ELAHERE Concentrate for solution for infusion Ref.[113939] Active ingredients: Mirvetuximab soravtansine

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Ocular disorders

Mirvetuximab soravtansine can cause severe ocular adverse reactions, including visual impairment (predominantly blurred vision), keratopathy (corneal disorders), dry eye, photophobia, and eye pain (see sections 4.7 and 4.8).

Patients should be referred to an eye care professional for an ophthalmic exam before initiation of mirvetuximab soravtansine.

Before the start of each cycle, the patient should be advised to report any new or worsening ocular symptoms to the treating physician or qualified individual.

If ocular symptoms develop, an ophthalmic exam should be conducted, the patient’s ophthalmic report should be reviewed and the dose of mirvetuximab soravtansine may be modified based on the severity of the findings (see section 4.2).

Use of lubricating eye drops during treatment with mirvetuximab soravtansine is recommended. In patients who develop ≥Grade 2 corneal adverse reactions, ophthalmic topical steroids are recommended for subsequent cycles of mirvetuximab soravtansine (see section 4.2).

The physician should monitor patients for ocular toxicity and withhold, reduce, or permanently discontinue mirvetuximab soravtansine based on the severity and persistence of ocular adverse reactions (see section 4.2).

Patients should be advised to avoid use of contact lenses during treatment with mirvetuximab soravtansine unless directed by a healthcare professional.

Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with mirvetuximab soravtansine (see section 4.8).

Patients should be monitored for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnoea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations.

Mirvetuximab soravtansine treatment should be withheld for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤Grade 1 and dose reduction should be considered. Mirvetuximab soravtansine should be permanently discontinued in all patients with Grade 3 or 4 pneumonitis (see section 4.2). Patients who are asymptomatic may continue dosing of mirvetuximab soravtansine with close monitoring.

Peripheral neuropathy

Peripheral neuropathy has occurred with mirveutximab soravtansine, including Grade ≥3 reactions (see section 4.8).

Patients should be monitored for signs and symptoms of neuropathy, such as paraesthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening peripheral neuropathy, mirvetuximab soravtansine dose should be withheld, reduced, or permanently discontinued based on the severity of peripheral neuropathy (see section 4.2).

Embryo-foetal toxicity

Based on its mechanism of action, mirvetuximab soravtansine could cause embryo-foetal harm when administered to a pregnant patient because it contains a genotoxic compound (DM4) and affects actively dividing cells.

Patients of childbearing potential should use effective contraception during treatment with mirvetuximab soravtansine and for 7 months after the last dose (see section 4.6).

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

This medicinal product contains 2.11 mg of polysorbate 20 in each vial.

Clinical drug-drug interaction studies with ELAHERE have not been conducted.

DM4 is a CYP3A4 substrate. Concomitant use of ELAHERE with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure (see section 5.2), which may increase the risk of ELAHERE adverse reactions (see section 4.8). If concomitant use with strong CYP3A4 inhibitors (e.g. ceritinib, clarithromycin, cobicistat, idelalisib, itraconazole, ketoconazole, nefazodone, posaconazole, ritonavir, telithromycin, voriconazole) cannot be avoided, patients should be closely monitored for adverse reactions. Strong CYP3A4 inducers (e.g., phenytoin, rifampicin, carbamazepine) may decrease the exposure of unconjugated DM4.

Women of childbearing potential/Contraception

The pregnancy status in patients of childbearing potential should be verified prior to initiating mirvetuximab soravtansine treatment.

Patients of childbearing potential should use effective contraception during treatment with mirvetuximab soravtansine and for 7 months after the last dose.

Pregnancy

Based on its mechanism of action, mirvetuximab soravtansine can cause embryo-foetal harm when administered to a pregnant patient because it contains a genotoxic compound (DM4) and affects actively dividing cells (see sections 5.1 and 5.3). Human immunoglobulin G (IgG) is known to cross the placental barrier; therefore, mirvetuximab soravtansine has the potential to be transmitted from the pregnant patient to the developing foetus. There are no available human data on mirvetuximab soravtansine use in pregnant patients to inform a drug-associated risk. No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine.

Administration of ELAHERE to pregnant patients is not recommended, and patients should be informed of the potential risks to the foetus if they become or wish to become pregnant. Patients who become pregnant must immediately contact their doctor. If a patient becomes pregnant during treatment with ELAHERE or within 7 months following the last dose, close monitoring is recommended.

Breast-feeding

It is unknown whether mirvetuximab soravtansine/metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded as human immunoglobulin G (IgG) is known to pass on in breast milk. ELAHERE should not be used during breast-feeding and for 1 month after the last dose.

Fertility

Fertility studies have not been conducted with mirvetuximab soravtansine or DM4. There are no data on the effect of ELAHERE on human fertility. However, given the mechanism of action of ELAHERE leads to microtubule disruption and death of rapidly dividing cells, there is the potential for drug-related fertility effects.

ELAHERE has moderate influence on the ability to drive and use machines. If patients experience visual disturbances, peripheral neuropathy, fatigue, or dizziness during treatment with mirvetuximab soravtansine, they should be instructed not to drive or use machines until complete resolution of symptoms is confirmed.

Summary of safety profile

The most common adverse reactions with mirvetuximab soravtansine were blurred vision (43%), nausea (41%), diarrhoea (39%), fatigue (35%), abdominal pain (30%), keratopathy (29%), dry eye (27%), constipation (26%), vomiting (23%), decreased appetite (22%), peripheral neuropathy (20%), headache (19%), asthenia (18%), AST increased (16%), and arthralgia (16%).

The most commonly reported serious adverse reactions were pneumonitis (4%), small intestinal obstruction (3%), intestinal obstruction (3%), pleural effusion (2%), abdominal pain (2%), dehydration (1%), constipation (1%), nausea (1%), ascites (1%) and thrombocytopenia (<1%).

Adverse reactions that most commonly led to dose reduction or dose delay were blurred vision (17%), keratopathy (10%), dry eye (5%), neutropenia (5%), keratitis (4%), cataract (3%), visual acuity reduced (3%), thrombocytopenia (3%), peripheral neuropathy (3%), and pneumonitis (3%).

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received mirvetuximab soravtansine, including most commonly, gastrointestinal disorders (4%), respiratory, thoracic, and mediastinal disorders (3%), blood and lymphatic system disorders (1%), nervous system disorders (1%), and eye disorders (1%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on pooled data from 4 clinical studies which included 682 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer (collectively referenced as Epithelial Ovarian Cancer (EOC) treated with mirvetuximab soravtansine 6 mg/kg AIBW administered once every 3 weeks. The median duration of treatment with mirvetuximab soravtansine was 19.1 weeks (range: 3, 132 weeks).

The adverse reaction frequencies from clinical studies are based on all-cause adverse event frequencies, for which, after thorough assessment, a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.

Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000). Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness.

Table 4. Tabulated list of all grade adverse reactions in patients treated with mirvetuximab soravtansine in clinical studies:

¹ Peripheral neuropathy grouped term includes hypoaesthesia, neuropathy peripheral, neurotoxicity, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and polyneuropathy (see section Description of selected adverse reactions).
² Keratopathy group term includes corneal cyst, corneal deposits, corneal disorder, corneal epithelial microcysts, corneal epithelium defect, corneal erosion, corneal opacity, corneal pigmentation, keratitis, keratitis interstitial, keratopathy, limbal stem cell deficiency, and punctate keratitis (see section Description of selected adverse reactions).
³ Cataract grouped term includes cataract, cataract cortical, and cataract nuclear (see section Description of selected adverse reactions).
⁴ Blurred vision event grouped term includes accommodation disorder, diplopia, hypermetropia, presbyopia, refraction disorder, vision blurred, visual impairment, visual acuity reduced, and vitreous floaters (see section Description of selected adverse reactions).
⁵ Dry eye grouped term includes dry eye and lacrimation decreased (see section Description of selected adverse reactions).
⁶ Ocular discomfort grouped term includes eye irritation, eye pruritus, foreign body sensation in eye, and ocular discomfort (see section Description of selected adverse reactions).
⁷ Pneumonitis group term includes interstitial lung disease, organising pneumonia, pneumonitis, pulmonary fibrosis, and respiratory failure (see section Description of selected adverse reactions).
⁸ Abdominal pain grouped term includes abdominal discomfort, abdominal pain, abdominal pain lower, and abdominal pain upper.
⁹ Infusion related reaction/hypersensitivity grouped term includes SMQ Hypersensitivity narrow and flushing, erythema, erythema of eyelid.

Description of selected adverse reactions

Ocular disorders

Ocular adverse reactions (grouped terms) occurred in 59% of patients with EOC treated with mirvetuximab soravtansine. Eleven percent (11%) of patients experienced Grade 3 ocular adverse reactions and <1% experienced Grade 4 events. The most common ≥ Grade 3 ocular adverse reactions were blurred vision and keratopathy (both 5%, grouped terms) and cataract (4%).

The median time to onset for first ocular adverse reaction was 5.1 weeks (range: 0.1 to 68.6). Of the patients who experienced ocular events, 53% had complete resolution (Grade 0) and 38% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade). At the last follow-up, 0.3% (2/682) patients had ≥ Grade 3 ocular adverse events (1 patient with Grade 3 decreased visual acuity and 1 patient with Grade 4 cataract).

Ocular adverse reactions led to dose delays in 24% of patients, and dose reductions in 15% of patients. Ocular adverse reactions led to permanent discontinuation of mirvetuximab soravtansine in 1% of patients.

Pneumonitis

Pneumonitis (grouped terms) occurred in 10% of patients with EOC treated with mirvetuximab soravtansine, including 0.9% (6/682) patients with Grade 3 events, and 0.2% (1/682) patient with a Grade 4 event. Two patients (0.3%) died due to respiratory failure. One patient (0.2%) died due to respiratory failure in the setting of Grade 1 pneumonitis and lung metastases confirmed at autopsy. One patient (0.2%) died due to respiratory failure of unknown aetiology without concurrent pneumonitis.

The median time to onset of pneumonitis was 18.1 weeks (range 1.6 to 97.0). Pneumonitis resulted in mirvetuximab soravtansine dose delays in 3%, dose reductions in 1%, and permanent discontinuation in 3% of patients.

Peripheral neuropathy

Peripheral neuropathy (grouped terms) occurred in 36% of patients with EOC treated with mirvetuximab soravtansine across clinical studies; 3% of patients experienced Grade 3 peripheral neuropathy.

The median time to onset of peripheral neuropathy was 5.9 weeks (range 0.1 to 126.7). Peripheral neuropathy resulted in mirvetuximab soravtansine dose delays in 2%, dose reductions in 4%, and led to permanent discontinuation in 0.7% of patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

ELAHERE is incompatible with sodium chloride 9 mg/mL (0.9%) solution for infusion. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.