Leaflet RYBREVANT 1600mg concentrate for solution for infusion
Indicated for: non-small cell lung cancer
Route of administration: infusion
Substance: amivantamab (monoclonal antibody)
ATC: L01FX18 (Antineoplastic and immunomodulating agents | Monoclonal antibodies and antibody drug conjugates | Other monoclonal antibodies and antibody drug conjugates)
Risk of severe allergic reaction. Seek urgent medical help if serious symptoms occur.
This medicine is subject to additional monitoring.
Use during breastfeeding only on medical advice.
Use during pregnancy only on medical advice.
Amivantamab is a monoclonal antibody used in the treatment of non-small cell lung cancer (NSCLC) with mutations in the EGFR (epidermal growth factor receptor) gene. It works by binding to EGFR and MET receptors, thereby inhibiting cellular signaling that promotes cancer cell growth and survival.
Amivantamab is administered intravenously, typically once a week during the initial weeks of treatment, followed by less frequent administrations as per the protocol established by the physician. The treatment is particularly indicated for patients with EGFR exon 20 mutations, which are resistant to other targeted therapies.
Common side effects include infusion-related reactions, skin rashes, diarrhea, nausea, and fatigue. In rare cases, severe reactions such as pneumonitis or liver toxicity may occur.
Patients receiving amivantamab should be closely monitored for adverse reactions and treatment efficacy. It is essential that the treatment is administered under the supervision of an oncologist experienced in targeted therapies. Amivantamab represents a promising option for patients with advanced NSCLC, offering a chance to control the disease in cases with specific genetic mutations.
General data about RYBREVANT 1600mg
- Substance: amivantamab
- Date of latest medicines list: 01-06-2026
- Product code: W71435001
- Concentration: 1600mg
- Pharmaceutical form: concentrate for solution for infusion
- Quantity: 1
- Product type: Original
- Price: 23834.00 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for amivantamab
Concentrations available for amivantamab
- 1600mg
- 2240mg
- 2400mg
- 350mg
- 3520mg
Leaflet RYBREVANT 1600mg
Contents of the package leaflet for the medicine RYBREVANT 1600mg concentrate for solution for infusion
1. NAME OF THE MEDICINAL PRODUCT
Rybrevant 1600 mg solution for injection
Rybrevant 2240 mg solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Rybrevant 1600 mg solution for injection
One mL of solution for injection contains 160 mg amivantamab.
One 10 mL vial of solution for injection contains 1600 mg of amivantamab.
Rybrevant 2240 mg solution for injection
One mL of solution for injection contains 160 mg amivantamab.
One 14 mL vial of solution for injection contains 2240 mg of amivantamab.
Amivantamab is a fully-human Immunoglobulin G1 (IgG1)-based bispecific antibody directed againstthe epidermal growth factor (EGF) and mesenchymal-epidermal transition (MET) receptors, producedby a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.
Excipient with known effect:One mL of solution contains 0.6 mg of polysorbate 80.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
The solution is colourless to pale yellow.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Rybrevant subcutaneous formulation is indicated:
- in combination with lazertinib for the first-line treatment of adult patients with advancednon-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858Rsubstitution mutations.
- as monotherapy for treatment of adult patients with advanced NSCLC with activating EGFR
Exon 20 insertion mutations, after failure of platinum-based therapy.
4.2 Posology and method of administration
Treatment with Rybrevant subcutaneous formulation should be initiated and supervised by a physicianexperienced in the use of anticancer medicinal products.
Before initiation of Rybrevant subcutaneous formulation, EGFR mutation status in tumour tissue orplasma specimens must be established using a validated test method. If no mutation is detected in aplasma specimen, tumour tissue should be tested if available in sufficient amount and quality due tothe potential for false negative results using a plasma-test. Once EGFR mutation status has beenestablished, testing does not need to be repeated (see section 5.1).
Rybrevant subcutaneous formulation should be administered by a healthcare professional with accessto appropriate medical support to manage administration-related reactions if they occur.
PosologyPremedications should be administered to reduce the risk of administration-related reactions with
Rybrevant subcutaneous formulation (see below “Dose modifications” and “Recommendedconcomitant medicinal products”).
The recommended dosages of Rybrevant subcutaneous formulation in combination with lazertinib oras monotherapy based on baseline body weight, are provided in Table 1.
Table 1: Recommended dosage of Rybrevant subcutaneous formulation
Body weight at baseline* Recommended Dosing scheduledose
Less than 80 kg 1600 mg - Weekly (total of 4 doses) from Weeks 1 to 4
- Every 2 weeks starting at Week 5 onwards
Greater than or equal to 2240 mg - Weekly (total of 4 doses) from Weeks 1 to 480 kg - Every 2 weeks starting at Week 5 onwards
* Dose adjustments not required for subsequent body weight changes.
When given in combination with lazertinib, it is recommended to administer Rybrevant subcutaneousformulation any time after lazertinib when given on the same day. Refer to section 4.2 of the lazertinib
Summary of Product Characteristics for recommended lazertinib dosing information.
Duration of treatmentIt is recommended that patients are treated with Rybrevant subcutaneous formulation until diseaseprogression or unacceptable toxicity.
Missed doseIf a dose of Rybrevant subcutaneous formulation is missed between Weeks 1 to 4, it should beadministered within 24 hours. If a dose of Rybrevant subcutaneous formulation is missed from Week 5onward, it should be administered within 7 days. Otherwise, the missed dose should not beadministered and the next dose should be administered per the usual dosing schedule.
Dose modificationsDosing 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 interruptionis longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 2. See alsospecific dose modifications for specific adverse reactions below Table 2.
If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product
Characteristics for information about dose modifications.
Table 2: Recommended dose modifications for adverse reactions
Dose* Dose after 1st Dose after 2nd Dose after 3rdinterruption for adverse interruption for adverse interruption for adversereaction reaction reaction1600 mg 1050 mg 700 mg Discontinue Rybrevant2240 mg 1600 mg 1050 mg subcutaneous formulation
* Dose at which the adverse reaction occurred
Administration-related reactions
Premedications should be administered to reduce the risk of administration-related reactions with
Rybrevant subcutaneous formulation (see “Recommended concomitant medicinal products”).
Injections should be interrupted at the first sign of administration-related reactions. Additionalsupportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics andantiemetics) should be administered as clinically indicated (see section 4.4).
- Grade 1-3 (mild-severe): Upon recovery of symptoms, resume Rybrevant subcutaneousformulation injections. Concomitant medicinal products should be administered at the nextdose, including dexamethasone (20 mg) or equivalent (see Table 3).
- Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant.
Venous thromboembolic (VTE) events with concomitant use with lazertinib
At the initiation of treatment, prophylactic anticoagulants should be administered to prevent VTEevents in patients receiving Rybrevant subcutaneous formulation in combination with lazertinib.
Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct actingoral anticoagulant (DOAC) or a low‑molecular weight heparin (LMWH). Use of Vitamin Kantagonists is not recommended.
For VTE events associated with clinical instability (e.g., respiratory failure or cardiac dysfunction),both drugs should be withheld until the patient is clinically stable. Thereafter, both medicinal productscan be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation,discontinue Rybrevant. Treatment can continue with lazertinib at the same dose (see section 4.4).
Skin and nail reactions
Prophylactic therapy with oral and topical antibiotics is recommended to reduce the risk and severityof skin and nail reactions in patients receiving Rybrevant. Non-comedogenic skin moisturiser(ceramide-based or other formulations that provide long lasting skin hydration and exclude dryingagents are preferred) on the face and whole body (except scalp) and chlorhexidine solution to washhands and feet is also recommended. Patients should be instructed to limit sun exposure during and for2 months after Rybrevant therapy. For further information about prophylaxis for skin and nailreactions, see section 4.4.
If the patient develops a Grade 1-2 skin or nail reaction, supportive care should be initiated asclinically indicated; if there is no improvement after 2 weeks, dose reduction should be considered forpersistent Grade 2 rash (see Table 2). If the patient develops a Grade 3 skin or nail reaction, supportivecare should be initiated as clinically indicated, and interruption of Rybrevant subcutaneousformulation should be considered until the adverse reaction improves. Upon recovery of the skin ornail reaction to ≤ Grade 2, Rybrevant subcutaneous formulation should be resumed at a reduced dose.
If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see section 4.4).
Interstitial lung diseaseRybrevant subcutaneous formulation should be withheld if interstitial lung disease (ILD) or ILD-likeadverse reactions (pneumonitis) is suspected. If the patient is confirmed to have ILD or ILD-likeadverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4).
Recommended concomitant medicinal products
Prior to the initial dose (Week 1, Day 1), antihistamines, antipyretics, and glucocorticoids should beadministered to reduce the risk of administration-related reactions (see Table 3). For subsequent doses,antihistamines and antipyretics are required to be administered. Glucocorticoids should also bere-initiated after prolonged dose interruptions. Antiemetics should be administered as needed.
Table 3: Dosing schedule of premedications
Premedication Dose Route of Recommended dosingadministration window prior to
Rybrevant subcutaneousformulationadministration
Antihistamine* Diphenhydramine (25 to Intravenous 15 to 30 minutes50 mg) or equivalent Oral 30 to 60 minutes
Antipyretic* Paracetamol/Acetaminophen Intravenous 15 to 30 minutes(650 to 1000 mg) or Oral 30 to 60 minutesequivalent
Glucocorticoid† Dexamethasone (20 mg) or Intravenous 45 to 60 minutesequivalent Oral At least 60 minutes
Glucocorticoid‡ Dexamethasone (10 mg) or Intravenous 45 to 60 minutesequivalent Oral 60 to 90 minutes
* Required at all doses.† Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an administration-relatedreaction.‡ Optional for subsequent doses.
Special populationsPaediatric population
There is no relevant use of amivantamab in the paediatric population in the treatment of NSCLC.
ElderlyNo dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2).
Renal impairmentNo formal studies of amivantamab in patients with renal impairment have been conducted. Based onpopulation pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild ormoderate renal impairment. Caution is required in patients with severe renal impairment asamivantamab 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 recommendationsabove.
Hepatic impairmentNo formal studies of amivantamab in patients with hepatic impairment have been conducted. Based onpopulation 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 notbeen studied in this patient population (see section 5.2). If treatment is started, patients should bemonitored for adverse reactions with dose modifications per the recommendations above.
Method of administrationRybrevant solution for injection is for subcutaneous use only.
Rybrevant subcutaneous formulation is not intended for intravenous administration and should begiven by subcutaneous injection only, using the doses specified. See section 6.6 for instructions onhandling of the medicinal product before administration.
Inject the required volume of Rybrevant subcutaneous formulation into the subcutaneous tissue of theabdomen over approximately 5 minutes. Do not administer at other sites of the body as no data areavailable.
Pause or slow delivery rate if the patient experiences pain. In the event pain is not alleviated bypausing or slowing down delivery rate, a second injection site may be chosen on the opposite side ofthe abdomen to deliver the remainder of the dose.
If administering with a subcutaneous infusion set, ensure that the full dose is delivered through theinfusion set. Sodium chloride 9 mg/mL (0.9%) solution may be utilised to flush remaining medicinalproduct through the line.
Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, not intact orwithin 5 cm around the periumbilical area.
Injection sites should be rotated for successive injections.
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
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
Administration-related reactions
Administration-related reactions occurred in patients treated with Rybrevant subcutaneous formulation(see section 4.8).
Prior to the initial injection (Week 1 Day 1), antihistamines, antipyretics, and glucocorticoids shouldbe administered to reduce the risk of administration-related reactions. For subsequent doses,antihistamines and antipyretics should be administered.
Patients should be treated in a setting with appropriate medical support to treat administration-relatedreactions. At the first sign of administration-related reactions of any severity, injections should beinterrupted, if ongoing, and post-injection medicinal products should be administered as clinicallyindicated. Upon resolution of symptoms, the injection should be resumed. For Grade 4 or recurrent
Grade 3 administration-related reactions, Rybrevant should be permanently discontinued (seesection 4.2).
Interstitial lung diseaseInterstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported inpatients treated with amivantamab, including fatal events (see section 4.8). Patients should bemonitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptomsdevelop, 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 beinitiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILDor ILD-like adverse reactions (see section 4.2).
Venous thromboembolic (VTE) events with concomitant use with lazertinib
In patients receiving amivantamab in combination with lazertinib, VTE events, including deep veinthrombosis (DVT) and pulmonary embolism (PE), were reported (see section 4.8). Fatal events wereobserved with amivantamab intravenous formulation.
Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct actingoral anticoagulant (DOAC) or a low molecular weight heparin (LMWH). Use of Vitamin Kantagonists is not recommended.
Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treatedwith 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 beresumed 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, dry skin, and skin ulcer occurred in patients treatedwith amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for2 months after Rybrevant therapy. Protective clothing and use of broad-spectrum UVA/UVBsunscreen are advisable. A prophylactic approach to rash prevention is recommended. This includesprophylactic therapy, at treatment initiation, 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 oralantibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin 1%) for the next 9 months oftreatment. Non‑comedogenic skin moisturiser (ceramide-based or other formulations that providelong-lasting skin hydration and exclude drying agents are preferred) on the face and whole body(except scalp) and chlorhexidine solution to wash hands and feet is recommended beginning on Day 1and continued for the duration of treatment.
Prescriptions for topical and/or oral antibiotics and topical corticosteroids are recommended to beavailable at the time of initial dosing to minimise any delay in reactive management should rashdevelop despite prophylactic treatment. If skin reactions develop, supportive care, topicalcorticosteroids and topical and/or oral antibiotics should be administered. For Grade 3 orpoorly-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 lackimprovement within 2 weeks should be referred promptly to a dermatologist. Rybrevant should bedose 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 bediscontinued if TEN is confirmed.
Eye disordersEye 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 ophthalmologistand 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 contentThis medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially“sodium-free” (see section 6.6).
Polysorbate content
This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 6 mg per10 mL vial, or 8.4 mg per 14 mL vial. Polysorbates may cause hypersensitivity reactions.
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 excretionand hepatic enzyme-mediated metabolism of intact amivantamab are unlikely to be major eliminationroutes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination ofamivantamab. Due to the high affinity to a unique epitope on EGFR and MET, amivantamab is notanticipated to alter drug-metabolising enzymes.
Vaccines
No clinical data are available on the efficacy and safety of vaccinations in patients takingamivantamab. 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 aftercessation of amivantamab treatment.
PregnancyThere are no human data to assess the risk of amivantamab use during pregnancy. No animalreproductive 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 ofembryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism ofaction and findings in animal models, amivantamab could cause foetal harm when administered to apregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatmentof the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnantwhile taking this medicinal product, the patient should be informed of the potential risk to the foetus(see section 5.3).
Breast-feedingIt is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, which is decreasing to low concentrations soonafterwards. 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 notabsorbed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom amivantamab therapy taking into account the benefit of breast-feeding for the child and thebenefit of therapy for the woman.
FertilityThere are no data on the effect of amivantamab on human fertility. Effects on male and female fertilityhave 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 seesection 4.8 (e.g., dizziness, fatigue, visual impairment). If patients experience treatment-relatedsymptoms, including vision-related adverse reactions, affecting their ability to concentrate and react, itis recommended that they do not drive or use machines until the effect subsides.
4.8 Undesirable effects
Rybrevant as monotherapy
In the dataset of Rybrevant intravenous formulation as monotherapy (N=380), the most frequentadverse reactions in all grades were rash (76%), infusion-related reactions (67%), nail toxicity (47%),hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%), andconstipation (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 adversereactions leading to treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%).
Tabulated list of adverse reactionsTable 4 summarises the adverse drug reactions that occurred in patients receiving Rybrevant asmonotherapy.
The data reflects exposure to Rybrevant intravenous formulation in 380 patients with locally advancedor metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patientsreceived amivantamab 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg). The medianexposure 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. Frequencycategories 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 (frequencycannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in the order of decreasingseriousness.
Table 4: Adverse reactions in patients receiving Rybrevant as monotherapy (N=380)
System organ class Frequency Any grade Grade 3-4
Adverse reaction category (%) (%)
Metabolism and nutrition disordersHypoalbuminaemia* (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 disordersDizziness* Very common 13 0.3†
Eye disordersVisual impairment* Common 3 0
Growth of eyelashes* 1 0
Other eye disorders* 6 0
Keratitis Uncommon 0.5 0
Uveitis 0.3 0
Respiratory, thoracic and mediastinal disordersInterstitial lung disease* Common 3 0.5†
Gastrointestinal disordersDiarrhoea 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 disordersAlanine aminotransferase increased Very common 15 2
Aspartate aminotransferase increased 13 1
Blood alkaline phosphatase increased 12 0.5†
Skin and subcutaneous tissue disordersRash* Very common 76 3†
Nail toxicity* 47 2†
Dry skin* 19 0
Pruritus 18 0
Skin ulcer Uncommon 0.8 0
Toxic epidermal necrolysis 0.3 0.3†
Musculoskeletal and connective tissue disordersMyalgia Very common 11 0.3†
General disorders and administration site conditionsOedema* Very common 26 0.8†
Fatigue* 26 0.8†
Pyrexia 11 0
Injury, poisoning and procedural complicationsInfusion-related reaction Very common 67 2
* Grouped terms† Grade 3 events only
Rybrevant in combination with lazertinib
Overall, the safety profile of Rybrevant subcutaneous formulation was consistent with the establishedsafety profile of Rybrevant intravenous formulation, with a lower incidence of administration-relatedreactions and VTEs observed with the subcutaneous formulation compared to the intravenousformulation.
In the dataset of Rybrevant (either intravenous or subcutaneous formulations) in combination withlazertinib (N=752), the most frequent adverse reactions of any grade (≥ 20% patients) were rash(87%), nail toxicity (67%), hypoalbuminaemia (48%), hepatotoxicity (43%), stomatitis (43%), oedema(42%), fatigue (35%), paraesthesia (29%), constipation (26%), diarrhoea (26%), dry skin (25%),decreased appetite (24%), nausea (24%), and pruritus (23%).
Clinically relevant differences between the intravenous and subcutaneous formulations, when given incombination with lazertinib, were observed for administration-related reactions (63% for intravenousvs. 14% for subcutaneous) and VTE (37% for intravenous vs. 11% for subcutaneous).
Serious adverse reactions were reported in 14% of patients who received Rybrevant subcutaneousformulation in combination with lazertinib, including ILD (4.2%), VTE (2.7%), hepatotoxicity (2.1%),and fatigue (1.5%). Seven percent of patients discontinued Rybrevant subcutaneous formulation due toadverse reactions. In patients treated with Rybrevant subcutaneous formulation in combination withlazertinib, the most frequent adverse reactions of any grade (≥ 1% patients) leading to discontinuationof Rybrevant subcutaneous formulation were ILD (3.6%) and rash (1.5%).
Tabulated list of adverse reactionsThe adverse reactions for Rybrevant (either intravenous or subcutaneous formulation) when receivedin combination with lazertinib are summarised in Table 5.
The safety data below reflect exposure to Rybrevant (either intravenous or subcutaneous formulation)in combination with lazertinib in 752 patients with locally advanced or metastatic NSCLC, including421 patients in MARIPOSA, 125 patients in PALOMA-2 cohorts 1 and 6, and 206 patients in
PALOMA-3 subcutaneous arm. Patients received Rybrevant (either intravenous or subcutaneousformulation) until disease progression or unacceptable toxicity. The median duration of treatment withamivantamab overall for both intravenous and subcutaneous formulations was 9.9 months (range: 0.1to 31.4 months). Median duration on treatment for the subcutaneous formulation was 5.7 months(range: 0.1 to 13.2 months) while median duration on treatment for the intravenous formulation was18.5 months (range: 0.2 to 31.4 months).
Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories 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 (frequencycannot be estimated from the available data).
Table 5: Adverse reactions for Rybrevant (either intravenous or subcutaneous formulation)when received in combination with lazertinib (N=752)
System Organ Class Frequency Any grade Grade 3-4
Adverse Reaction category (%) (%)
Metabolism and nutrition disordersHypoalbuminaemia* Very common 48 4.5
Decreased appetite 24 0.8
Hypocalcaemia 19 1.2
Hypokalaemia 13 2.7
Hypomagnesaemia Common 6 0
Nervous system disordersParaesthesia*, a Very common 29 1.3
Dizziness* 12 0
Eye disordersOther eye disorders* Very common 19 0.5
Visual impairment* Common 3.6 0
Keratitis 1.7 0.3
Growth of eyelashes* 1.7 0
Vascular disordersVenous thromboembolism
Amivantamab intravenous*, b Very common 37 11
Amivantamab subcutaneous*, c Very common 11 0.9
Respiratory, thoracic, and mediastinal disorders
Interstitial lung disease* Common 3.6 1.7
Gastrointestinal disordersStomatitis* Very common 43 2.0
Constipation 26 0
Diarrhoea 26 1.7
Nausea 24 0.8
Vomiting 15 0.5
Abdominal pain* 10 0.1
Haemorrhoids Common 8 0.1
Hepatobiliary disordersHepatotoxicity* Very common 43 7
Skin and subcutaneous tissue disordersRash* Very common 87 23
Nail toxicity* 67 8
Dry skin* 25 0.7
Pruritus 23 0.3
Skin ulcer Common 3.9 0.5
Palmar-plantar erythrodysaesthesia syndrome 3.9 0.1
Urticaria 1.6 0
Musculoskeletal and connective tissue disordersMyalgia Very common 15 0.5
Muscle spasms 13 0.4
General disorders and administration site conditionsOedema* Very common 42 2.7
Fatigue* 35 3.5
Pyrexia 11 0
Injection site reactions*, c, d Common 8 0
Injury, poisoning, and procedural complications
Infusion-/Administration-related reactions
Amivantamab intravenousb, e Very common 63 6
Amivantamab subcutaneousc, f Very common 14 0.3
* Grouped terms.a Applicable only to lazertinib.b Frequency based on amivantamab intravenous study only (MARIPOSA [N=421]).c Frequency based on amivantamab subcutaneous studies only (PALOMA-2 cohorts 1 and 6 [N=125] and PALOMA-3subcutaneous arm [N=206]).d Injection site reactions are local signs and symptoms associated with subcutaneous mode of administration.e Infusion-related reactions are systemic signs and symptoms associated with infusion of amivantamab intravenous.f Administration-related reactions are systemic signs and symptoms associated with administration of amivantamabsubcutaneous.
Description of selected adverse reactionsAdministration-related reactions
Overall, administration-related reactions occurred in 14% of patients treated with Rybrevantsubcutaneous formulation in combination with lazertinib. In PALOMA-3, administration-relatedreactions were reported in 13% of patients treated with Rybrevant subcutaneous formulation incombination with lazertinib compared to 66% when treated with Rybrevant intravenous formulation incombination with lazertinib. The most frequent signs and symptoms of administration-relatedreactions include dyspnoea, flushing, fever, chills, nausea, and chest discomfort. Median time to onsetof first administration-related reactions was 2.1 hours (range: 0.0 to 176.5 hours). Mostadministration-related reactions (98%) were Grades 1 or 2 in severity.
Injection site reactionsOverall, injection site reactions occurred in 8% of patients treated with Rybrevant subcutaneousformulation in combination with lazertinib. All injection site reactions were Grade 1 or 2 in severity.
The most frequent symptom of injection site reactions was erythema.
Interstitial lung diseaseInterstitial lung disease (ILD) or ILD-like adverse reactions have been reported with the use ofamivantamab as well as with other EGFR inhibitors. ILD was reported in 3.6% of patients treated with
Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib, including2 (0.3%) patients with a fatal reaction. Patients with a medical history of ILD, including drug-induced
ILD or radiation pneumonitis, were excluded from PALOMA-2 and PALOMA-3.
Venous thromboembolic (VTE) events with concomitant use with lazertinib
VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), were reportedin 11% of patients receiving Rybrevant subcutaneous formulation in combination with lazertinib in
PALOMA-2 and PALOMA-3. Most cases were Grade 1 or 2, with Grade 3 events occurring in3 (0.9%) patients. Additionally, 269 (81%) of these 331 patients receiving Rybrevant subcutaneousformulation took prophylactic anticoagulants with a direct oral anticoagulant or low molecular weightheparin within the first four months of study treatment. In PALOMA-3, the incidence of VTEreactions was 9% for patients treated with Rybrevant subcutaneous formulation in combination withlazertinib, compared to 13% when treated with Rybrevant intravenous formulation in combinationwith lazertinib, with similar rates of prophylactic anticoagulant use in both treatment arms (80% in thesubcutaneous arm vs. 81% in the intravenous arm). For patients who did not receive prophylacticanticoagulants, the overall incidence of VTE was 17% for patients treated with Rybrevantsubcutaneous formulation in combination with lazertinib with all VTE reactions reported as Grade 1-2and serious VTE reactions reported in 4.8% of these patients, compared to an overall incidence of 23%for patients treated with Rybrevant intravenous formulation in combination with lazertinib with
Grade 3 VTE reactions reported in 10% and serious VTE reactions reported in 8% of these patients.
Skin and nail reactions
Rash (including dermatitis acneiform), pruritus, and dry skin have occurred in patients treated with
Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib. Rashoccurred in 87% of patients, leading to discontinuation of Rybrevant in 0.7% of patients. Most caseswere Grade 1 or 2, with Grade 3 and Grade 4 reactions occurring in 23% and 0.1% of patients,respectively.
A Phase 2 study in patients treated with Rybrevant in combination with lazertinib was conducted toassess the use of prophylactic therapy with an oral antibiotic, a topical antibiotic on the scalp, amoisturiser on the face and whole body (except scalp), and an antiseptic on hands and feet (seesections 4.2 and 4.4). A reduction in the incidence of ≥ Grade 2 dermatologic adverse events duringthe first 12 weeks of treatment was demonstrated, compared with the standard dermatologicmanagement used in clinical practice (38.6% vs. 76.5%, p<0.0001). In addition, there was a reductionin ≥ Grade 2 adverse events involving the scalp in the first 12 weeks of treatment (8.6% vs. 29.4%)along with lower incidence of dose reductions (7.1% vs. 19.1%), interruptions (15.7% vs. 33.8%), andtreatment discontinuations (1.4% vs. 4.4%) due to dermatological adverse events.
Eye disordersEye disorders, including keratitis (1.7%), occurred in patients treated with Rybrevant (eitherintravenous or subcutaneous formulation). Other reported adverse reactions included growth ofeyelashes, visual impairment, and other eye disorders.
Special populationsElderly
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.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is no information on overdose with Rybrevant subcutaneous formulation and no known specificantidote for overdose. In the event of an overdose, treatment with Rybrevant should be stopped, thepatient should be monitored for any signs or symptoms of adverse events and appropriate generalsupportive measures should be instituted immediately until clinical toxicity has diminished orresolved.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code:
L01FX18.
Rybrevant subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20).rHuPH20 works locally and transiently to degrade hyaluronan ((HA), a naturally occurringglycoaminoglycan found throughout the body) in the extracellular matrix of the subcutaneous space bycleaving the linkage between the two sugars (N-acetylglucosamine and glucuronic acid), whichcomprise HA.
Mechanism of actionAmivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immunecell-directing activity that targets tumours with activating EGFR mutations such as Exon 19 deletions,
Exon 21 L858R substitution and Exon 20 insertion mutations. Amivantamab binds to the extracellulardomains of EGFR and MET.
Amivantamab disrupts EGFR and MET signalling functions through blocking ligand binding andenhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. Thepresence of EGFR and MET on the surface of tumour cells also allows for targeting of these cells fordestruction by immune effector cells, such as natural killer cells and macrophages, throughantibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.
Pharmacodynamic effectsAfter the first full dose of Rybrevant subcutaneous formulation, mean serum EGFR and METconcentrations decreased substantially and remained suppressed for the duration of treatment for allstudied doses.
Albumin
Rybrevant subcutaneous formulation decreased serum albumin concentration, a pharmacodynamiceffect of MET inhibition, typically during the first 8 weeks (see section 4.8); thereafter, albuminconcentration stabilised for the remainder of amivantamab treatment.
Clinical experience of Rybrevant subcutaneous formulation
The efficacy of Rybrevant subcutaneous formulation in patients with EGFR-mutated locally advancedor metastatic NSCLC is based on achieving non-inferior PK exposure to intravenous amivantamab inthe non-inferiority study PALOMA-3 (see section 5.2). The study demonstrated non-inferior efficacyof subcutaneous to intravenous amivantamab given in combination with lazertinib in patients with
EGFR-mutated locally advanced or metastatic NSCLC whose disease has progressed on or aftertreatment with osimertinib and platinum-based chemotherapy.
Clinical experience of Rybrevant intravenous formulation
Previously-untreated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations(MARIPOSA)
NSC3003 (MARIPOSA) is a randomised, open-label, active-controlled, multicentre phase 3 studyassessing the efficacy and safety of Rybrevant intravenous formulation in combination with lazertinibas compared to osimertinib monotherapy as first-line treatment in patients with EGFR-mutated locallyadvanced or metastatic NSCLC not amenable to curative therapy. Patient samples were required tohave one of the two common EGFR mutations (Exon 19 deletion or Exon 21 L858R substitutionmutation), as identified by local testing. Tumour tissue (94%) and/or plasma (6%) samples for allpatients were tested locally to determine EGFR Exon 19 deletion and/or Exon 21 L858R substitutionmutation status using polymerase chain reaction (PCR) in 65% and next generation sequencing (NGS)in 35% of patients.
A total of 1074 patients were randomised (2:2:1) to receive Rybrevant intravenous formulation incombination with lazertinib, osimertinib monotherapy, or lazertinib monotherapy until diseaseprogression or unacceptable toxicity. Rybrevant intravenous formulation was administeredintravenously at 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) once weekly for4 weeks, then every 2 weeks thereafter starting at week 5. Lazertinib was administered at 240 mgorally once daily. Osimertinib was administered at a dose of 80 mg orally once daily. Randomisationwas stratified by EGFR mutation type (Exon 19 deletion or Exon 21 L858R), race (Asian ornon-Asian), and history of brain metastasis (yes or no).
Baseline demographics and disease characteristics were balanced across the treatment arms. Themedian age was 63 (range: 25-88) years with 45% of patients ≥ 65 years; 62% were female; and 59%were Asian, and 38% were White. Baseline Eastern Cooperative Oncology Group (ECOG)performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and90% had Stage IV cancer at initial diagnosis. With regard to EGFR mutation status, 60% were
Exon 19 deletions and 40% were Exon 21 L858R substitution mutations.
Rybrevant intravenous formulation in combination with lazertinib demonstrated a statisticallysignificant improvement in progression-free survival (PFS) by BICR assessment.
The final analysis of OS demonstrated a statistically significant improvement in OS for Rybrevantintravenous formulation in combination with lazertinib compared to osimertinib (see Table 6 and
Figure 2).
Table 6: Efficacy results in MARIPOSA
Rybrevant intravenousformulation + lazertinib Osimertinib(N=429) (N=429)
Progression-free survival (PFS)a
Number of events 192 (45%) 252 (59%)
Median, months (95% CI) 23.7 (19.1, 27.7) 16.6 (14.8, 18.5)
Hazard Ratio (95% CI); p-value 0.70 (0.58, 0.85); p=0.0002
Overall survival (OS)
Number of events 173 (40%) 217 (51%)
Median, months (95% CI) NE (42.9, NE) 36.7 (33.4, 41.0)
Hazard Ratio (95% CI); p-value 0.75 (0.61, 0.92); p=0.0048
Objective response rate (ORR)a,b
ORR % (95% CI) 80% (76%, 84%) 77% (72%, 81%)
Duration of response (DOR)a,b
Median (95% CI), months 25.8 (20.3, 33.9) 18.1 (14.8, 20.1)
BICR = blinded independent central review; CI = confidence interval; NE = not estimable
PFS results are from data cut-off 11 August 2023 with a median follow-up of 22.0 months. DOR and ORR results arefrom data cut-off 13 May 2024 with a median follow-up of 31.3 months. OS results are from data cut-off 04 December2024 with a median follow-up of 37.8 months.a BICR by RECIST v1.1.b Based on confirmed responders.
Figure 1: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICRassessment
Figure 2: Kaplan-Meier curve of OS in previously untreated NSCLC patients
Intracranial ORR and DOR by BICR were pre-specified endpoints in MARIPOSA. In the subset ofpatients with intracranial lesions at baseline, the combination of Rybrevant intravenous formulationand lazertinib, demonstrated similar intracranial ORR to the control. Per protocol, all patients in
MARIPOSA had serial brain MRIs to assess intracranial response and duration. Results aresummarised in Table 7.
Table 7: Intracranial ORR and DOR by BICR assessment in subjects with intracraniallesions at baseline - MARIPOSA
Rybrevant intravenousformulation + lazertinib Osimertinib(N=180) (N=186)
Intracranial tumour response assessment
Intracranial ORR (CR+PR), % 78% 77%(95% CI) (71%, 84%) (71%, 83%)
Complete response 64% 59%
Intracranial DOR
Number of responders 140 144
Median, months (95% CI) 35.0 (20.4, NE) 25.1 (22.1, 31.2)
CI = confidence interval
NE = not estimable
Intracranial ORR and DOR results are from data cut-off 04 Dec 2024 with a median follow-up of 37.8 months.
Previously-treated non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations(CHRYSALIS)
CHRYSALIS is a multicentre, open-label, multi-cohort study conducted to assess the safety andefficacy of Rybrevant intravenous formulation 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%) samplesfor all patients were tested locally to determine EGFR Exon 20 insertion mutation status using nextgeneration sequencing (NGS) in 46% of patients and/or polymerase chain reaction (PCR) in 41% ofpatients; for 4% of patients, the testing methods were not specified. Patients with untreated brainmetastases or a history of ILD requiring treatment with prolonged steroids or otherimmunosuppressive agents within the last 2 years were not eligible for the study. Rybrevantintravenous formulation was administered intravenously at 1050 mg for patients < 80 kg or 1400 mgfor patients ≥ 80 kg once weekly for 4 weeks, then every 2 weeks starting at Week 5 until loss ofclinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessedoverall 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 independentcentral 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% werefemale; and 52% were Asian and 37% were White. The median number of prior therapies was2 (range: 1 to 7 therapies). At baseline, 29% had ECOG performance status of 0 and 70% had ECOGperformance status of 1; 57% never smoked; 100% had Stage IV cancer; and 25% had previoustreatment for brain metastases. Insertions in Exon 20 were observed at 8 different residues; the mostcommon residues were A767 (22%), S768 (16%), D770 (12%), and N771 (11%).
Efficacy results are summarised in Table 8.
Table 8: Efficacy results in CHRYSALIS
Investigator assessment(N=114)
Overall response ratea, 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 intervala Confirmed responseb 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 assessmentwas 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.
ImmunogenicityAnti-drug antibodies (ADA) were uncommonly detected after treatment with Rybrevant subcutaneousformulation. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
Among the 389 participants who received Rybrevant subcutaneous formulation as monotherapy or aspart of combination therapy, 37 participants (10%) were positive for treatment-emergent antibodies torHuPH20. The immunogenicity to rHuPH20 observed in these participants did not impact thepharmacokinetics of amivantamab.
ElderlyNo overall differences in effectiveness were observed between patients ≥ 65 years of age and patients< 65 years of age.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with
Rybrevant in all subsets of the paediatric population in NSCLC (see section 4.2 for information onpaediatric use).
5.2 Pharmacokinetic properties
Following subcutaneous administration, the geometric mean (%CV) of amivantamab bioavailability is66.6% (14.9%) with a median time to reach maximum concentration of 3 days, based on the individualamivantamab PK parameter estimates for participants receiving subcutaneous administration in thepopulation PK analysis.
For the every 2-week subcutaneous dosing regimen, the geometric mean (%CV) maximum troughconcentration of amivantamab after the 4th weekly dose was 335 µg/mL (32.7%). The mean AUC1weekincreased 3.5-fold from the first dose to Cycle 2 Day 1. Maximum trough concentration ofamivantamab after subcutaneous administration as monotherapy and in combination with lazertinib istypically observed at the end of the weekly dosing (Cycle 2 Day 1). Amivantamab steady-stateconcentration is reached by approximately Week 13. The geometric mean (%CV) steady-state troughconcentration of amivantamab at Cycle 4 Day 1 was 206 µg/mL (39.1%).
Table 9 lists the observed geometric mean (%CV) maximum trough concentrations (Cycle 2 Day 1
Ctrough) and Cycle 2 area under the concentration time curve (AUCDay 1-15) following the recommendeddoses of amivantamab administered subcutaneously and intravenously in patients with NSCLC. These
PK endpoints were the basis for the demonstration of non-inferiority that supports the intravenous tosubcutaneous bridging.
Table 9: Summary of serum pharmacokinetics parameters of amivantamab in patientswith NSCLC (PALOMA-3 Study)
Parameter Rybrevant subcutaneous Rybrevant intravenousformulation formulation1600 mg 1050 mg(2240 mg for body weight ≥ 80 kg) (1400 mg for body weight ≥ 80 kg)
Geometric mean (%CV)
Cycle 2 Day 1 Ctrough 335 (32.7%) 293 (31.7%)(µg/mL)
Cycle 2 AUC(Day1-15) 135861 (30.7%) 131704 (24.0%)(µg/mL)
DistributionBased on the individual amivantamab PK parameter estimates for participants receiving subcutaneousadministration in the population PK analysis, the geometric mean (%CV) total volume of distributionfor amivantamab administered subcutaneously is 5.69 L (23.8%).
EliminationBased on the individual amivantamab PK parameter estimates for participants receiving subcutaneousadministration in the population PK analysis, the estimated geometric mean (% CV) linear CL andassociated-terminal half-life is 0.224 L/day (26.0%) and 18.8 days (34.3%), respectively.
Special populationsElderly
No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based onage (21-88 years).
Renal impairmentNo clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patientswith mild (60 ≤ creatinine clearance [CrCl] < 90 mL/min), moderate (29 ≤ CrCl < 60 mL/min) orsevere (15 ≤ CrCl < 29 mL/min) renal impairment. Data in patients with severe renal impairment arelimited (n=1), but there is no evidence to suggest that dose adjustment is required in these patients.
The effect of end-stage renal disease (CrCl < 15 mL/min) on amivantamab pharmacokinetics isunknown.
Hepatic impairmentChanges 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[(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)] or moderate(1.5×ULN < total bilirubin ≤ 3×ULN and any AST) hepatic impairment. Data in patients withmoderate hepatic impairment are limited (n=1), but there is no evidence to suggest that doseadjustment is required in these patients. The effect of severe (total bilirubin > 3 times ULN) hepaticimpairment on amivantamab pharmacokinetics is unknown.
Paediatric populationThe PK of amivantamab 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 dosetoxicity.
Carcinogenicity and mutagenicityNo animal studies have been performed to establish the carcinogenic potential of amivantamab.
Routine genotoxicity and carcinogenicity studies are generally not applicable to biologicpharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA orchromosomal material.
Reproductive toxicologyNo animal studies have been conducted to evaluate the effects on reproduction and foetaldevelopment; however, based on its mechanism of action, amivantamab can cause foetal harm ordevelopmental anomalies. As reported in the literature, reduction, elimination, or disruption of embryofoetal or maternal EGFR signalling can prevent implantation, cause embryo foetal loss during variousstages of gestation (through effects on placental development), cause developmental anomalies inmultiple organs or early death in surviving foetuses. Similarly, knock out of MET or its ligandhepatocyte 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 tocross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to thedeveloping foetus.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Recombinant human hyaluronidase (rHuPH20)
EDTA disodium salt dihydrate
Glacial acetic acid
L-methionine
Polysorbate 80 (E433)
Sodium acetate trihydrate
Sucrose
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.
6.3 Shelf life
Unopened vial2 years
Prepared syringe
Chemical and physical in-use stability has been demonstrated up to 24 hours at 2°C to 8°C followedby up to 24 hours at 15°C to 30°C. From a microbiological point of view, unless the method of dosepreparation precludes the risk of microbial contamination, the product should be used immediately. Ifnot 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 preparing the syringe, see section 6.3.
6.5 Nature and contents of container
10 mL solution in a Type 1 glass vial with an elastomeric closure and aluminium seal with a flip-offcap containing 1600 mg amivantamab. Pack size of 1 vial.
14 mL solution in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off cap containing 2240 mg amivantamab. Pack size of 1 vial.
6.6 Special precautions for disposal and other handling
Rybrevant subcutaneous formulation is for single use only and is ready to use.
The solution for injection should be prepared using aseptic technique as follows:
Preparation- Determine the dose required and the appropriate Rybrevant subcutaneous formulation vialneeded based on the patient’s baseline weight (see section 4.2).
- Patients < 80 kg receive 1600 mg and for patients ≥ 80 kg, 2240 mg weekly from Weeks 1 to 4and then every 2 weeks starting at Week 5 onwards.
- Remove the appropriate Rybrevant subcutaneous formulation vial from refrigerated storage(2°C to 8°C).
- Check that the Rybrevant solution is colourless to pale yellow. Do not use if opaque particles,discolouration or other foreign particles are present.
- Equilibrate Rybrevant subcutaneous formulation to room temperature (15°C to 30°C) for atleast 15 minutes. Do not warm Rybrevant subcutaneous formulation in any other way. Do notshake.
- Withdraw the required injection volume of Rybrevant subcutaneous formulation from the vialinto an appropriately sized syringe using a transfer needle. Smaller syringes require less forceduring preparation and administration.
- Rybrevant subcutaneous formulation is compatible with stainless steel injection needles,polypropolene and polycarbonate syringes, and polyethylene, polyurethane, andpolyvinylchloride subcutaneous infusion sets. A sodium chloride 9 mg/mL (0.9%) solution mayalso be used to flush an infusion set if needed.
- Replace the transfer needle with the approriate ancillaries for transport or administration. Use ofa 21G to 23G needle or infusion set is recommended to ensure ease of administration.
Storage of prepared syringe
The prepared syringe should be administered immediately. If immediate administration is not possible,store the prepared syringe refrigerated at 2°C to 8°C for up to 24 hours followed by at roomtemperature of 15°C to 30°C for up to 24 hours. The prepared syringe should be discarded if stored formore than 24 hours refrigerated or more than 24 hours at room temperature. If stored in therefrigerator, the solution should come up to room temperature before administration.
DisposalThis medicinal product is for single use only. Any unused medicinal product or waste material shouldbe disposed of in accordance with local requirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.