Rybrevant 350 mg Concentrate for solution for infusion

RYBREVANT is indicated:

• in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal-growth factor receptor (EGFR) exon 20 insertion mutations.
• in combination with carboplatin and pemetrexed for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with osimertinib.
• as monotherapy for the treatment of adult patients with locally advanced or metastatic (NSCLC) with activating (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

RYBREVANT should be administered by a healthcare professional with appropriate medical support to manage infusion-related reactions (IRRs) if they occur (see section 4.4). Administer pre-infusion medications (see Pre-infusion medications). Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 4 and 5, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2. When considering the use of RYBREVANT, EGFR, exon 20 insertion mutation presence should be established using a validated test (see section 5.1).

Posology - adults (u2265 18 years)

Every 3 Weeks

The recommended dosage of RYBREVANT, when used in combination with carboplatin and pemetrexed, is provided in Table 1 (see Infusion Rates u2013 Table 4).

Table 1: Recommended Dose and 3-week Dosing Schedule for RYBREVANT

Body weight at Baseline a Recommended Dose Schedule Number of 350 mg/7 mL RYBREVANT Vials

a Dose adjustments not required for subsequent body weight changes. When used in combination with carboplatin and pemetrexed, RYBREVANT should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then RYBREVANT. See Clinical Studies and Posology and Method of Administration for dosing instructions for carboplatin and pemetrexed.

Every 2 Weeks

The recommended dosage of RYBREVANT monotherapy is provided in Table 2, see Infusion Rates-Table 5).

Table 2: Recommended Dose and 2-week Dosing Schedule for RYBREVANT

Body weight at Baseline a Recommended Dose Schedule Number of 350 mg/7 mL RYBREVANT Vials

Less than 80 kg 1400 mg Weekly (total of 4 doses) from Weeks 1 to 4 u2022 Week 1 - split infusion on Day 1 and Day 2 u2022 Weeks 2 to 4 - infusion on Day 1 4 1750 mg Every 3 weeks starting at Week 7 onwards 5 Greater than or equal to 80 kg 1750 mg Weekly (total of 4 doses) for Weeks 1 to 4 u2022 Week 1 - split infusion on Day 1 and Day 2 u2022 Weeks 2 to 4 - infusion on Day 1 5 2100 mg Every 3 weeks starting at Week 7 onwards 6

Less than 80 kg 1050 mg Weekly (total of 4 doses) from Weeks 1 to 4 u2022 Week 1 - split infusion on Day 1 and Day 2 u2022 Weeks 2 to 4 - infusion on Day 1 3 Every 2 weeks starting at Week 5 onwards Greater than or equal to 80 kg 1400 mg Weekly (total of 4 doses) from Weeks 1 to 4 u2022 Week 1 - split infusion on Day 1 and Day 2 u2022 Weeks 2 to 4 - infusion on Day 1 4 Every 2 weeks starting at Week 5 onwards

a Dose adjustments not required for subsequent body weight changes

Duration of treatment

It is recommended that patients are treated with RYBREVANT until unacceptable toxicity or lack of clinical benefit.

Pre-infusion medications

Prior to initial infusion of RYBREVANT (Week 1, Days 1 and 2), administer antihistamines, antipyretics, and glucocorticoids to reduce the risk of IRRs. For subsequent doses, administer antihistamines and antipyretics. Administer antiemetics as needed.

Table 3: Pre-Medications

Medication Dose Route of Administration Dosing Window Prior to RYBREVANT administration Antihistamine * Diphenhydramine IV 15 to 30 minutes Oral 30 to 60 minutes

* Required at all doses. u2021 Required at initial dose (Week 1, Days 1) + Required at second dose (Week 1, Day 2); optional for subsequent doses.

Infusion Rates

Administer RYBREVANT infusion every 3 weeks intravenously according to the infusion rates in Table 4 and administer RYBREVANT infusion every 2 weeks intravenously according to the infusion rates in Table 5. Due to the frequency of IRRs at the first dose, infusion via a peripheral vein at Week 1 and Week 2 should be considered to minimise medicine exposure in the event of an IRR; infusion via central line may be administered for subsequent weeks. It is recommended for the first dose to be diluted as close to administration as possible to allow for maximal flexibility in IRR management.

Table 4: Infusion Rates for RYBREVANT Every 3 Weeks (25 to 50 mg) or equivalent

Antipyretic Paracetamol (650 to 1 000 mg) or equivalent IV 15 to 30 minutes Oral 30 to 60 minutes Glucocorticoid u2021 Dexamethasone (20 mg) or equivalent IV 60 to 120 minutes Glucocorticoid + Dexamethasone (10 mg) or equivalent IV 45 to 60 minutes

Body Weight Less than 80 kg

* Starting at Week 7, patients are dosed every 3 weeks. u2020 Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions.

Week Dose (per 250 mL bag) Initial Infusion Rate Subsequent Infusion Rateu2020 Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 mL/hr 75 mL/hr Week 1 Day 2 1050 mg 33 mL/hr 50 mL/hr Week 2 1400 mg 65 mL/hr Week 3 1400 mg 85 mL/hr Week 4 1400 mg 125 mL/hr Subsequent weeks* 1750 mg 125 mL/hr

Body Weight Greater Than or Equal to 80 kg

Week Dose (per 250 mL bag) Initial Infusion Rate Subsequent Infusion Rate Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 mL/hr 75 mL/hr Week 1 Day 2 1400 mg 25 mL/hr 50 mL/hr Week 2 1750 mg 65 mL/hr Week 3 1750 mg 85 mL/hr Week 4 1750 mg 125 mL/hr Subsequent weeks* 2100 mg 125 mL/hr

Table 5: Infusion Rates for RYBREVANT Every 2 Weeks Administration

Body Weight Less Than 80 kg

Week Dose (per 250 mL bag) Initial Infusion Rate Subsequent Infusion Rate u2020 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

Body Weight Greater Than or Equal to 80 kg

Week Dose (per 250 mL bag) Initial Infusion Rate Subsequent Infusion Rate 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. u2020 Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions.

Missed dose(s)

If a planned dose of RYBREVANT 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

The recommended dose reductions for adverse reactions are listed in Table 6

Table 6: RYBREVANT Dosage Reductions for Adverse Reactions

The recommended dosage modifications for adverse reactions are provided in Table 7.

Table 7: RYBREVANT Dosage Modifications for Adverse Reactions

Dose 1 st Dose Reduction 2 nd Dose Reduction 3 rd Dose Modification 1 050 mg 700 mg 350 mg Discontinue RYBREVANT 1 400 mg 1 050 mg 700 mg 1750 mg 1400 mg 1050 mg 2100 mg 1750 mg 1400 mg

Adverse Reaction Severity Dose Modification

Infusion-Related Reactions (IRR) (see section 4.4) Grade 1 to 3 u2022 Interrupt infusion at the first sign of IRRs. u2022 Additional supportive medications (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated. u2022 Upon resolution of symptoms, resume infusion at 50 % of the previous rate. u2022 If there are no additional symptoms, the rate may be increased per the recommended infusion rate (see Tables 4 and 5). u2022 Pre-medications should be administered prior to the next dose. Recurrent Grade 3 or Grade 4 Permanently discontinue

Interstitial Lung Disease /Pneumonitis (see section 4.4) Suspected ILD/ pneumonitis Withhold Confirmed ILD/ pneumonitis Permanently discontinue Grade 1 u2022 Supportive care should be initiated.

Hypersensitivity to amivantamab or to any of the excipients of RYBREVANT (see section 6.1).

The data described in this section reflects the safety profile of patients with locally advanced or metastatic NSCLC, including 380 patients who received RYBREVANT monotherapy in Study EDI1001, 151 patients who received RYBREVANT in combination with carboplatin and pemetrexed in Study NSC3001, 130 patients who received RYBREVANT in combination with carboplatin and pemetrexed in Study NSC3002.

Infusion-related reactions

Infusion-related reactions may occur in patients treated with RYBREVANT. The most frequent signs and symptoms include chills, nausea, dyspnea, flushing, chest discomfort, and vomiting. Infusion-related reactions occurred in 60% of patients treated with RYBREVANT. 93 % of IRRs were Grade 1-2. 99 % of IRRs occurred at the first infusion with a median time to onset of 60 minutes. The most frequent signs and symptoms include chills, nausea, dyspnoea, flushing, chest discomfort, and vomiting. Prior to initial infusion (Week 1) of RYBREVANT, administer antihistamines, antipyretics, and glucocorticoids to reduce the risk of IRRs. For subsequent doses, administer antihistamines and antipyretics. Administer the initial infusion of RYBREVANT in split doses on Week 1, Days 1 and 2 (see section 4.2). Treat patients with RYBREVANT in a setting with appropriate medical support necessary to treat IRRs. Interrupt RYBREVANT infusion at the first sign of IRRs and institute post-infusion medication as clinically indicated. Upon resolution of symptoms, resume the infusion at 50 % of the previous rate. For recurrent Grade 3 or 4 IRRs, permanently discontinue RYBREVANT (see section 4.2).

Interstitial lung disease

Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) occurred in 2.4 % of patients treated with RYBREVANT, including 0,1% fatal events. Patients with a medical history of ILD, medicine-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD have not been studied. Monitor patients for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, interrupt treatment with RYBREVANT pending investigation of these symptoms. Evaluate suspected ILD and initiate appropriate treatment as necessary. Discontinue RYBREVANT in patients with confirmed ILD (see section 4.2).

Skin and nail reactions

Skin and nail reactions may occur in patients treated with RYBREVANT. Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with RYBREVANT. Most cases were Grade 1 or 2, with Grade 3 events occurring in 8.3% of patients. Rash leading to RYBREVANT discontinuation occurred in 1.2% 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 RYBREVANT. Most events were Grade 1 or 2, with Grade 3-4 nail toxicity occurring in 3 % of patients. Toxic epidermal necrolysis (TEN) has been reported. Permanently discontinue RYBREVANT if TEN is confirmed. A prophylactic approach to rash prevention should be considered. Instruct patients to limit sun exposure during and for 2 months after RYBREVANT therapy. Protective clothing and use of sunscreen is advisable. Alcohol-free emollient cream is recommended for dry areas with the use of RYBREVANT. If skin or nail reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 or poorly-tolerated Grade 2 events, add systemic antibiotics and oral steroids and consider dermatologic consultation. Withhold, dose reduce, or permanently discontinue RYBREVANT based on severity (see section 4.2).

Eye disorders

Eye disorders, including keratitis (0.5 %), occurred in patients treated with RYBREVANT. Other reported adverse reactions included dry eye, blurred vision, eye pruritus, visual impairment, aberrant eyelash growth, ocular hyperaemia, conjunctival hyperaemia, blepharitis and uveitis. All events were Grade 1-2. Refer patients presenting with worsening eye symptoms promptly to an ophthalmologist and advise discontinuation of contact lenses until symptoms are evaluated.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per 7 mL, that is to say essentially u2018sodium-freeu2019.

No medicine interaction studies have been performed. 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.

Women of childbearing potential / Contraception

Due to the risk that RYBREVANT can cause foetal harm when administered to pregnant women, advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT. Male patients must use effective contraception (e.g., condom) and not donate or store semen during treatment and for 3 months after the last dose of RYBREVANT.

Pregnancy

There are no human or animal data to assess the risk of RYBREVANT in pregnancy. Administration of other EGFR and MET inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-foetal development, embryolethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, RYBREVANT could cause foetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking this medicine, the patient should be informed of the potential risk to the foetus.

Breastfeeding

It is not known whether RYBREVANT is excreted in human or animal milk or affects milk production. Because of the potential for serious adverse reactions from RYBREVANT in breastfed infants, advise women not to breastfeed during treatment with RYBREVANT and for 3 months following the last dose of RYBREVANT.

Fertility

No data are available to determine potential effects of RYBREVANT on fertility in males or females.

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.

Summary of the safety profile

The safety data below reflect exposure to RYBREVANT in 661 patients with locally advanced or metastatic NSCLC, including 380 patients who received RYBREVANT monotherapy in Study EDI1001 and 151 patients who received RYBREVANT in combination with carboplatin and pemetrexed in Study NSC3001, 130 patients who received RYBREVANT in combination with carboplatin and pemetrexed in Study NSC3002. Patients received RYBREVANT, until disease progression or unacceptable toxicity. The most frequent adverse reactions u2265 20 % were rash, IRR, nail toxicity, hypoalbuminaemia, oedema, fatigue, stomatitis, nausea, constipation, decreased appetite, increased alanine aminotransferase. Serious adverse reactions in > 1 % of patients included ILD, IRR, and rash. 5.9 % of patients discontinued RYBREVANT due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR, rash and ILD.

Table 8 presents adverse reactions reported in patients treated with RYBREVANT in Studies EDI1001, NSC3001, NSC3002.

Tabulated list of adverse reactions Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (frequency cannot be estimated from the available data).

Table 8 : Adverse reactions in Patients with NSCLC with exon 20 Insertion Mutations with RYBREVANT (N= 108 2 )

System Organ Class Adverse Reaction Frequency (all grades) All Grades (%) Grade 3-4 (%) Skin and subcutaneous tissue disorders Rash* Very common 79 8 Nail toxicity* Very common 50 3 Dry skin* Very common 17 0 Pruritus Very common 15 0 Toxic epidermal necrolysis Uncommon 0.2 0.2 Injury, poisoning and procedural complications Infusion-related reaction Very common 60 3 Gastrointestinal disorders Nausea Very common 30 0,6 Stomatitis* Very common 31 2 Constipation Very common 30 0.2 Vomiting Very common 17 1 Diarrhoea Very common 14 2

System Organ Class Adverse Reaction Frequency (all grades) All Grades (%) Grade 3-4 (%) Abdominal pain* Very Common 10 0.6 Hemorrhoids Common 6 0,3 Metabolism and nutrition disorders Hypoalbuminaemia* Very common 32 3 Decreased appetite Very common 23 0,9 Hypocalcaemia Very common 11 0.6 Hypokalaemia Very Common 14 4 Hypomagnesaemia Very Common 10 0.6 General disorders and administration site conditions Oedema* Very common 31 1 Fatigue* Very common 32 3 Pyrexia Very common 12 0 Investigations Alanine aminotransferase increased Very common 20 3 Aspartate aminotransferase increased Very common 17 0.9 Blood alkaline phosphatase increased Very common 11 0.5 Nervous system disorders Dizziness* Very common 11 0.2 Musculoskeletal and connective tissue disorders Myalgia Very common 8 0.5 Eye disorders Other eye disorders* Common 7 0 Visual impairment* Common 3 0 Growth of eyelashes* Uncommon 0.8 0 Keratitis Uncommon 0.5 0

System Organ Class Adverse Reaction Frequency (all grades) All Grades (%) Grade 3-4 (%) Uveitis Uncommon 0.2 0 Respiratory, thoracic and mediastinal disorders Interstitial lung disease* Common 2 1 * Grouped terms

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Alternatively, suspected adverse reactions may be reported directly to Janssen Pharmaceutica (see section 7 for contact details or visit: www.innovativemedicine.jnj.com).

Symptoms and signs

There is no information on overdosage with RYBREVANT.

Treatment

There is no known specific antidote for RYBREVANT overdose. In the event of an overdose, stop RYBREVANT, undertake general supportive measures until clinical toxicity has diminished or resolved.