AUMSEQA Film-coated tablet Ref.[116271] Active ingredients: Aumolertinib

Assessment of EGFR mutation status

When considering the use of Aumseqa as a treatment for patients with locally advanced or metastatic NSCLC, it is necessary to determine the mutation status of EGFR. A validated EGFR mutation test should be performed using either tumour DNA derived from a tissue sample or circulating tumour DNA (ctDNA) obtained from a plasma sample.

Positive determination of EGFR mutation status using either a tissue-based or plasma-based test indicates eligibility for treatment with Aumseqa. However, if a plasma-based ctDNA test is used and the result is negative, it is advisable to follow-up with a tumour tissue-based test wherever possible, as a plasma-based test may provide a false negative result. Only tests with demonstrated utility for the determination of EGFR mutation status should be used.

QTc interval prolongation

QTc interval prolongation has occurred in subjects treated with Aumseqa (see section 4.8). One sudden cardiac death was reported in clinical studies with Aumseqa. Subjects with clinically important cardiac abnormalities in rhythm and conduction, as measured by resting ECG, were excluded from the clinical studies.

Patients should be informed of the risk of QT prolongation, its signs and symptoms (palpitations, dizziness, syncope or even cardiac arrest) and be advised to contact their physician immediately if these occur.

An ECG must be performed prior to treatment initiation, at least once during the first 3 weeks of therapy, and periodically thereafter as clinically indicated. Heart rate corrected QT (QTc) should be less than 480 msec prior to treatment initiation and, in the presence of an abnormal QT, practitioners should thoroughly reassess the benefit/risk of initiating Aumseqa (see section 4.3). In case QTc interval prolongation is between 480 msec and 500 msec, initiation of treatment with Aumseqa should remain exceptional and be accompanied by close monitoring.

Treatment discontinuation and dose modification are recommended in patients who develop confirmed QTc interval prolongation >480 msec (see section 4.2). Patients with prolonged QTc intervals, who develop symptoms or signs of severe arrhythmia, including, but not limited to, torsade de pointes and ventricular tachycardia, should permanently discontinue treatment with Aumseqa and be immediately treated as per standard of care.

Concomitant administration of medicinal products known to prolong the QTc interval may increase the risk of QTc interval prolongation and should be avoided whenever possible during treatment with Aumseqa. Patients should be treated with caution and closely monitored for QTc interval prolongation if use of a suitable alternative is not possible (see sections 4.2, 4.5 and 4.8).

Patients with congestive heart failure, electrolyte abnormalities or who are using medicinal products known to prolong the QT interval (see section 4.5) should undergo regular electrocardiogram (ECG) and electrolyte monitoring. In case of severe vomiting and/or diarrhoea, an assessment of serum electrolytes abnormalities, especially hypokalaemia/hypomagnesemia, must be performed (see section 4.2).

Cardiac failure

Cardiac failure, including life threatening or fatal events, have occurred uncommonly in subjects treated with Aumseqa (see section 4.8). Subjects were required to have LVEF >40% to be included in the clinical studies.

For patients with known cardiovascular risk factors or conditions that may affect LVEF, cardiac function should be monitored, with at least LVEF assessment prior to treatment initiation and during treatment with Aumseqa, as clinically indicated. For patients who develop symptomatic congestive heart failure during treatment, cardiac monitoring including LVEF assessment should be considered, and Aumseqa should be permanently discontinued (see sections 4.2 and 4.8).

Interstitial lung disease (ILD)

ILD has been reported in subjects treated with Aumseqa (see section 4.8). ILD may be fatal or life-threatening. Subjects 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 studies. Patients with acute episodes and/or exacerbations of pulmonary symptoms (e.g., dyspnoea, cough, or fever) with no clear cause should be investigated for possible ILD during treatment with Aumseqa. Treatment should be interrupted while conducting investigation of these symptoms. If ILD is confirmed, Aumseqa should be permanently discontinued, and appropriate treatment for ILD initiated.

Venous thromboembolic events

Thromboembolic events, including deep vein thrombosis, pulmonary embolism and cerebral infarction, have been reported in subjects treated with Aumseqa, including in subjects receiving anti-thrombotic agents (see section 4.8). If clinical signs and symptoms of thromboembolic events occur or are suspected, patients should be evaluated promptly, followed by appropriate treatment. Aumseqa should be withheld, and the patient stabilised before resuming therapy.

Increased blood creatine phosphokinase (CPK) and risk of rhabdomyolysis

Increased blood CPK occurred in clinical studies at the recommended dose (see section 4.8). While in most cases increased blood CPK was asymptomatic and did not lead to discontinuations, Grade 3 CPK elevations with muscular symptoms and Grade 4 CPK elevations with or without muscular symptoms, indicative of rhabdomyolysis, also occurred.

Blood CPK should be obtained before initiating Aumseqa and periodically during treatment, as clinically indicated.

Patients should be advised to report any unexplained muscle pain, tenderness, or weakness, trouble moving arms or legs, dark tea-coloured urine, or decreased urination.

Concomitant administration of Aumseqa should be avoided with medicinal products that can increase blood CPK or strong CYP3A4 inhibitors as they may increase the risk of blood CPK elevation and/or muscle symptoms (see section 4.5).

If rhabdomyolysis occurs, Aumseqa should be withheld and treatment for rhabdomyolysis should be initiated as clinically indicated (see section 4.2).

Co-administration with CYP3A4 inhibitors

Co-administration of Aumseqa with moderate or strong CYP3A4 inhibitors should be avoided. If concurrent use of strong CYP3A4 inhibitors (such as grapefruit juice, clarithromycin, itraconazole or lopinavir) cannot be avoided, the dose of Aumseqa should be reduced from 110 mg to 55 mg (see section 4.5).

Routine monitoring

Renal function

Increased blood CPK (see above) can be associated with acute renal impairment. Renal function should be monitored prior to initiating Aumseqa, and periodically during treatment as clinically indicated.

Liver function

Liver function test abnormalities (including increases in alanine aminotransferase [ALT] aspartate aminotransferase [AST], and blood bilirubin levels) have been observed during treatment with aumolertinib, including rarely reported drug-induced liver injury (DILI). Liver function should be monitored prior to initiating Aumseqa, and periodically during treatment as clinically indicated. The frequency of monitoring may be adjusted according to the severity of liver function abnormalities or symptoms.

Lactose

Aumseqa contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains <1 mmol sodium (23 mg) per daily dose, that is to say essentially "sodium-free".

Active substances that may increase aumolertinib plasma concentrations

Co-administration with CYP3A4 inhibitors

Aumolertinib is mainly metabolised by CYP3A4 enzymes. In a drug-drug interaction (DDI) study, co-administration of aumolertinib with a strong CYP3A4 inhibitor (itraconazole) significantly increased aumolertinib exposure (area under the plasma concentration-time curve [AUC] increased 3.7-fold). Co-administration of Aumseqa with moderate (e.g., verapamil, fluconazole) or strong (e.g., grapefruit juice, clarithromycin, itraconazole, lopinavir) CYP3A4 inhibitors should be avoided. If concurrent use of strong CYP3A4 inhibitors cannot be avoided, the dose of Aumseqa should be reduced from 110 mg to 55 mg (see section 4.2).

Co-administration with BCRP and P-gp inhibitors

Based on in vitro data, aumolertinib is a substrate of P-glycoprotein (P-gp) and breast-cancer resistance protein (BCRP). Concomitant administration of aumolertinib with medicinal products that are inhibitors of these transporter proteins should be avoided, as it may result in increased aumolertinib plasma concentrations. If co-administration with such inhibitors is unavoidable, clinical monitoring is recommended.

Active substances that may decrease aumolertinib plasma concentrations

Co-administration with CYP3A4 inducers

In a DDI study, co-administration of aumolertinib with a strong CYP3A4 inducer (rifampicin) decreased aumolertinib exposure (AUC decreased by approximately 90%). Co-administration of Aumseqa with moderate (e.g., bosentan, efavirenz) or strong (e.g., rifampicin, carbamazepine, phenytoin sodium, St. John's wort) CYP3A4 inducers is not recommended.

Potential for aumolertinib to affect the exposure to other medicinal products

CYP3A substrates

Aumolertinib decreased the exposure of midazolam (a sensitive CYP3A substrate) by approximately 27% in a clinical study. Aumolertinib is therefore considered a weak inducer of CYP3A and may decrease concentrations of medicinal products that are CYP3A substrates. Concomitant use with sensitive CYP3A substrates for which small changes in exposure may lead to loss of efficacy (e.g., some hormonal contraceptives, certain oncology or anti-infective agents) or with CYP3A substrates with a narrow therapeutic index (e.g., tacrolimus, cyclosporine, sirolimus, fentanyl) should be avoided. If concomitant use cannot be avoided, clinical response should be monitored and dose adjustment of the CYP3A substrate considered, in accordance with its prescribing information.

Interactions with drug transporters

Based on in vitro studies, aumolertinib is an inhibitor of P-glycoprotein (P-gp). In a clinical DDI study, aumolertinib increased the average steady-state maximum concentration (C_max) and AUC of fexofenadine (sensitive P-gp substrate) by 86% and 67%, respectively. Caution should be taken when administering Aumseqa with medicinal products that are sensitive P-gp substrates with a narrow therapeutic window (e.g., digoxin, dabigatran, colchicine), and these patients should be closely monitored for signs of changed tolerability as a result of increased exposure of the concomitant medicinal products whilst receiving Aumseqa.

Based on an in vitro study, aumolertinib is an inhibitor of multidrug and toxin extrusion (MATE)1 and organic cation transporter (OCT)1. No clinical studies have been performed to investigate interactions with MATE1 and OCT1 substrates; therefore, the potential in vivo effect of concomitant inhibition of MATE1 or OCT1 by Aumseqa is unknown. Caution is recommended when aumolertinib is co-administered with sensitive MATE1 or OCT1 substrates with a narrow therapeutic index.

Based on an in vitro study, aumolertinib is an inhibitor of BCRP. No clinical studies have been performed to investigate interactions with BCRP. Therefore, co-administration of aumolertinib with sensitive BCRP substrates should be avoided. If such co-administration is unavoidable, close clinical monitoring for increased exposure or adverse effects of the BCRP substrate is recommended.

Effect of gastric acid reducing active substances on aumolertinib

No clinically relevant changes in aumolertinib exposure are anticipated with gastric acid reducing agents such as famotidine or omeprazole. Aumseqa may be co-administered with gastric acid reducing agents without dose adjustment.

Women of childbearing potential/Contraception

Women of childbearing potential should be advised to avoid becoming pregnant while receiving Aumseqa. Female patients should use highly effective contraception during treatment and for 4 weeks after completion of treatment with Aumseqa.

Aumseqa may decrease the efficacy of hormonal contraceptives (see section 4.5). Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring). Females using hormonal contraceptives should be counselled to use an alternative contraceptive method (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use and for 4 weeks after discontinuation of Aumseqa.

Pregnancy

There are no data from the use of aumolertinib in pregnant women. Studies in animals have shown reproductive and developmental toxicity (see section 5.3). Mechanistically, all EGFR targeting medicinal products have the potential to cause foetal harm. Based on its mechanism of action and preclinical data, Aumseqa should not be used during pregnancy.

Breast-feeding

It is unknown whether aumolertinib or metabolites are excreted in human milk. A risk to the breast-feeding newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Aumseqa and for 4 weeks after completion of treatment with Aumseqa.

Fertility

In animal studies, impacts on fertility effects were observed in females (see section 5.3). There are no clinical data on the effect of aumolertinib on human fertility.

Aumseqa has minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported in some patients following administration with Aumseqa. Patients experiencing these symptoms should be advised not to drive or use machines until these symptoms resolve.

Summary of the safety profile

The most frequently reported adverse reactions in subjects treated with Aumseqa were aspartate aminotransferase (AST) increased (40.4%), hyponatraemia (37.2%), alanine aminotransferase (ALT) increased (33%), blood CPK increased (31.7%), white blood cell (WBC) count decreased (30.6%), platelet count decreased (29.4%), upper respiratory tract infections (23.3%), and rash (22.8%). The most frequently reported Grade ≥ 3 adverse reaction was blood CPK increased (7.5%).

The most common serious adverse reactions were venous thromboembolism (4.2%), lower respiratory tract and lung infections (2.8%), and urinary tract infection (1.1%).

Treatment discontinuation due to adverse reactions occurred in 2.2% of subjects. The most common adverse reaction leading to treatment discontinuation was ILD, occurring in 0.4% of subjects.

Treatment interruption and dose reduction due to adverse reactions occurred in 12.1% and 3.1% of subjects, respectively. The most common adverse reaction leading to interruption or dose reduction was blood CPK increased (occurring in 6.1% and 2.0% of subjects, respectively); dose interruption due to ALT increased occurred in 1.8% of subjects.

Tabulated list of adverse reactions

The data described in this section reflect exposure to Aumseqa in subjects with EGFR mutation-positive NSCLC. 545 subjects received Aumseqa at the recommended dose of 110 mg once a day in 2 multicentre pivotal studies: 1 phase 3 study in the first-line setting (HS-10296-03-01, AENEAS) and 1 phase ½ study in pre-treated subjects (HS-10296-12-01, APOLLO) (see section 5.1).

Adverse reactions reported are presented in Table 2 and listed by system organ class, MedDRA term and frequency with the most frequent reactions listed first.

The following definitions apply to the frequency terminology used hereafter: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000 <1/100); rare (≥1/10 000, <1/1 000); very rare (<1/10 000); 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 2. Adverse reactions reported in subjects treated with Aumseqa:

Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
The severity of adverse reactions was assessed based on the CTCAE, defining Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening, and Grade 5 = death.
^a Includes: acute sinusitis, laryngopharyngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, and upper respiratory tract infection.
^b Includes: cystitis, pyelonephritis acute, urethritis, and urinary tract infection.
^c Includes: atypical pneumonia, bronchitis, pneumonia, and sputum purulent.
^d Includes: conjunctivitis and conjunctivitis allergic.
^e Includes: blood sodium decreased, hyponatraemia*.
^f Includes: blood potassium decreased, hypokalaemia*.
^g Includes: dry eye and xerophthalmia.
^h Includes: visual impairment and blurred vision.
ⁱ Includes: eye pain, and ocular discomfort.
^j Includes: ocular hyperaemia, conjunctival haemorrhage, and eye haemorrhage.
^k Includes: abnormal sensation in eye, and foreign body sensation in eyes.
^l Includes: corneal exfoliation and corneal opacity.
^m Includes: eyelid oedema and swelling of eyelid.
ⁿ Includes: cardiac failure, cardiac failure chronic, ejection fraction decreased, and pulmonary oedema.
° Includes: blood pressure increased, hypertension.
^p Includes: deep vein thrombosis, pulmonary embolism, venous thrombosis limb, cerebral infarction and cerebral thrombosis.
^q Includes: cough, productive cough, and upper-airway cough syndrome.
^r Includes: bronchiolitis, interstitial lung disease, and pneumonitis.
^s Includes: aphthous ulcer, dry mouth, glossodynia, mouth ulceration, oral pain, stomatitis, and tongue ulceration.
^t Includes: drug eruption, papule, macule, rash, rash maculo-papular, rash papular, rash pruritic, rash pustular, and urticaria.
^u Includes: dermatitis and dermatitis acneiform.
^v Includes: erythema and erythema nodosum.
^w Includes: neutropenia, neutrophil count decreased, and white blood cell count decreased*.
^x Includes: platelet count decreased*, and thrombocytopenia.
^y Includes: blood bilirubin increased, and hyperbilirubinemia.
^* Represent incidence of laboratory findings, not of adverse events

Description of selected adverse reactions

Interstitial lung disease (ILD)

In clinical studies (N=545), ILD was reported in 16 subjects (2.9%) treated with Aumseqa 110 mg. One fatal case of ILD was reported. The median time-to-onset of ILD was 124 days (range: 2 days – 932 days). The median time-to-resolution of ILD was 41 days (range: 14 days - 702 days). For specific recommendations, refer to sections 4.2 and 4.4.

Cardiac failure

In clinical studies (N=545), cardiac failure was reported in 4 subjects (0.7%). Two subjects (0.4%) reported cardiac failure of Grade ≥ 3. The median time-to-onset of any Grade cardiac failure was 249 days (range: 84 days – 381 days), and the median time-to-resolution was 35 days (range: 22 days – 160 days). One subject with cardiac failure died due to pulmonary oedema and upper gastrointestinal haemorrhage. Four subjects (0.7%) had a decline in LVEF of ≥ 10% to an absolute value < 50%. Nineteen subjects (3.5%) had a decline in LVEF of ≥ 15% but the absolute LVEF remained ≥ 50% in these subjects. For specific recommendations, refer to sections 4.2 and 4.4.

QTc prolongation

In clinical studies (N=545), QT prolongation was reported in 51 subjects (9.4%) treated with Aumseqa 110 mg. In 4 subjects (0.7%) the events were Grade ≥ 3. The median time-to-onset of any Grade QT prolongation was 22 days (range: 1 day – 839 days) and the median time-to-resolution was 100 days (1 day – 1,068 days). Seven subjects (1.3%) had symptomatic events, 4 (0.7%) of which were Grade ≥ 3. The reported symptomatic events were cardiac arrest, cardio-respiratory arrest, sudden cardiac death, syncope (n=2), and ventricular arrhythmia (n=2 The median time-to-onset of syncope and ventricular arrhythmia was 204 days and 252 days, respectively. Two subjects with QT prolongation died: 1 due to sudden cardiac death and 1 due to cardio-respiratory arrest. 5 subjects (0.9%) had a maximum absolute QTcF interval > 500 msec and 23 subjects (4.2%) had a maximum change in QTcF from baseline > 60 msec. For specific recommendations, refer to sections 4.2 and 4.4.

Diarrhoea

In clinical studies (N=545), diarrhoea was reported in 72 subjects (13.2%) treated with Aumseqa 110 mg. In 4 subjects (0.7%) the events were Grade ≥ 3. The median time-to-onset of any Grade diarrhoea was 27 days (range: 1 day – 1,046 days) and the median time-to-resolution was 13 days (1 day – 846 days). Three subjects (0.6%) experienced SAEs of diarrhoea. 1 subject reported potassium imbalance. Six subjects reported hypokalaemia of Grade 3. For specific recommendations, refer to section 4.2.

Elevated blood creatinine phosphokinase (CPK) and rhabdomyolysis

In clinical studies (N=545), elevated blood CPK was reported in 173 subjects (31.7%) treated with Aumseqa 110 mg. In 41 subjects (7.5%), the events were Grade ≥ 3. The median time-to-onset of any Grade blood CPK increased was 64 days (range: 1 day – 926 days) and the median time-to-resolution was 215 days (4 days – 1,156 days). Elevated blood CPK led to treatment discontinuation in 1 subject (0.2%). Events of elevated Blood CPK were considered rhabdomyolysis if they were Grade 3 with muscle related symptoms or Grade 4 with or without muscle related symptoms. In total, 14 subjects (2.6%) treated with Aumseqa 110 mg were considered to have experienced rhabdomyolysis. For specific recommendations, refer to sections 4.2 and 4.4.

Hepatic dysfunction

In clinical studies (N=545), hepatic dysfunction was reported in 204 subjects (37.4%) treated with Aumseqa 110 mg. In 20 (3.7%) of these subjects the events were Grade ≥ 3. The median time-to-onset of any Grade hepatic dysfunction was 44 days (range: 1 day – 841 days) and the median time-to-resolution was 62 days (2 days – 1,036 days). AST and ALT elevations were reported in 118 (21.7%) and 110 (20.2%) subjects, respectively. Thirteen subjects (2.4%) reported AST increased of Grade ≥ 3 and 5 subjects (0.9%) reported ALT increased of Grade ≥ 3. One subject (0.2%) reported drug-induced liver injury of Grade ≥ 3 with a time-to-onset of 8 days and a time-to-resolution of 6 days. For specific recommendations, refer to sections 4.2 and 4.4.

Venous thromboembolism (VTE)

In clinical studies (N=545), VTE (including deep vein thrombosis, pulmonary embolism, and venous thrombosis limb) was reported in 39 subjects (7.2%) treated with Aumseqa 110 mg. In 17 subjects (3.1%) the events were Grade ≥ 3. The median time-to-onset of any Grade VTE was 229 days (range: 8 days – 1,087 days) and the median time-to-resolution was 142 days (7 days – 830 days). Pulmonary embolism was reported by 21 subjects (3.9%), with 15 (2.8%) of the events being Grade ≥ 3. Venous thrombosis limb was reported by 16 subjects (2.9%), with 2 (0.4%) of the events being Grade ≥ 3. Deep vein thrombosis was reported by 9 subjects (1.7%), with 1 (0.2%) of the events being Grade ≥ 3. In addition, cerebral infarction and cerebral thrombosis were respectively reported in 4 (0.7%) and 1 (0.2%) subjects, with 3 (0.6%) of the events being Grade ≥ 3. For specific recommendations, refer to sections 4.2 and 4.4.

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.

Not applicable.