Adverse Reactions

TIVDAK can cause severe ocular adverse reactions, including conjunctivitis, keratopathy (keratitis, punctate keratitis, and ulcerative keratitis), and dry eye (increased lacrimation, eye pain, eye discharge, pruritus, irritation, and foreign body sensation), that may lead to changes in vision and/or corneal ulceration.

Ocular adverse reactions occurred in 55% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common ocular adverse reactions were conjunctivitis (32%), dry eye (24%), keratopathy (17%), and blepharitis (5%). Grade 3 ocular adverse reactions occurred in 3.3% of patients, including severe ulcerative keratitis in 1.2% of patients. Nine patients (2.1%) experienced ulcerative keratitis (including one with perforation requiring corneal transplantation), six (1.4%) conjunctival ulcer, four (0.9%) corneal erosion, two (0.5%) conjunctival erosion, and two (0.5%) symblepharon.

The median time to onset of the first ocular adverse reaction was 1.2 months (range, 0-17.1). Of the patients who experienced ocular events, 59% had complete resolution and 31% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Ocular adverse reactions led to permanent discontinuation of TIVDAK in 6% of patients with cervical cancer.

In innovaTV 301, 8 (3.2%) patients experienced delayed ocular adverse reactions occurring more than 30 days after discontinuation of TIVDAK. These adverse reactions included 3 patients with ulcerative keratitis, and one patient (each) with keratitis, punctate keratitis and corneal erosion, blepharitis and conjunctival hyperemia, conjunctival scar, and conjunctivitis and xerophthalmia.

Refer patients to an eye care provider to conduct an ophthalmic exam prior to initiation of TIVDAK, prior to every cycle for the first nine cycles, and as clinically indicated. The exam should include visual acuity, slit lamp exam of the anterior segment of the eye, and an assessment of normal eye movement and ocular signs or symptoms which include dry or irritated eyes, eye secretions or blurry vision.

Adhere to the required premedication and eye care before, during, and after infusion to reduce the risk of ocular adverse reactions [see Dosage and Administration (2.2)]. Monitor for ocular toxicity and promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold, reduce, or permanently discontinue TIVDAK based on the severity or persistence of the ocular adverse reaction [see Dosage and Administration (2.3)].

5.2 Peripheral Neuropathy

Peripheral neuropathy occurred in 39% of patients with cervical cancer treated with TIVDAK across clinical trials; 6% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral sensory neuropathy (23%), peripheral neuropathy (5%), paresthesia (3.8%), peripheral sensorimotor neuropathy (3.3%), muscular weakness (2.8%), and peripheral motor neuropathy (2.4%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain-Barre syndrome.

The median time to onset of peripheral neuropathy was 2.4 months (range, 0-11.3). Of the patients who experienced peripheral neuropathy, 18% had complete resolution and 21% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade) at last follow up. Peripheral neuropathy led to discontinuation of TIVDAK in 7% of patients with cervical cancer.

Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, withhold dose, then dose reduce, or permanently discontinue TIVDAK based on the severity of peripheral neuropathy [see Dosage and Administration (2.3)].

5.3 Hemorrhage

Hemorrhage occurred in 51% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reaction was epistaxis (33%). Grade 3 hemorrhage occurred in 4% of patients.

The median time to onset of hemorrhage was 0.3 months (range, 0-10.4). Of the patients who experienced hemorrhage, 71% had complete resolution and 12% had partial resolution (defined as a decrease in severity by one or more grades from the worst grade) at last follow-up.

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 [see Dosage and Administration (2.3)].

5.4 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, 4 patients (0.9%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms indicative of pneumonitis. Symptoms may include hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such 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 [see Dosage and Administration (2.3)].

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions, including events of fatal or life-threatening SJS, can occur in patients treated with TIVDAK. Severe cutaneous adverse reactions occurred in 1.6% of patients with cervical cancer treated with TIVDAK across clinical trials. Grade ≥3 severe cutaneous adverse reactions occurred in 0.5% of patients, including 1 patient who had a fatal outcome.

Monitor patients for signs or symptoms of severe cutaneous adverse reactions, which include target lesions, worsening skin reactions, blistering or peeling of the skin, painful sores in mouth, nose, throat, or genital area, fever or flu-like symptoms, and swollen lymph nodes. If signs or symptoms of severe cutaneous adverse reactions occur, withhold TIVDAK until the etiology of the reaction has been determined. Early consultation with a specialist is recommended to ensure greater diagnostic accuracy and appropriate management. Permanently discontinue TIVDAK for confirmed Grade 3 or 4 severe cutaneous adverse reactions, including SJS [see Dosage and Administration (2.3)].

5.6 Embryo-Fetal Toxicity

Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman. The small molecule component of TIVDAK, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose.

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 [see Use in Specific Populations (8.1, 8.3), and Clinical Pharmacology (12.1)].

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)]

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:

¹ 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.
² 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.
³ Corneal adverse reactions includes keratitis, punctate keratitis, corneal erosion, ulcerative keratitis, corneal degeneration, corneal opacity, and keratopathy.
⁴ Dry eye includes dry eye, eye discharge, eye pruritus, eye pain, eye irritation, and lacrimation increased.
⁵ Nausea includes nausea and retching.
⁶ Diarrhea includes diarrhea and gastroenteritis.
⁷ Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, and abdominal pain lower.
⁸ Fatigue includes fatigue and asthenia.
⁹ 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.
¹⁰ Rash includes rash maculo-papular, eczema, rash macular, rash pustular, dermatitis acneiform, erythema, rash, urticaria, dermatitis, and rash erythematous.
¹¹ Urinary tract infection includes urinary tract infection, pyelonephritis acute, cystitis, and urinary tract infection bacterial.

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:

¹ 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.

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 (14.2)]. 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:

¹ Fatigue includes fatigue and asthenia.
² Nausea includes nausea and retching.
³ Diarrhea includes diarrhea, gastroenteritis, and colitis.
⁴ Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal distention and abdominal discomfort.
⁵ 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.
⁶ Rash includes rash, rash maculo-papular, rash macular, dermatitis acneiform, dermatitis allergic, and erythema.
⁷ 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.
⁸ Conjunctival adverse reactions includes conjunctivitis, conjunctival abrasion, conjunctival erosion, conjunctival hyperemia, conjunctival scar, noninfective conjunctivitis, ocular hyperemia, and conjunctival hemorrhage.
⁹ Dry eye includes dry eye and lacrimation increased.
¹⁰ Corneal adverse reactions includes keratitis, punctate keratitis, ulcerative keratitis, corneal erosion, corneal scar, keratopathy, and corneal bleeding.
¹¹ Periorbital adverse reactions includes blepharitis, meibomianitis, eye pruritus, entropion, trichiasis, chalazion, and meibomian gland dysfunction.
¹² Myalgia includes myalgia, musculoskeletal discomfort, and musculoskeletal pain
¹³ Pain in extremity includes pain in extremity and limb discomfort.
¹⁴ Urinary tract infection includes urinary tract infection, urinary tract infection bacterial, and cystitis.

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:

¹ 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.

7.1 Effects of Other Drugs on TIVDAK

Strong CYP3A4 Inhibitors

MMAE is a CYP3A4 substrate. Concomitant use of TIVDAK with strong CYP3A4 inhibitors may increase unconjugated MMAE exposure [see Clinical Pharmacology (12.3)], which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for adverse reactions of TIVDAK when used concomitantly with strong CYP3A4 inhibitors.

Risk Summary

Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on TIVDAK use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of the small molecule component of TIVDAK, MMAE, to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at exposures below the clinical exposure at the recommended dose (see Data). Advise patients of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data

Animal Data

No embryo-fetal development studies in animals have been performed with tisotumab vedotin-tftv. In an embryo-fetal development study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of TIVDAK, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose).

Risk Summary

There are no data on the presence of tisotumab vedotin-tftv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with TIVDAK and for 3 weeks after the last dose.

TIVDAK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy testing

Verify pregnancy status in females of reproductive potential prior to initiating TIVDAK treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose.

Males

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.

Infertility

Females

Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), TIVDAK may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

Males

Based on findings from animal studies, TIVDAK may impair male fertility [see Nonclinical Toxicology (13.1)].

Safety and effectiveness of TIVDAK in pediatric patients have not been established.

Of the 425 patients with cervical cancer treated with TIVDAK across clinical trials, 14% were ≥65 years of age and 2.4% were >75 years of age. Grade ≥3 adverse reactions occurred in 60% of patients ≥65 years and in 55% of patients <65 years. Drug was discontinued due to an adverse reaction in 25% of patients ≥65 years and in 13% of patients <65 years. Clinical studies of TIVDAK did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

Avoid use of TIVDAK in patients with moderate or severe hepatic impairment [aspartate aminotransferase (AST) >3 x upper limit of normal (ULN) or total bilirubin >1.5 × ULN] [see Clinical Pharmacology (12.3)].

In patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 × ULN and any AST), closely monitor patients for adverse reactions of TIVDAK, but no dosage adjustment in the starting dose of TIVDAK is recommended.