HYRNUO

Hyrnuo therapy should be initiated and supervised by physicians experienced in the use of anti-cancer therapies. Patient selection The presence of HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations in tumour specimens must be confirmed using a validated test prior to initiation of therapy with Hyrnuo.

Posology Adults The recommended dose of Hyrnuo is 20 mg (two 10 mg tablets) taken twice a day until disease progression or unacceptable toxicity. If vomiting occurs after taking Hyrnuo, the patient must not take an additional dose. The next dose should be taken at its scheduled time.

Missed Dose If a dose of Hyrnuo is missed, the dose should be taken as soon as the patient remembers prior to the next scheduled dose, but not within 30 minutes of the next scheduled dose. The patient should not take two doses together to make up for a missed dose.

Dose Modifications due to Adverse Reactions Management of adverse reactions may require dose interruption, dose reduction and / or discontinuation of Hyrnuo. The recommended dose reduction levels are outlined in Table 1. Patients who are unable to tolerate 10 mg once daily should discontinue Hyrnuo treatment permanently.

8).

Table 2:

Recommended Dose Modifications for Hyrnuo for Adverse Reactions Adverse Reaction Severitya Recommended Hyrnuo dose modification and measures Diarrhoea Intolerable or - Withhold Hyrnuo until recovery to Grade ≤1. Adverse Reaction Severitya Recommended Hyrnuo dose modification and measures recurrent Grade 2 - Resume Hyrnuo at the same dose or the next lower dose as clinically appropriate.

Grade 3 - Withhold Hyrnuo until recovery to Grade ≤1. - For first occurrence, resume Hyrnuo at the same dose or the next lower dose. - For re-occurrence, resume Hyrnuo at the next lower dose. 4) Grade 4 - Permanently discontinue Hyrnuo.

Grade 2, 3 or 4 ALT and/or AST without increased total bilirubin or Grade 3 total bilirubin - Interrupt Hyrnuo until recovery to ≤ Grade 1 or baseline. - Resume Hyrnuo at the next lower dose. 4) ALT or AST ≥ 3× ULN with total bilirubin ≥ 2× ULN or Grade 4 total bilirubin - Permanently discontinue Hyrnuo.

4) Any Grade - Permanently discontinue Hyrnuo. Intolerable or recurrent Grade 2 - Withhold Hyrnuo until recovery to Grade ≤1. - Resume Hyrnuo at the same dose or the next lower dose as clinically appropriate. Grade 3 - Withhold Hyrnuo until recovery to Grade ≤1.

Summary of the safety profile The safety profile of Hyrnuo is based on data from 287 patients with advanced NSCLC harbouring activating HER2 (ERBB2) mutations and/or EGFR mutations who had received Hyrnuo at 20 mg twice daily in the single-arm SOHO-01 clinical study (whole study 20 mg BID).

8%). 4 % of patients. 1%). 5%). 1% of patients who received Hyrnuo. 4%). 8%) who received Hyrnuo. 3%). 5% of patients who received Hyrnuo. 1%). 6% of patients who received Hyrnuo. 1%). Tabulated list of adverse reactions Adverse reactions reported in the SOHO-01 study (whole study 20 mg BID) are listed in Table 4.

The ADRs are classified according to the MedDRA system organ class and frequency. Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: 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 (cannot be estimated from available data).

Within each frequency group, adverse drug reactions are presented in order of decreasing seriousness.

Table 4:

Adverse Drug Reactions Reported in SOHO-01 Study (whole study 20 mg BID safety population, N=287) FrequencySystem Organ Class (MedDRA)a Adverse Reaction All Grades Grades 3 and 4 Diarrhoea Very common Very commonGastrointestinal disorders Vomiting Very common Common FrequencySystem Organ Class (MedDRA)a Adverse Reaction All Grades Grades 3 and 4 Nausea Very common Common Stomatitisb Very common Uncommon Abdominal painc Common Rashd Very common Common Paronychiae Very common Uncommon Pruritus Very common Uncommon Dry skinf Very common Alopecia Common Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome Common Hypokalaemia Very common CommonMetabolism and nutrition disorders Decreased appetite Very common Common Aspartate aminotransferase increased Very common Common Alanine aminotransferase increased Very common Common Weight decreased Very common Lipase increased Very common Uncommon Blood creatine increased Very common Uncommon Amylase increased Very common Uncommon Glucose increasedg,h Very common Uncommon Magnesium decreasedg Very common Uncommon Albumin decreasedg Very common Uncommon Calcium decreasedg Very common Common Sodium decreasedg Very common Common Triglycerides increasedg Very common Uncommon Lymphocyte count decreasedg Very common Common Investigations Alkaline phosphatase increasedg Very common Uncommon White blood cell decreasedg Very common Common Bilirubin increasedg Very common Uncommon Blood and lymphatic system disorders Anaemia Very common Common General disorders and Fatiguei Common Uncommon FrequencySystem Organ Class (MedDRA)a Adverse Reaction All Grades Grades 3 and 4 Administration site conditions Cardiac disorders Cardiac arrhythmiaj Common Common Eye disorders Ocular toxicityk Common Uncommon Respiratory, thoracic and mediastinal disorders ILD/pneumonitis Uncommon Uncommon a Graded per NCI CTCAE version 5 b Stomatitis includes cheilitis, mouth ulceration, mucosal inflammation stomatitis c Abdominal pain includes abdominal distention, abdominal pain, abdominal pain upper d Rash includes acne, acne varioliformis, dermatitis acneiform, eczema, erythema, folliculitis, rash, rash erythematous, rash maculopapular, rash pruritic, skin exfoliation e Paronychia includes ingrowing nail, nail disorder, nail infection, onychalgia, onychoclasis onycholysis, onychomadesis, paronychia f Dry skin includes dry skin, xeroderma g The incidence is based on values reported as laboratory abnormalities (worsening from baseline).

Diarrhoea Diarrhoea has been reported during treatment with Hyrnuo and can be severe, leading to dehydration and electrolyte imbalance, including hypokalaemia which may lead to cardiac arrhythmias, if untreated. 8). g. loperamide), and to increase fluid and electrolyte intake at first sign of diarrhoea or increased bowel movement frequency.

2). 8). Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to initiation of Hyrnuo, and monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations.

2). 8). Patients with a history of steroid- dependent ILD/pneumonitis have not been studied. , dyspnoea, cough, fever). 2). 8). Patients presenting with new or worsening eye symptoms should promptly be referred to an ophthalmologist. 2). 8).

Amylase and lipase should be monitored regularly during treatment with Hyrnuo. 2). Embryo-foetal toxicity Based on findings from animal studies and its mechanisms of action, Hyrnuo may cause foetal harm when administered to pregnant women.

6). Male patients with female partners of childbearing potential should also be advised to use highly effective contraception during treatment with Hyrnuo and for 1 week after the last dose to prevent pregnancy. 6). Information about excipients Hyrnuo contains lactose.

Patients with rare hereditary problems of fructose intolerance, galactose intolerance, galactosaemia or glucose-galactose malabsorption should not take this medicine.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.