Rybrevant - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Rybrevant 350 mg concentrate for solution for infusion.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One mL of concentrate for solution for infusion contains 50 mg amivantamab.

One 7 mL vial contains 350 mg of amivantamab.

Amivantamab is a fully-human Immunoglobulin G1 (IgG1)-based bispecific antibody directed against the epidermal growth factor (EGF) and mesenchymal-epidermal transition (MET) receptors, produced by a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.

The solution is colourless to pale yellow, with a pH of 5.7 and an osmolality of approximately 310 mOsm/kg.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Rybrevant as monotherapy is indicated for treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) Exon 20 insertion mutations, after failure of platinum-based therapy.

4.2 Posology and method of administration

Treatment with Rybrevant should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Rybrevant should be administered by a healthcare professional with access to appropriate medical support to manage infusion-related reactions (IRRs) if they occur.

Before initiation of Rybrevant therapy, EGFR Exon 20 insertion mutation-positive status must be established using a validated test method (see section 5.1).

Posology

Premedications should be administered to reduce the risk of IRRs with Rybrevant (see below “Dose modifications” and “Recommended concomitant medicinal products”).

The recommended dose of Rybrevant is provided in Table 1, and the dosing schedule is provided in Table 2 (see below “Infusion rates”).

Table 1:   Recommended dose of Rybrevant

Body weight of patient (at baseline )	Recommended dose	Number of vials
Less than 80 kg	1,050 mg	3
Greater than or equal to 80 kg	1,400 mg	4

Dose adjustments not required for subsequent body weight changes

Table 2:   Dosing schedule for Rybrevant

Weeks	Schedule
Weeks 1 to 4	Weekly (total of 4 doses)
Week 5 onwards	Every 2 weeks starting at Week 5

Duration of treatment

It is recommended that patients are treated with Rybrevant until disease progression or unacceptable toxicity.

Missed dose

If a planned dose is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.

Dose modifications

Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to < Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 3. See also specific dose modifications for specific adverse reactions below Table 3.

Table 3:   Recommended dose modifications for adverse reactions

Body weight (at baseline)	Initial dose	1st dose modification	2nd dose modification	3rd dose modification
Less than 80 kg	1,050 mg	700 mg	350 mg	Discontinue Rybrevant
Greater than or equal to 80 kg	1,400 mg	1,050 mg	700 mg

Infusion-related reactions

Interrupt infusion at the first sign of IRRs. Additional supportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated (see section 4.4).

• • Grade 1–3 (mild-severe): Upon recovery of symptoms, resume infusion at 50% of the previous

rate. If there are no additional symptoms, the rate may be increased per the recommended infusion rate (see Table 5). Concomitant medicinal products should be administered at the next dose (see Table 4).

• • Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant.

Skin and nail reactions

If the patient develops a Grade 2 skin or nail reaction, supportive care should be initiated; if there is no improvement after 2 weeks, dose reduction should be considered (see Table 3). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated, and interruption of Rybrevant should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to < Grade 2, Rybrevant should be resumed at a reduced dose. If the patient develops Grade 4 skin reactions (including toxic epidermal necrolysis (TEN)), permanently discontinue Rybrevant (see section 4.4).

Interstitial lung disease

If the patient develops interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4).

Recommended concomitant medicinal products

Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 4). For subsequent doses, antihistamines and antipyretics are required to be administered. Antiemetics should be administered as needed.

Table 4:   Dosing schedule of premedications

Premedication	Dose	Route of administration	Recommended dosing window prior to Rybrevant administration
Antihistamine	Diphenhydramine (25 to 50 mg) or equivalent	Intravenous	15 to 30 minutes
		Oral	30 to 60 minutes
Antipyretic	Paracetamol/A­cetaminophen (650 to 1,000 mg)	Intravenous	15 to 30 minutes
		Oral	30 to 60 minutes
Glucocorticoid1	Dexamethasone (10 mg) or Methylprednisolone (40 mg) or equivalent	Intravenous	45 to 60 minutes

* Required at all doses.

J Required at initial dose (Week 1, Days 1 and 2); optional for subsequent doses.

Special populations

Paediatric population

There is no relevant use of amivantamab in the paediatric population in the treatment of non-small cell lung cancer.

Elderly

No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2).

Renal impairment

No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendation­s above.

Hepatic impairment

No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment. Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendation­s above.

Method of administration

Rybrevant is for intravenous use. It is administered as an intravenous infusion following dilution with sterile 5% glucose solution or sodium chloride 9 mg/mL (0.9%) solution for injection. Rybrevant must be administered with in-line filtration.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Infusion rates

Following dilution, the infusion should be administered intravenously at the infusion rates presented in Table 5 below. Due to the frequency of IRRs at the first dose, amivantamab should be infused via a peripheral vein at Week 1 and Week 2; infusion via a central line may be administered for subsequent weeks when the risk of IRR is lower (see section 6.6). It is recommended for the first dose to be prepared as close to administration as possible to maximise the likelihood of completing the infusion in the event of an IRR.

Table 5:   Infusion rates for Rybrevant administration

1,050 mg dose
Week	Dose (per 250 mL bag)	Initial infusion rate	Subsequent infusion rate1
Week 1 (split dose infusion)
Week 1 Day 1	350 mg	50 mL/hr	75 mL/hr
Week 1 Day 2	700 mg	50 mL/hr	75 mL/hr
Week 2	1,050 mg	85 mL/hr
Subsequent weeks	1,050 mg	125 mL/hr
1,400 mg dose
Week	Dose (per 250 mL bag)	Initial infusion rate	Subsequent infusion rate1
Week 1 (split dose infusion)
Week 1 Day 1	350 mg	50 mL/hr	75 mL/hr
Week 1 Day 2	1,050 mg	35 mL/hr	50 mL/hr
Week 2	1,400 mg	65 mL/hr
Week 3	1,400 mg	85 mL/hr
Subsequent weeks	1,400 mg	125 mL/hr

* After Week 5, patients are dosed every 2 weeks.

J Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of IRRs.

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 (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 should be evaluated and appropriate treatment should be initiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILD (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. 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

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 6 summarises the adverse drug reactions that occurred in patients receiving amivantamab.

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 1,050 mg (for patients < 80 kg) or 1,400 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 (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); 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 6:   Adverse reactions in patients receiving amivantamab

System organ class Adverse reaction	Frequency category	Any Grade (%)	Grade 3–4 (%)
Metabolism and nutrition disorders
Hypoalbuminaemiaa (see section 5.1)	Very common	31	2*
Decreased appetite		16	0.5*
Hypocalcaemia		10	0.3*
Nervous system disorders
Dizzinessb	Very common	13	0.3*

Eye disorders
Visual impairment	Common	3	0
Growth of eyelashesd		1	0
Other eye disorders6		6	0
Keratitis	Uncommon	0.5	0
Uveitis		0.3	0
Respiratory, thoracic and mediastinal disorders
Interstitial lung diseasef	Common	3	0.5
Gastrointestinal disorders
Diarrhoea	Very common	11	2
Stomatitisg		24	0.5
Nausea		23	0.5
Constipation		23	0
Vomiting		12	0.5
Abdominal painh	Common	9	0.8
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
Rashi	Very common	76	3
Nail toxicityj		47	2
Dry skink		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 cone	itions
Oedemal	Very common	26	0.8
Fatiguem		26	0.8
Injury, poisoning and procedural complications
Infusion-related reaction	Very common	67	2

Description of selected adverse reactions

Infusion-related reactions

Infusion-related reactions occurred in 67% of patients treated with amivantamab. 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).

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. 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).

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, and dry skin occurred in 76% of patients treated with amivantamab. 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. Paronychia occurred in patients treated with amivantamab. Most events were Grade 1 or 2, with Grade 3 paronychia occurring in 1.8% of patients (see section 4.4).

Eye disorders

Eye disorders, including keratitis (0.5%), occurred in 9% of patients treated with amivantamab. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. All 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 a clinical study of patients with locally advanced or metastatic NSCLC treated with amivantamab, 3 (0.9%) of the 347 evaluable patients tested positive for 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.

4.9 Overdose

No maximum tolerated dose has been determined in a clinical study in which patients received up to 1,750 mg administered intravenously. There is no known specific antidote for amivantamab overdose. In the event of an overdose, treatment with Rybrevant should be stopped, the patient should be monitored for any signs or symptoms of adverse events and appropriate general supportive measures should be instituted immediately until clinical toxicity has diminished or resolved.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code: L01FX18.

Mechanism of action

Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating EGFR Exon 20 insertion mutations.

Amivantamab binds to the extracellular domains of EGFR and MET.

Amivantamab disrupts EGFR and MET signalling functions through blocking ligand binding and enhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. The presence of EGFR and MET on the surface of tumour cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.

Pharmacodynamic effects

Albumin

Amivantamab decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks (see section 4.8); thereafter, albumin concentration stabilised for the remainder of amivantamab treatment.

Clinical efficacy and safety

CHRYSALIS is a multicentre, open-label, multi-cohort study conducted to assess the safety and efficacy of Rybrevant in patients with locally advanced or metastatic NSCLC. Efficacy was evaluated in 114 patients with locally advanced or metastatic NSCLC who had EGFR Exon 20 insertion mutations, whose disease had progressed on or after platinum-based chemotherapy, and who had a median follow-up of 12.5 months. Tumour tissue (93%) and/or plasma (10%) samples for all patients were tested locally to determine EGFR Exon 20 insertion mutation status using next generation sequencing (NGS) in 46% of patients and/or polymerase chain reaction (PCR) in 41% of patients; for 4% of patients, the testing methods were not specified. Patients with untreated brain metastases or a history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study. Rybrevant was administered intravenously at 1,050 mg for patients < 80 kg or 1,400 mg for patients > 80 kg once weekly for 4 weeks, then every 2 weeks starting at Week 5 until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessed overall response rate (ORR), defined as confirmed complete response (CR) or partial response (PR) based on RECIST v1.1. In addition, the primary endpoint was assessed by a blinded independent central review (BICR). Secondary efficacy endpoints included duration of response (DOR).

The median age was 62 (range: 36–84) years, with 41% of the patients > 65 years of age; 61% were female; and 52% were Asian and 37% were White. The median number of prior therapies was 2 (range: 1 to 7 therapies). At baseline, 29% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 70% had ECOG performance status of 1; 57% never smoked; 100% had Stage IV cancer; and 25% had previous treatment for brain metastases. Insertions in Exon 20 were observed at 8 different residues; the most common residues were A767 (22%), S768 (16%), D770 (12%), and N771 (11%).

Efficacy results are summarised in Table 7.

Table 7:   Efficacy results in CHRYSALIS

	Investigator assessment (N=114)
Overall response rate a, b (95% CI)	37% (28%, 46%)
Complete response	0%
Partial response	37%
Duration of response
Medianc (95% CI), months	12.5 (6.5, 16.1)
Patients with DOR > 6 months	64%

CI = Confidence Interval

a Confirmed response

b ORR and DOR results by investigator assessment were consistent with those reported by BICR assessment; ORR by

BICR assessment was 43% (34%, 53%), with a 3% CR rate and a 40% PR rate, median DOR by BICR assessment was 10.8 months (95% CI: 6.9, 15.0), and patients with DOR > 6 months by BICR assessment was 55%.

c Based on Kaplan-Meier estimate.

Anti-tumour activity was observed across studied mutation subtypes.

Elderly

No overall differences in effectiveness were observed between patients > 65 years of age and patients < 65 years of age.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Rybrevant in all subsets of the paediatric population in non-small cell lung cancer (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Amivantamab area under the concentration-time curve (AUC1 week) increases proportionally over a dose range from 350 to 1,750 mg.

Following administration of Rybrevant at the recommended dose and schedule, the mean serum AUC1 week was approximately 2.9-fold higher after the fifth dose, following the weekly dosing, compared to the first dose.

Steady state was achieved approximately 2 months into the every 2-week dosing period (by the ninth infusion) at 1,050 mg, and the mean serum AUC1 week was approximately 2.4 fold higher at steady state compared to the first dose.

Distribution

Amivantamab geometric mean (CV%) total volume of distribution, based on population PK parameter estimates, was 5.37 (21%) L following administration of the recommended dose of Rybrevant.

Elimination

Amivantamab clearance is higher with low doses (< 350 mg) but linear within the clinical dose range. The geometric mean (CV%) linear clearance was estimated to be 225 (25%) mL/day, based on population PK modelling. The geometric mean (CV%) terminal half-life associated with linear clearance, derived based on population PK parameter estimates, was 15.7 (26%) days, following administration of the recommended dose of Rybrevant as monotherapy.

Special populations

Elderly

No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (32–87 years).

Renal impairment

No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patients with mild (60 < creatinine clearance [CrCl] < 90 mL/min) and moderate (29 < CrCl < 60 mL/min) renal impairment. The effect of severe renal impairment (15 < CrCl < 29 mL/min) on amivantamab pharmacokinetics is unknown.

Hepatic impairment

Changes in hepatic function are unlikely to have any effect on the elimination of amivantamab since IgG1-based molecules such as amivantamab are not metabolised through hepatic pathways.

No clinically meaningful effect in the pharmacokinetics of amivantamab was observed based on mild hepatic impairment [(total bilirubin < ULN and AST > ULN) or (ULN < total bilirubin < 1.5 x ULN)]. The effect of moderate (total bilirubin 1.5 to 3 times ULN) and severe (total bilirubin > 3 times ULN) hepatic impairment on amivantamab pharmacokinetics is unknown.

Paediatric population

The pharmacokinetics of Rybrevant in paediatric patients have not been investigated.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

Carcinogenicity and mutagenicity

No animal studies have been performed to establish the carcinogenic potential of amivantamab. Routine genotoxicity and carcinogenicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material.

Reproductive toxicology

No animal studies have been conducted to evaluate the effects on reproduction and foetal development; however, based on its mechanism of action, amivantamab can cause foetal harm or developmental anomalies. As reported in the literature, reduction, elimination, or disruption of embryo foetal or maternal EGFR signaling can prevent implantation, cause embryo foetal loss during various stages of gestation (through effects on placental development), cause developmental anomalies in multiple organs or early death in surviving foetuses. Similarly, knock out of MET or its ligand hepatocyte growth factor (HGF) was embryonic lethal due to severe defects in placental development, and foetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to the developing foetus.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Ethylenediami­netetraacetic acid (EDTA) disodium salt dihydrate L-Histidine

L-Histidine hydrochloride monohydrate

L-Methionine

Polysorbate 80 (E433)

Sucrose

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Unopened vial

24 months

After dilution

Chemical and physical in-use stability has been demonstrated for 10 hours at 15°C to 25°C in room light. From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

7 mL concentrate in a Type 1 glass vial with an elastomeric closure and aluminium seal with a flip-off cap containing 350 mg amivantamab. Pack size of 1 vial.

6.6 Special precautions for disposal and other handling

Prepare the solution for intravenous infusion using aseptic technique as follows:

Preparation

• •     Determine the dose required (either 1,050 mg for patients < 80 kg or 1,400 mg for patients

> 80 kg) and the number of Rybrevant vials needed based on patient’s baseline weight (see section 4.2). Each vial contains 350 mg of amivantamab.

• • Check that the Rybrevant solution is colourless to pale yellow. Do not use if discolouration or

visible particles are present.

• • Withdraw and then discard a volume of either 5% glucose solution or sodium chloride 9 mg/mL

(0.9%) solution for injection from the 250 mL infusion bag that is equal to the required volume of Rybrevant solution to be added (discard 7 mL diluent from the infusion bag for each vial). Infusion bags must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).

• • Withdraw 7 mL of Rybrevant from each vial needed then add it to the infusion bag. Each vial

contains a 0.5 mL overfill to ensure sufficient extractable volume. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.

• • Gently invert the bag to mix the solution. Do not shake.
• • Visually inspect for particulate matter and discolouration prior to administration. Do not use if

discolouration or visible particles are observed.

Administration

• • Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow

regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.

• • Do not infuse Rybrevant concomitantly in the same intravenous line with other agents.
• • The diluted solution should be administered within 10 hours (including infusion time) at room

temperature (15°C to 25°C) and in room light.

• • Due to the frequency of IRRs at the first dose, amivantamab should be infused via a peripheral

vein at Week 1 and Week 2; infusion via a central line may be administered for subsequent weeks when the risk of IRR is lower. See infusion rates in section 4.2.

Disposal

This medicinal product is for single use only and any unused medicinal product that is not administered within 10 hours should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1594/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION