Mirvetuximab soravtansine

PubChem compound: 131704323

Interactions

Mirvetuximab soravtansine interacts in the following cases:

Strong CYP3A4 inhibitors

DM4 is a CYP3A4 substrate. Concomitant use of mirvetuximab soravtansine with strong CYP3A4 inhibitors may increase unconjugated DM4 exposure, which may increase the risk of mirvetuximab soravtansine adverse reactions. 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.

Severe renal impairment

Mirvetuximab soravtansine has not been evaluated in patients with severe renal impairment (CLcr 15 to <30 mL/min) or end-stage renal disease and the potential need for dose adjustment in these patients cannot be determined.

Moderate hepatic impairment, severe hepatic impairment

Mirvetuximab soravtansine should be avoided in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN with any AST).

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. 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 mirvetuximab soravtansine 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 mirvetuximab soravtansine or within 7 months following the last dose, close monitoring is recommended.

Nursing mothers

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. Mirvetuximab soravtansine should not be used during breast-feeding and for 1 month after the last dose.

Carcinogenesis, mutagenesis and fertility

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.

Fertility

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

Effects on ability to drive and use machines

Mirvetuximab soravtansine 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.

Adverse reactions


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.

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

System Organ Class Frequency category Adverse reactions
Infections and infestations Very common Urinary tract infection
Blood and lymphatic system
disorders
Very common Anaemia, thrombocytopenia
Common Neutropenia
Metabolism and nutrition
disorders
Very common Decreased appetite, hypomagnesaemia
Common Hypokalaemia, dehydration
Psychiatric disorders Common Insomnia
Nervous system disorders Very common Peripheral neuropathy1, headache
Common Dysgeusia, dizziness
Eye disorders Very common Keratopathy2, cataract3, blurred vision
event4, photophobia, eye pain, dry eye5
Common Ocular discomfort6
Vascular disorders Common Hypertension
Respiratory, thoracic and
mediastinal disorders
Very commonPneumonitis7, dyspnoea, cough
Gastrointestinal disorders Very common Diarrhoea, abdominal pain8,
constipation, abdominal distension,
vomiting, nausea
Common Ascites, gastro-oesophageal reflux
disease, stomatitis, dyspepsia
Hepatobiliary disorders Common Hyperbilirubinaemia
Skin and subcutaneous tissue
disorders
Common Pruritus
Musculoskeletal and connective
tissue disorders
Very commonArthralgia
Common Myalgia, back pain, pain in extremity,
muscle spasms
General disorders and
administration site conditions
Very commonFatigue
Common Pyrexia
Investigations Very common Aspartate aminotransferase increased,
alanine aminotransferase increased
Common Blood alkaline phosphatase increased,
gamma-glutamyl transferase increased,
weight decreased
Injury, poisoning and procedural
complication
Common Infusion related

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.

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