RYBREVANT Concentrate for solution for infusion Ref.[28354] Active ingredients: Amivantamab

Source: European Medicines Agency (EU)  Revision Year: 2025  Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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.

Infusion-related reactions

Infusion-related reactions commonly occurred in patients treated with amivantamab (see section 4.8).

Prior to initial infusion (Week 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs. For subsequent doses, antihistamines and antipyretics should be administered. The initial infusion should be administered in split doses on Week 1, Day 1 and 2.

Patients should be treated in a setting with appropriate medical support to treat IRRs. Infusions should be interrupted at the first sign of IRRs of any severity and post-infusion medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the infusion should be resumed at 50% of the previous rate. For recurrent Grade 3 or Grade 4 IRRs, Rybrevant should be permanently discontinued (see section 4.2).

Interstitial lung disease

Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab, including fatal events (see section 4.8). Patients should be monitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, treatment with Rybrevant should be interrupted pending investigation of these symptoms. Suspected ILD or ILD-like adverse reactions should be evaluated and appropriate treatment should be initiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILD or ILD-like adverse reactions (see section 4.2).

Venous thromboembolic (VTE) events with concomitant use with lazertinib

In patients receiving Rybrevant in combination with lazertinib, VTE events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), including fatal events, were reported (see section 4.8). Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended.

Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treated with anticoagulation as clinically indicated. For VTE events associated with clinical instability treatment should be withheld until the patient is clinically stable. Thereafter, both drugs can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, Rybrevant should be discontinued. Treatment can continue with lazertinib at the same dose (see section 4.2).

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Protective clothing and use of broad-spectrum UVA/UVB sunscreen are advisable. Alcohol-free emollient cream is recommended for dry areas. A prophylactic approach to rash prevention should be considered. This includes prophylactic therapy with an oral antibiotic (e.g., doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin 1%) for the next 9 months of treatment. Non-comedogenic skin moisturiser on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet should be considered beginning on Day 1 and continued for the first 12 months of treatment.

Prescriptions for topical and/or oral antibiotics and topical corticosteroids are recommended to be available at the time of initial dosing to minimise any delay in reactive management should rash develop despite prophylactic treatment. If skin reactions develop, topical corticosteroids and topical and/or oral antibiotics should be administered. For Grade 3 or poorly-tolerated Grade 2 events, systemic antibiotics and oral steroids should also be administered. Patients presenting with severe rash that has an atypical appearance or distribution or lack improvement within 2 weeks should be referred promptly to a dermatologist. Rybrevant should be dose reduced, interrupted, or permanently discontinued based on severity (see section 4.2).

Toxic epidermal necrolysis (TEN) has been reported. Treatment with this medicinal product should be discontinued if TEN is confirmed.

Eye disorders

Eye disorders, including keratitis, occurred in patients treated with amivantamab (see section 4.8). Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated. For dose modifications for Grade 3 or 4 eye disorders, see section 4.2.

Sodium content

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially “sodium-free”. This medicinal product may be diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6).

4.5. Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been performed. As an IgG1 monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact amivantamab are unlikely to be major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of amivantamab. Due to the high affinity to a unique epitope on EGFR and MET, amivantamab is not anticipated to alter drug-metabolising enzymes.

Vaccines

No clinical data are available on the efficacy and safety of vaccinations in patients taking amivantamab. Avoid the use of live or live-attenuated vaccines while patients are taking amivantamab.

4.6. Fertility, pregnancy and lactation

Women of child-bearing potential/Contraception

Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment.

Pregnancy

There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug-associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product the patient should be informed of the potential risk to the foetus (see section 5.3).

Breast-feeding

It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards. A risk to the breast-fed child cannot be excluded during this short period just after birth, although IgGs are likely to be degraded in the gastrointestinal tract of the breast-fed child and not absorbed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from amivantamab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of amivantamab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

4.7. Effects on ability to drive and use machines

Rybrevant may have moderate influence on the ability to drive and use machines. Please see section 4.8 (e.g., dizziness, fatigue, visual impairment). If patients experience treatment-related symptoms, including vision-related adverse reactions, affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

4.8. Undesirable effects

Summary of the safety profile

In the dataset of amivantamab as monotherapy (N=380), the most frequent adverse reactions in all grades were rash (76%), infusion-related reactions (67%), nail toxicity (47%), hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%), and constipation (23%). Serious adverse reactions included ILD (1.3%), IRR (1.1%), and rash (1.1%). Three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%).

Tabulated list of adverse reactions

Table 7 summarises the adverse drug reactions that occurred in patients receiving amivantamab as monotherapy.

The data reflects exposure to amivantamab in 380 patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patients received amivantamab 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg). The median exposure to amivantamab was 4.1 months (range: 0.0 to 39.7 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 7. Adverse reactions in patients receiving amivantamab as monotherapy:

System organ class
Adverse reaction
Frequency
category
Any Grade
(%)
Grade 3-4
(%)
Metabolism and nutrition disorders
Hypoalbuminaemia* (see section 5.1) Very common 31 2
Decreased appetite 16 0.5
Hypocalcaemia 10 0.3
Hypokalaemia Common 9 2
Hypomagnesaemia 8 0
Nervous system disorders
Dizziness* Very common 13 0.3
Eye disorders
Visual impairment* Common 3 0
Growth of eyelashes* 1 0
Other eye disorders* 6 0
Keratitis Uncommon 0.50
Uveitis 0.3 0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease* Common 3 0.5
Gastrointestinal disorders
Diarrhoea Very common 11 2
Stomatitis* 24 0.5
Nausea 23 0.5
Constipation 23 0
Vomiting 12 0.5
Abdominal pain* Common 9 0.8
Haemorrhoids 3.7 0
Hepatobiliary disorders
Alanine aminotransferase increased Very common 15 2
Aspartate aminotransferase increased 13 1
Blood alkaline phosphatase increased 12 0.5
Skin and subcutaneous tissue disorders
Rash* Very common 76 3
Nail toxicity* 47 2
Dry skin* 19 0
Pruritus 18 0
Toxic epidermal necrolysis Uncommon 0.3 0.3
Musculoskeletal and connective tissue disorders
Myalgia Very common 11 0.3
General disorders and administration site conditions
Oedema* Very common 26 0.8
Fatigue* 26 0.8
Pyrexia 11 0
Injury, poisoning and procedural complications
Infusion related reaction Very common 67 2

* Grouped terms
Grade 3 events only

Summary of the safety profile

In the dataset of amivantamab in combination with carboplatin and pemetrexed (N=301), the most frequent adverse reactions in all grades were rash (83%), neutropenia (57%), nail toxicity (53%), infusion related reactions (51%), fatigue (43%), stomatitis (39%), nausea (43%), thrombocytopenia (40%), constipation (40%), oedema (40%), decreased appetite (33%), hypoalbuminaemia (32%), alanine aminotransferase increased (26%), aspartate aminotransferase increased (23%), vomiting (22%), and hypokalaemia (20%). Serious adverse reactions included rash (2.7%), venous thromboembolism (2.3%), thrombocytopenia (2.3%) and ILD (2.0%). Eight percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (2.7%), rash (2.3%), ILD (2.3%), and nail toxicity (1.0%).

Table 8 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with chemotherapy.

The data reflects exposure to amivantamab in combination with carboplatin and pemetrexed in 301 patients with locally advanced or metastatic non-small cell lung cancer. Patients received amivantamab 1400 mg (for patients <80 kg) or 1750 mg (for patients ≥80 kg) weekly for 4 weeks. Starting at Week 7, patients received amivantamab 1750 mg (for patients <80 kg) or 2100 mg (for patients ≥80 kg) every 3 weeks. The median exposure to amivantamab in combination with carboplatin and pemetrexed was 7.7 months (range: 0.0 to 28.1 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 8. Adverse reactions in patients receiving amivantamab in combination with carboplatin and pemetrexed:

System organ class
Adverse reaction
Frequency
category
Any Grade
(%)
Grade 3-4
(%)
Blood and lymphatic system disorders
Neutropenia Very common 57 39
Thrombocytopenia 40 12
Metabolism and nutrition disorders
Decreased appetite Very common 33 1.3
Hypoalbuminaemia* 32 3.7
Hypokalaemia 20 6.6
Hypomagnesaemia 13 1.3
Hypocalcaemia 12 1.0
Nervous system disorders
Dizziness* Common 10 0.3
Vascular disorders
Venous thromboembolism* Very common 14 3.0
Eye disorders
Other eye disorders* Common 7.3 0
Visual impairment* 3.00
Growth of eyelashes Uncommon 0.3 0
Keratitis 0.3 0
Uveitis 0.3 0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease* Common 2.3 1.7
Gastrointestinal disorders
Nausea Very common 43 1.0
Constipation 40 0.3
Stomatitis* 39 3.0
Vomiting 22 2.0
Diarrhoea 19 2.3
Abdominal pain* Common 11 0.3
Haemorrhoids 9.3 0.7
Hepatobiliary disorders
Alanine aminotransferase increased Very common 26 4.3
Aspartate aminotransferase increased 23 0.7
Blood alkaline phosphatase increased Common 10 0.3
Skin and subcutaneous tissue disorders
Rash* Very common 83 14
Nail toxicity* 53 4.3
Dry skin* 16 0
Pruritus 10 0
Musculoskeletal and connective tissue disorders
Myalgia Common 5.0 0.7
General disorders and administration site conditions
Fatigue* Very common 43 4.7
Oedema* 40 1.3
Pyrexia 14 0
Injury, poisoning and procedural complications
Infusion related reaction Very common 51 3.0

* Grouped terms

Summary of the safety profile

In the dataset of amivantamab in combination with lazertinib (N=421), the most frequent adverse reactions in all grades were rash (89%), nail toxicity (71%), infusion-related reactions (63%), hypoalbuminaemia (48%), hepatotoxicity (47%), oedema (47%), stomatitis (43%), venous thromboembolism (37%), paraesthesia (lazertinib) (34%), fatigue (32%), diarrhoea (29%), constipation (29%), dry skin (26%), pruritis (24%), decreased appetite (24%), hypocalcaemia (21%), nausea (21%) and other eye disorders (21%). The most frequent serious adverse reactions included venous thromboembolism (11%), pneumonia (4.0%), rash (3.1%), ILD/pneumonitis (2.9%), hepatotoxicity (2.4%), COVID-19 (2.4%), and IRR and pleural effusion (2.1%). Twenty-three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to Rybrevant discontinuation were rash (5.5%), infusion related reactions (4.5%), nail toxicity (3.6%), ILD (2.9%) and VTE (2.9%).

Table 9 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with lazertinib.

The data reflects exposure to amivantamab in combination with lazertinib in 421 patients with locally advanced or metastatic non-small cell lung cancer. Patients received amivantamab 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter. The median exposure to study treatment in the amivantamab and lazertinib combination group was 18.5 months (range: 0.2 to 31.4 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 9. Amivantamab adverse reactions in patients receiving amivantamab in combination with lazertinib:

System organ class
Adverse reaction
Frequency
category
Any Grade
(%)
Grade 3-4
(%)
Metabolism and nutrition disorders
Hypoalbuminaemia* Very common 48 5
Decreased appetite 24 1.0
Hypocalcaemia 21 2.1
Hypokalaemia 14 3.1
Hypomagnesaemia Common 5.0 0
Nervous system disorders
Paraesthesia* Very common 34 1.7
Dizziness* 130
Vascular disorders
Venous thromboembolism* Very common 37 11
Eye disorders
Other eye disorders* Very common 21 0.5
Visual impairment* Common 4.5 0
Keratitis 2.6 0.5
Growth of eyelashes* 1.9 0
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease/Pneumonitis* Common 3.1 1.2
Gastrointestinal disorders
Stomatitis* Very common 43 2.4
Diarrhoea 29 2.1
Constipation 29 0
Nausea 21 1.2
Vomiting 12 0.5
Abdominal pain* 11 0
Haemorrhoids Common 10 0.2
Hepatobiliary disorders
Hepatotoxicity Very common 47 9
Skin and subcutaneous tissue disorders
Rash* Very common 89 27
Nail toxicity* 71 11
Dry skin* 26 1.0
Pruritus 24 0.5
Palmar-plantar erythrodysaesthesia
syndrome
Common 6 0.2
Urticaria 1.2 0
Musculoskeletal and connective tissue disorders
Muscle spasms Very common 17 0.5
Myalgia 13 0.7
General disorders and administration site conditions
Oedema* Very common 47 2.9
Fatigue* 32 3.8
Pyrexia 12 0
Injury, poisoning and procedural complications
Infusion related reaction Very common 63 6

* Grouped terms
Assessed as ADR for lazertinib only.
The most common events included increased ALT (36%), increased AST (29%) and increase blood alkaline phosphatase (12%).

Description of selected adverse reactions

Infusion-related reactions

In patients treated with amivantamab monotherapy, infusion-related reactions occurred in 67% of patients. Ninety-eight percent of IRRs were Grade 1-2. Ninety-nine percent of IRRs occurred at the first infusion with a median time to onset of 60 minutes, and the majority occurring within 2 hours of infusion start. The most frequent signs and symptoms include chills, dyspnoea, nausea, flushing, chest discomfort, and vomiting (see section 4.4).

In patients treated with amivantamab in combination with carboplatin and pemetrexed, infusion-related reactions occurred in 50% of patients. Greater than 94% of IRRs were Grade 1-2. A majority of IRRs occurred at the first infusion with a median time to onset of 60 minutes (range 0-7 hours), and the majority occurring within 2 hours of infusion start. Occasionally an IRR can occur at re-initiation of amivantamab after prolonged dose interruptions of more than 6 weeks.

In patients treated with amivantamab in combination with lazertinib, infusion-related reactions occurred in 63% of patients. Ninety-four percent of IRRs were Grade 1-2. A majority of IRRs occurred at the first infusion with a median time to onset of 1 hour, and the majority occurring within 2 hours of infusion start. The most frequent signs and symptoms include chills, dyspnoea, nausea, flushing, chest discomfort, and vomiting (see section 4.4).

Occasionally an IRR can occur at re-initiation of amivantamab after prolonged dose interruptions of more than 6 weeks.

Interstitial lung disease

Interstitial lung disease or ILD-like adverse reactions have been reported with the use of amivantamab as well as with other EGFR inhibitors. Interstitial lung disease or pneumonitis was reported in 2.6% of patients treated with amivantamab monotherapy, 2.3% of patients treated with amivantamab in combination with carboplatin and pemetrexed and 3.1% of patients treated with amivantamab in combination with lazertinib, including 1 (0.2%) fatal case. Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from the clinical study (see section 4.4).

Venous thromboembolic (VTE) events with concomitant use with lazertinib

When Rybrevant is used in combination with lazertinib, VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), were reported in 37% of the 421 patients receiving Rybrevant in combination with lazertinib. Most cases were Grade 1 or 2, with Grade 3-4 events occurring in 11% of patients receiving Rybrevant in combination with lazertinib and deaths occurring in 0.5% of patients receiving Rybrevant in combination with lazertinib. For information on prophylactic anticoagulants and management of VTE events, see sections 4.2 and 4.4. In patients receiving Rybrevant in combination with lazertinib, the median time to first onset of a VTE event was 84 days. VTE events led to Rybrevant treatment discontinuation in 2.9% of patients.

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, and dry skin occurred in 76% of patients treated with amivantamab alone. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 3% of patients. Rash leading to amivantamab discontinuation occurred in 0.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 1.8% of patients.

Rash (including dermatitis acneiform), occurred in 83% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 14% of patients. Rash leading to amivantamab discontinuation occurred in 2.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab in combination with carboplatin and pemetrexed. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 4.3% of patients (see section 4.4).

Rash (including dermatitis acneiform), occurred in 89% of patients treated with amivantamab in combination with lazertinib. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 27% of patients. Rash leading to amivantamab discontinuation occurred in 5.5% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab in combination with lazertinib. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 11% of patients (see section 4.4).

Eye disorders

Eye disorders, including keratitis (0.5%), occurred in 9% of patients treated with amivantamab alone. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. All events were Grade 1-2.

Eye disorders, including keratitis (0.3%), occurred in 11% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Other reported adverse reactions included growth of eyelashes, visual impairment, uveitis, and other eye disorders. All events were Grade 1-2 (see section 4.4).

Eye disorders, including keratitis (2.6%) occurred in patients treated with amivantamab in combination with lazertinib. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. Most events were Grade 1-2 (see section 4.4).

Other special populations

Elderly

There are limited clinical data with amivantamab in patients 75 years of age or over (see section 5.1). No overall differences in safety were observed between patients ≥65 years of age and patients <65 years of age.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In clinical studies of patients with locally advanced or metastatic NSCLC treated with amivantamab, 4 of the 1862 (0.2%) participants who were treated with Rybrevant and evaluable for the presence of anti-drug antibodies (ADA), tested positive for treatment-emergent anti-amivantamab antibodies. There was no evidence of an altered pharmacokinetic, efficacy, or safety profile due to anti-amivantamab antibodies.

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.

6.2. Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

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