ELAHERE Solution for injection Ref.[107263] Active ingredients: Mirvetuximab soravtansine

5.1 Ocular Disorders

ELAHERE can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis.

Ocular adverse reactions occurred in 61% of patients with ovarian cancer treated with ELAHERE. Nine percent (9%) of patients experienced Grade 3 ocular adverse reactions, including visual impairment, keratopathy/keratitis (corneal disorders), dry eye, photophobia, and eye pain; and one patient (0.2%) experienced Grade 4 keratopathy. The most common (≥5%) ocular adverse reactions were visual impairment (49%), keratopathy (36%), dry eye (26%), cataract (15%), photophobia (13%), and eye pain (12%) [see Adverse Reactions (6.1)].

The median time to onset for first ocular adverse reaction was 1.2 months (range: 0.03 to 12.9). Of the patients who experienced ocular events, 49% had complete resolution and 39% 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 ELAHERE in 0.6% of patients.

Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment with ELAHERE are recommended [see Dosage and Administration (2.3)]. Advise patients to avoid use of contact lenses during treatment with ELAHERE unless directed by a healthcare provider.

Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms.

Monitor for ocular toxicity and withhold, reduce, or permanently discontinue ELAHERE based on severity and persistence of ocular adverse reactions [see Dosage and Administration (2.4)].

5.2 Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ELAHERE.

Pneumonitis occurred in 10% of patients treated with ELAHERE, including 0.8% with Grade 3 events, and 1 patient (0.2%) with a Grade 4 event. One patient (0.2%) died due to respiratory failure in the setting of pneumonitis and lung metastases. Pneumonitis resulted in ELAHERE dose reduction in 1%, dose interruptions in 3%, and permanent discontinuation in 3% of patients.

Monitor patients for pulmonary signs and symptoms of pneumonitis, which 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 ELAHERE for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤ Grade 1 and consider dose reduction. Permanently discontinue ELAHERE in all patients with Grade 3 or 4 pneumonitis [see Dosage and Administration (2.4)]. Patients who are asymptomatic may continue dosing of ELAHERE with close monitoring.

5.3 Peripheral Neuropathy

Peripheral neuropathy occurred in 36% of patients with ovarian cancer treated with ELAHERE across clinical trials; 2% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (19%), peripheral sensory neuropathy (9%), paraesthesia (6%), neurotoxicity (3%), hypoaesthesia (2%), peripheral motor neuropathy (1%), neuralgia (0.4%), polyneuropathy (0.2%) and oral hypoesthesia (0.2%).

The median time to onset of peripheral neuropathy was 1.3 months (range 0.03 to 29.1). Of the patients who experienced peripheral neuropathy, 28% had complete resolution and 13% 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 ELAHERE in 0.4% of patients.

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 dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of peripheral neuropathy [see Dosage and Administration (2.4)].

5.4 Embryo-Fetal Toxicity

Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following adverse reactions are discussed elsewhere in the labeling:

• Ocular Disorders [see Warnings and Precautions (5.1)].
• Pneumonitis [see Warnings and Precautions (5.2)].
• Peripheral Neuropathy [see Warnings and Precautions (5.3)].

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 pooled safety population described in WARNINGS AND PRECAUTIONS reflect exposure to ELAHERE in 464 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer at 6 mg/kg AIBW administered intravenously once every 3 weeks until disease progression or unacceptable toxicity in Study 0417; Study 0403 (NCT02631876), and Study 0401 (NCT01609556). The median duration of treatment was 4.3 months (range: 0.7 to 30.4).

Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study 0417

The safety of ELAHERE was evaluated in Study 0417, a single-arm, open-label study in patients (n=106) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer [see Clinical Studies (14)]. Patients received ELAHERE 6 mg/kg AIBW once every 3 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 4.2 months (range: 0.7 to 13.3).

Serious adverse reactions occurred in 31% of patients. The most common (≥2%) serious adverse reactions were intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Fatal adverse reactions occurred in 2% of patients, including small intestinal obstruction (1%) and pneumonitis (1%).

Permanent discontinuation of ELAHERE due to adverse reactions occurred in 11% of patients. The most common (≥2%) adverse reactions leading to permanent discontinuation were intestinal obstruction (2%) and thrombocytopenia (2%). One patient (0.9%) permanently discontinued ELAHERE due to visual impairment (unilateral decrease to BCVA ≤ 20/200 that resolved to baseline after discontinuation).

Dosage delays of ELAHERE due to an adverse reaction occurred in 39% of patients treated with ELAHERE. Adverse reactions which required dosage delays in ≥3% of patients included visual impairment (15%), keratopathy (11%), neutropenia (6%), dry eye (5%), cataracts (3%), and increased gamma-glutamyltransferase (3%).

Dose reductions of ELAHERE due to an adverse reaction occurred in 20% of patients. Adverse reactions which required dose reductions in ≥3% of patients included visual impairment (9%) and keratopathy (7%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, were vision impairment, fatigue, increased aspartate aminotransferase, nausea, increased alanine aminotransferase, keratopathy, abdominal pain, decreased lymphocytes, peripheral neuropathy, diarrhea, decreased albumin, constipation, increased alkaline phosphatase, dry eye, decreased magnesium, decreased leukocytes, decreased neutrophils, and decreased hemoglobin.

Table 4 summarizes the adverse reactions (≥10%) in patients treated with ELAHERE in Study 0417.

Table 4. Adverse Reactions (≥10%) in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Received ELAHERE in Study 0417:

Fatigue includes fatigue and asthenia.
^* Visual Impairment includes vision blurred, vitreous floaters, visual acuity reduced, diplopia, presbyopia, accommodation disorder, visual impairment, and refraction disorder.
^† Keratopathy includes corneal disorder, corneal epithelial microcysts, corneal epithelial defect, keratitis, keratopathy, corneal deposits, and punctate keratitis.
^‡ Dry eye includes dry eye and lacrimation increased.
^§ Eye pain includes eye pain and ocular discomfort.
^¶ Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort.
^# Peripheral neuropathy includes neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, polyneuropathy, and neurotoxicity.
^Þ Dyspnea includes dyspnea and exertional dyspnea.

Clinically relevant adverse reactions occurring in <10% of patients who received ELAHERE in Study 0417 included infusion related reactions/hypersensitivity (9%), pneumonitis (8%), thrombocytopenia (5%), and uveitis (1%).

Table 5 summarizes the laboratory abnormalities in Study 0417.

Table 5. Select Laboratory Abnormalities ≥10% for All Grades, or ≥2% for Grades 3-4 in Patients Who Received ELAHERE:

^* The denominator used to calculate the rate varied from 98 to 101 based on the number of patients with a baseline value and at least one post-treatment value.

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation against mirvetuximab soravtansine-gynx is highly dependent on the sensitivity and specificity of the assay. The observed incidence of anti-drug antibodies (including neutralizing antibody) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies to mirvetuximab soravtansine-gynx in other studies.

With a median duration of treatment of 4.3 months in Studies 0417, 0401, and 0403, a total of 55/423 (13%) ovarian cancer patients treated with mirvetuximab soravtansine-gynx at 6 mg/kg AIBW had at least 1 post-baseline positive sample for anti-mirvetuximab soravtansine-gynx antibodies. Of those patients, 28/423 patients (7%) had developed treatment-emergent ADA and 3/423 patients (0.7%) had treatment-enhanced ADA. Neutralizing antibodies were detected in 24/423 (6%) of patients.

Because of the low occurrence of anti-mirvetuximab soravtansine-gynx antibodies, the effect of these antibodies on the pharmacokinetics, efficacy, and/or safety of mirvetuximab soravtansine-gynx is unknown.

7.1 Effects of Other Drugs on ELAHERE

Strong CYP3A4 Inhibitors

DM4 is a CYP3A4 substrate. Concomitant use of ELAHERE with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure [see Clinical Pharmacology (12.3)], which may increase the risk of ELAHERE adverse reactions [see Adverse Reactions (6)]. Closely monitor patients for adverse reactions with ELAHERE when used concomitantly with strong CYP3A4 inhibitors [see Warnings and Precautions (5)].

Risk Summary

Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, ELAHERE has the potential to be transmitted from the mother to the developing fetus. There are no available human data on ELAHERE use in pregnant women to inform a drug-associated risk. No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine-gynx. Advise patients of the potential risk to a fetus.

The estimated 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 reproductive or developmental animal toxicity studies have been conducted with mirvetuximab soravtansine-gynx. The cytotoxic component of ELAHERE, DM4, disrupts microtubule function, is genotoxic, and can be toxic to actively dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.

Risk Summary

There are no data on the presence of mirvetuximab soravtansine-gynx in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ELAHERE and for 1 month after the last dose.

ELAHERE can cause embryo-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 ELAHERE.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose.

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

Of the 106 patients who were treated in Study 0417, 44% of patients were ≥65 years old. Grade ≥3 adverse reactions occurred in 49% of patients ≥65 years and in 51% <65 years. No clinically meaningful differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.

Population pharmacokinetic analysis indicates that age does not have a clinically meaningful effect on the pharmacokinetics of ELAHERE [see Clinical Pharmacology (12.3)].

No dosage adjustment of ELAHERE is recommended for patients with mild to moderate renal impairment (CLcr 30 to 90 mL/min). The effect of severe renal impairment (CLcr 15 to <30 mL/min) or end-stage renal disease on ELAHERE is unknown [see Clinical Pharmacology (12.3)].

Avoid use of ELAHERE in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).

No dosage adjustment of ELAHERE is recommended for patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) [see Clinical Pharmacology (12.3)].