ITOVEBI 9mg film-coated tablets medication leaflet

Itovebi 3 mg film-coated tablets

Itovebi 9 mg film-coated tablets

Itovebi 3 mg film-coated tablets

Each film-coated tablet contains 3 mg of inavolisib.

Each film-coated tablet contains 22 mg of lactose.

Itovebi 9 mg film-coated tablets

Each film-coated tablet contains 9 mg of inavolisib.

Each film-coated tablet contains 66 mg of lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Itovebi 3 mg film-coated tablets

Red, round convex-shaped film-coated tablet with an “INA 3” debossing on one side. Approximatediameter: 6 mm.

Itovebi 9 mg film-coated tablets

Pink, oval film-coated tablet with an “INA 9” debossing on one side. Approximate size: 13 mm(length), 6 mm (width).

Itovebi, in combination with palbociclib and fulvestrant, is indicated for the treatment of adult patientswith PIK3CA-mutated, oestrogen receptor (ER)-positive, HER2-negative, locally advanced ormetastatic breast cancer, following recurrence on or within 12 months of completing adjuvantendocrine treatment (see section 5.1).

Patients previously treated with a CDK 4/6 inhibitor in the (neo)adjuvant setting should have had aninterval of at least 12 months between termination of CDK 4/6 inhibitor treatment and the detection ofrecurrence.

In pre/perimenopausal women and in men, endocrine therapy should be combined with a luteinisinghormone-releasing hormone (LHRH) agonist.

Treatment with Itovebi should be initiated by a physician experienced in the use of anticancertherapies.

Patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer should beselected for treatment with Itovebi based on the presence of one or more PIK3CA mutations in atumour or plasma specimen using a CE-marked in vitro diagnostic (IVD) medical device with thecorresponding intended purpose (see section 5.1). If a CE-marked IVD is not available, an alternativevalidated test should be used. If a mutation is not detected in one specimen type, a mutation might bedetected in the other specimen type, if available.

The recommended dose of Itovebi is 9 mg taken orally once daily with or without food.

Itovebi should be administered in combination with palbociclib and fulvestrant. The recommendeddose of palbociclib is 125 mg taken orally once daily for 21 consecutive days followed by 7 days offtreatment to comprise a complete cycle of 28 days. The recommended dose of fulvestrant is 500 mgadministered intramuscularly on Days 1, 15, and 29, then once monthly thereafter. Please refer to the

Summary of Product Characteristics (SmPC) of palbociclib and fulvestrant for more information.

Treatment of pre/perimenopausal women and men with Itovebi should also include an LHRH agonistin accordance with local clinical practice.

It is recommended that patients are treated with Itovebi until disease progression or unacceptabletoxicity.

Patients should be encouraged to take their dose at approximately the same time each day. If a dose of

Itovebi is missed, it can be taken within 9 hours after the time it is usually taken. After more than9 hours, the dose should be skipped for that day. On the next day, Itovebi should be taken at the usualtime. If the patient vomits after taking the Itovebi dose, the patient should not take an additional doseon that day and should resume the usual dosing schedule the next day at the usual time.

Management of adverse reactions may require temporary interruption, dose reduction, ordiscontinuation of treatment with Itovebi. The recommended dose reduction guidelines for adversereactions are listed in Table 1.

Table 1: Dose reduction guidelines for adverse reactions

Dose level Dose and schedule

Starting dose 9 mg daily

First dose reduction 6 mg daily

Second dose reduction 3 mg dailyaa Itovebi treatment should be permanently discontinued if patients are unable to tolerate the 3 mg daily dose.

The dose of Itovebi may be re-escalated to a maximum daily dose of 9 mg based on clinical evaluationof the patient by the treating physician. Dose modification guidance for specific adverse reactions ispresented in Tables 2-4.

Table 2: Dose modification and management for hyperglycaemia

Fasting glucose levelsa Recommendation> ULN to 160 mg/dL - No adjustment of Itovebi required.(> ULN to 8.9 mmol/L) - Consider dietary modifications (e.g., low carbohydrate diet) andensure adequate hydration.

-  Consider initiating or intensifying oral anti-hyperglycaemictreatmentb for patients with risk factors for hyperglycaemiac.> 160 to 250 mg/dL - Interrupt Itovebi until fasting glucose level decreases to(> 8.9 - 13.9 mmol/L) ≤ 160 mg/dL (≤ 8.9 mmol/L).

-  Initiate or intensify anti-hyperglycaemic treatmentb.

-  Resume Itovebi at the same dose level.

-  If fasting glucose level persists > 200 - 250 mg/dL(> 11.1 - 13.9 mmol/L) for 7 days under appropriateanti-hyperglycaemic treatment, consultation with a healthcareprofessional experienced in the treatment of hyperglycaemia isrecommended.

> 250 to 500 mg/dL - Interrupt Itovebi.(> 13.9 - 27.8 mmol/L) - Initiate or intensify anti-hyperglycaemic treatmentb.

-  Administer appropriate hydration if required.

-  If fasting glucose level decreases to ≤ 160 mg/dL(≤ 8.9 mmol/L) within 7 days, resume Itovebi at the same doselevel.

-  If fasting glucose level decreases to ≤ 160 mg/dL(≤ 8.9 mmol/L) in ≥ 8 days, resume Itovebi at one lower doselevel (see Table 1).

-  If fasting glucose level > 250 to 500 mg/dL(> 13.9 - 27.8 mmol/L) recurs within 30 days, interrupt Itovebiuntil fasting glucose level decreases to ≤ 160 mg/dL(≤ 8.9 mmol/L). Resume Itovebi at one lower dose level (see

Table 1).

Fasting glucose levelsa Recommendation> 500 mg/dL - Interrupt Itovebi.(> 27.8 mmol/L) - Initiate or intensify anti-hyperglycaemic treatmentb.

-  Assess for volume depletion and ketosis and administerappropriate hydration.

-  If fasting glucose level decreases to ≤ 160 mg/dL(≤ 8.9 mmol/L), resume Itovebi at one lower dose level (see

Table 1).

-  If fasting glucose level > 500 mg/dL (> 27.8 mmol/L) recurswithin 30 days, permanently discontinue Itovebi.

ULN = upper limit of normala Fasting glucose levels (fasting plasma glucose [FPG] or fasting blood glucose [FBG]) should be checkedprior to initiation of treatment. Fasting glucose levels referenced in this table reflect hyperglycaemia gradingaccording to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

b Initiate applicable anti-hyperglycaemic treatments such as metformin, sodium-glucose cotransporter-2(SGLT2) inhibitors, insulin sensitisers (such as thiazolidinediones), dipeptidyl peptidase-4 (DPP-4)inhibitors, or insulin, and review the respective prescribing information for dosing and dose titrationrecommendations, including local hyperglycaemia treatment guidelines. Metformin was recommended in the

INAVO120 study as the preferred initial agent. See sections 4.4 and 4.8.

c See section 4.4 for risk factors for hyperglycaemia.

Stomatitis

Table 3: Dose modification and management for stomatitis

Gradea Recommendation

Grade 1 - No adjustment of Itovebi required.

-  Initiate or intensify appropriate medical therapy (e.g.,corticosteroid-containing mouthwash) as clinically indicated.

Grade 2 - Withhold Itovebi until recovery to Grade ≤ 1.

-  Initiate or intensify appropriate medical therapy. Resume

Itovebi at the same dose level.

-  For recurrent Grade 2 stomatitis, withhold Itovebi untilrecovery to Grade ≤ 1, then resume Itovebi at one lower doselevel (see Table 1).

Grade 3 - Withhold Itovebi until recovery to Grade ≤ 1.

-  Initiate or intensify appropriate medical therapy. Resume

Itovebi at one lower dose level (see Table 1).

Grade 4 - Permanently discontinue Itovebi.a Based on CTCAE version 5.0.

Other adverse reactions

Table 4: Dose modification and management for other adverse reactions

Gradea Recommendation

For all grades: Initiate supportive therapy and monitor as clinically indicated.

Grade 1 - No adjustment of Itovebi required.

Grade 2 - Consider interruption of Itovebi, if clinically indicated, untilrecovery to Grade ≤ 1.

-  Resume Itovebi at the same dose level.

Gradea Recommendation

For all grades: Initiate supportive therapy and monitor as clinically indicated.

Grade 3, first event - Interrupt Itovebi until recovery to Grade ≤ 1.

-  Resume Itovebi at the same dose level or at one lower doselevel based on clinical evaluation (see Table 1).

Grade 3, recurrent - Interrupt Itovebi until recovery to Grade ≤ 1.

OR - Resume Itovebi at one lower dose level (see Table 1).

Grade 4, non-life-threatening

Grade 4, life-threatening - Permanently discontinue Itovebi.a Based on CTCAE version 5.0.

The safety and efficacy of Itovebi in children and adolescents aged 0 - 17 years have not beenestablished. No data are available.

No dose adjustment of Itovebi is required in patients ≥ 65 years of age based on populationpharmacokinetic analysis. There are limited data in patients ≥ 65 years of age (see section 5.2).

The recommended starting dose of Itovebi for patients with moderate renal impairment (eGFR 30 to< 60 mL/min based on CKD-EPI) is 6 mg orally once daily. No dose adjustment is required in patientswith mild renal impairment (eGFR 60 to < 90 mL/min). The safety and efficacy of Itovebi have notbeen established in patients with severe renal impairment (see section 5.2).

No dose adjustment is required in patients with mild hepatic impairment (total bilirubin > ULN to≤ 1.5 × ULN or AST > ULN and total bilirubin ≤ ULN). The safety and efficacy of Itovebi have notbeen established in patients with moderate to severe hepatic impairment (see section 5.2).

Itovebi is for oral use. The tablets can be taken with or without food. The tablets should be swallowedwhole and not chewed, crushed, dissolved, or divided.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

The safety and efficacy of Itovebi in patients with Type 1 diabetes mellitus or Type 2 diabetes mellitusrequiring ongoing anti-hyperglycaemic therapy have not been studied as these patients were excludedfrom the INAVO120 study. Only 1 patient with Type 2 diabetes was included in the Itovebi arm of the

INAVO120 study, which should be considered when Itovebi is prescribed to patients with diabetesmellitus. Patients with a history of diabetes mellitus may require intensified anti-hyperglycaemictreatment and more frequent fasting glucose testing during Itovebi treatment. Treatment with Itovebishould not be initiated until fasting glucose levels are optimised. Consultation with a healthcareprofessional experienced in the treatment of hyperglycaemia should be considered before initiating

Itovebi.

Hyperglycaemia has been frequently reported in patients treated with Itovebi. Severe cases ofhyperglycaemia, including ketoacidosis with fatal complications, have occurred.

In the INAVO120 study, hyperglycaemia was managed with anti-hyperglycaemic treatment andadjustments of Itovebi as clinically indicated (see section 4.8). Short-term insulin may be used asrescue treatment for hyperglycaemia. There is limited experience in patients receiving insulin whenbeing treated with Itovebi. A potential for hypoglycaemia with anti-hyperglycaemic medicinalproducts (e.g., insulin, sulfonylureas) should be considered when used to manage hyperglycaemiaprior to Itovebi being interrupted or discontinued.

Before initiating treatment with Itovebi, patients should be advised of the signs and symptoms ofhyperglycaemia (e.g., excessive thirst, urinating more often, blurred vision, mental confusion,difficulty breathing, or increased appetite with weight loss) and to immediately contact a healthcareprofessional if these symptoms occur. Optimal hydration should be maintained prior to and duringtreatment.

Patients should be tested for fasting glucose levels (FPG or FBG) and HbA1C prior to treatment with

Itovebi and at regular intervals during treatment (see Table 5). Initiation of fasting glucose monitoringat home should be considered for patients who have risk factors for hyperglycaemia or who experiencehyperglycaemia. Metformin premedication can be considered in patients with risk factors forhyperglycaemia. All patients should be instructed on lifestyle changes (e.g., dietary modifications,physical activity).

Table 5: Schedule of fasting glucose monitoring and HbA1C

Recommended schedule for the monitoring of fasting glucose and

HbA1C levels in all patients treated with Itovebi

At screening, before Test for fasting glucose levels (FPG or FBG) and HbA1C levels andinitiating treatment optimise the patient’s blood glucose level (see Table 2).with Itovebi

After initiating Monitor/self-monitor fasting glucose once every 3 days for the first weektreatment with (Day 1 to 7), then once every week for the next 3 weeks (Day 8 to 28),

Itovebi then once every 2 weeks for the next 8 weeks, then once every 4 weeksthereafter, and as clinically indicated*.

Consider monitoring/self-monitoring fasting glucose levels morefrequently as clinically indicated* in patients with risk factors forhyperglycaemia including, but are not limited to, (pre)diabetes,

HbA1C ≥ 5.7%, BMI ≥ 30 kg/m2, ≥ 45 years of age, history of gestationaldiabetes, and family history of diabetes mellitus.

More frequent fasting glucose testing is required in patients withconcomitant use of corticosteroids, intercurrent infections, or otherconditions which may require intensified glycaemia management toprevent worsening of impaired glucose metabolism and potentialcomplications, including diabetic ketoacidosis. Monitoring of HbA1C andketones (preferably in blood), in addition to fasting glucose, isrecommended in these patients.

Initiate or adjust anti-hyperglycaemic treatment as required (seesection 4.2).

Recommended schedule for the monitoring of fasting glucose and

HbA1C levels in all patients treated with Itovebi

HbA1C should be monitored every 3 months.

If hyperglycaemia Monitor fasting glucose more closely as clinically indicated*.develops after Based on the severity of the hyperglycaemia, Itovebi dosing may beinitiating treatment interrupted, reduced, or discontinued as described in Table 2 (seewith Itovebi section 4.2).

During anti-hyperglycaemic treatment, fasting glucose levels shouldcontinue to be monitored at least once a week for 8 weeks, followed byonce every 2 weeks, and as clinically indicated*.

* All glucose monitoring should be performed at the physician’s discretion as clinically indicated.

Stomatitis

Stomatitis has been reported in patients treated with Itovebi (see section 4.8). Based on the severity ofstomatitis, Itovebi dosing may be interrupted, reduced, or permanently discontinued (see Table 3).

Corticosteroid mouthwash was recommended for prophylaxis of stomatitis in the INAVO120 study.

Among patients who received Itovebi in combination with palbociclib and fulvestrant, prophylaxiscontaining dexamethasone or triamcinolone was used in 19.1% and 1.2% of patients, respectively.

Patients should be advised to start alcohol-free corticosteroid mouthwash at the first sign of stomatitisand to avoid alcohol- or peroxide-containing mouthwashes as they may exacerbate the condition (seesection 4.8). Dietary modifications (e.g., avoiding spicy foods) should be considered.

Use in patients who previously received a CDK4/6 inhibitor

Information on the efficacy of the combination of Itovebi, palbociclib, and fulvestrant is very limitedin patients who previously received a CDK4/6 inhibitor as part of neoadjuvant or adjuvant treatment.

Efficacy may be lower in such patients.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucoseglucose-galactose galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially ‘sodium-free’.

No interaction studies have been performed.

CYP inhibitors and inducers

Clinical study results indicated that the predominant metabolites of inavolisib are not mediated by

CYP enzymes, and that hydrolysis was the major metabolic pathway. This suggests a low likelihoodof clinically relevant interactions between inavolisib and CYP inhibitors or inducers.

Inavolisib induces CYP3A and is a time-dependent inhibitor of CYP3A in vitro. Therefore, inavolisibshould be used with caution in combination with sensitive CYP3A4 substrates with a narrowtherapeutic index (e.g., alfentanil, astemizole, cisapride, cyclosporine, quinidine, sirolimus,tacrolimus) as inavolisib may increase or decrease the systemic exposure of these substrates.

In addition, inavolisib induces CYP2B6, CYP2C8, CYP2C9, and CYP2C19 in vitro. Therefore,inavolisib should be used with caution in combination with sensitive substrates of these enzymes witha narrow therapeutic index (e.g., paclitaxel, warfarin, phenytoin, S-mephenytoin) as inavolisib maydecrease their systemic exposure and consequently lead to decreased efficacy.

Females

Patients should be advised to use effective non-hormonal contraception during treatment with Itovebiand for 1 week after the last dose of Itovebi.

Males

It is not known if inavolisib is present in semen. To avoid potential foetal exposure during pregnancy,male patients with female partners of childbearing potential or pregnant female partners should use acondom during treatment with Itovebi and for 1 week after the last dose of Itovebi.

The pregnancy status of females of reproductive potential should be verified prior to initiating Itovebitherapy. Pregnant women should be clearly advised of the potential risk to the foetus.

There are no or limited amount of data from the use of inavolisib in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). Itovebi is not recommended duringpregnancy and in women of childbearing potential not using contraception.

It is unknown whether inavolisib/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with

Itovebi and for 1 week after the last dose of Itovebi.

No human data on the effect of inavolisib on fertility are available. Based on animal studies, inavolisibmay impact fertility in females and males of reproductive potential (see section 5.3).

Itovebi has minor influence on the ability to drive or use machines because fatigue has been reportedduring treatment with Itovebi.

The most common adverse reactions in patients who received Itovebi were hyperglycaemia (59.9%),stomatitis (51.2%), diarrhoea (48.1%), thrombocytopenia (48.1%), fatigue (37.7%), anaemia (37%),nausea (27.8%), decreased appetite (23.5%), rash (22.8%), headache (21%), weight decreased(17.3%), vomiting (14.8%), and urinary tract infection (13%).

The most common serious adverse reactions reported in patients who received Itovebi were anaemia(1.9%), diarrhoea (1.2%), and urinary tract infection (1.2%).

Permanent discontinuation of Itovebi due to an adverse reaction occurred in 3.1% of patients. Theadverse reactions leading to permanent discontinuation of Itovebi were hyperglycaemia (1.2%),stomatitis (0.6%), alanine transaminase (ALT) increased (0.6%), and weight decreased (0.6%).

Tabulated list of adverse drug reactions

Adverse drug reactions, based on data from 162 patients with locally advanced or metastatic breastcancer who received Itovebi in combination with palbociclib and fulvestrant in the INAVO120

Phase 3, randomised study, and from post-marketing surveillance are listed by MedDRA system organclass in Table 6. The median duration of Itovebi treatment at the time of the analysis was 9.2 months(range: 0 to 38.8 months).

Within each system organ class, the adverse reactions are ranked by frequency, with the most frequentreactions first. The corresponding frequency category for each adverse drug reaction is based on thefollowing 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), not known (cannot be estimated fromavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 6: Adverse drug reactions observed in patients treated with Itovebi

Itovebi + palbociclib + fulvestrant

System organ class N=162

Adverse reaction Frequency category All grades (%) Grade 3-4 (%)(all grades)

Urinary tract infection Very common 13 1.2*

Thrombocytopenia Very common 48.1 14.2

Anaemia Very common 37 6.2*

Hyperglycaemiaa Very common 59.9 5.6*

Decreased appetite Very common 23.5 0

Hypokalaemia Very common 16 2.5

Hypocalcaemia Common 8.6 1.2*

Ketoacidosis Uncommonb - -

Headache Very common 21 0

Dry eye Common 8.6 0

Stomatitisc Very common 51.2 5.6*

Diarrhoea Very common 48.1 3.7*

Nausea Very common 27.8 0.6*

Abdominal pain Very Common 15.4 0.6*

Itovebi + palbociclib + fulvestrant

System organ class N=162

Adverse reaction Frequency category(all grades) All grades (%) Grade 3-4 (%)

Vomiting Very common 14.8 0.6*

Dysgeusia Common 8.6 0

Dyspepsia Common 8 0

Rashd Very common 22.8 0

Alopecia Very common 18.5 0

Dry skine Very common 13 0

Dermatitisf Common 2.5 0

Folliculitis Common 1.2 0

Fatigue Very common 37.7 1.9*

Alanine Very common 17.3 3.7*aminotransferaseincreased

Weight decreased Very common 17.3 3.7*

Blood insulin increased Common 6.2 0

Grading according to CTCAE version 5.0.

* No Grade 4 events were observed.a Includes hyperglycaemia, blood glucose increased, hyperglycaemic crisis, glycated serum protein increased,glucose tolerance impaired, diabetes mellitus, Type 2 diabetes mellitus, and glycosylated haemoglobinincreased.

b Adverse reaction reported during post-marketing experience. The frequency category was estimated as theupper limit of the 95% confidence interval calculated on the basis of the total number of patients exposed to

Itovebi in clinical trials.

c Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, andstomatitis.

d Includes rash, rash erythematous, rash maculo-papular, rash papular, rash pruritic, and rash pustular.e Includes dry skin, skin fissures, xerosis, and xeroderma.f Includes dermatitis, dermatitis acneiform, and dermatitis bullous.

Description of selected adverse drug reactions

In the INAVO120 study, hyperglycaemia of any grade was reported in 59.9% of patients treated with

Itovebi in combination with palbociclib and fulvestrant; Grade 2 and Grade 3 events were reported in38.3% and 5.6% of patients, respectively (based on CTCAE version 5.0). Among the patients whoexperienced hyperglycaemia, the rate of new onset of hyperglycaemia events was highest during thefirst two months of treatment with a median time to first onset of 7 days (range: 2 to 955 days).

In the 97 patients who received Itovebi in combination with palbociclib and fulvestrant andexperienced hyperglycaemia, 74.2% (72/97) received anti-hyperglycaemic medicines including

SGLT2 inhibitors, thiazolidinediones, and DPP-4 inhibitors for prophylaxis or treatment ofhyperglycaemia. All patients who received anti-hyperglycaemic medicines received metformin as asingle agent or in combination with other anti-hyperglycaemic medicines (i.e., insulin, DPP-4inhibitors, and sulfonylureas); and 11.3% (11/97) received insulin (see section 4.4).

In patients with fasting glucose levels > 160 mg/dL (> 8.9 mmol/L) with at least one level (see

Table 2) improvement in fasting blood glucose levels (n=52), the median time to improvement was8 days (range: 2 to 43 days).

Hyperglycaemia led to interruption of Itovebi in 27.8%, to dose reduction of Itovebi in 2.5%, and todiscontinuation of Itovebi in 1.2% of patients.

Stomatitis

Stomatitis was reported in 51.2% of patients treated with Itovebi in combination with palbociclib andfulvestrant; Grade 1 events were reported in 32.1% of patients, Grade 2 events in 13.6% of patients,and Grade 3 events in 5.6% of patients. Among patients who experienced stomatitis, the median timeto first onset was 13 days (range: 1 to 610 days).

Stomatitis led to interruption of Itovebi in 9.9%, to dose reduction of Itovebi in 3.7%, and todiscontinuation of Itovebi in 0.6% of patients.

In patients who received Itovebi in combination with palbociclib and fulvestrant, 24.1% used amouthwash containing dexamethasone for management of stomatitis (see section 4.4).

Diarrhoea was reported in 48.1% of patients treated with Itovebi in combination with palbociclib andfulvestrant; Grade 1 events were reported in 27.8% of patients, Grade 2 events in 16.7% of patients,and Grade 3 events in 3.7% of patients. Among patients who experienced diarrhoea, the median timeto first onset was 15 days (range: 2 to 602 days).

Diarrhoea led to interruption of Itovebi in 6.8%, to dose reduction of Itovebi in 1.2%, and did not leadto discontinuation of Itovebi in any patients.

Anti-diarrhoeal medicines (e.g., loperamide) were used in 28.4% of patients who received Itovebi incombination with palbociclib and fulvestrant to manage symptoms.

Analysis of the safety of Itovebi comparing patients ≥ 65 years of age (14.8%) to younger patients(85.2%) suggests a higher incidence of Itovebi dose modification/interruptions (79.2% versus 68.1%).

Reporting 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.

The highest dose of Itovebi administered in the INAVO120 study was 18 mg in one patient. This eventof accidental overdose was resolved in one day and did not require treatment or lead to dosemodification of any study drugs.

Patients who experience overdose should be closely supervised and supportive care instituted. Thereare no known antidotes for Itovebi.

Pharmacotherapeutic group: Antineoplastic agents, PI3K inhibitors, ATC Code: not yet assigned

Inavolisib is an inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalyticsubunit alpha isoform protein (p110α; encoded by the PIK3CA gene). In addition, inavolisib promotesthe degradation of mutated p110α (mutant degrader). The PI3K signalling pathway is commonlydysregulated in HR-positive breast cancer, often due to activating PIK3CA mutations. With its dualmechanism of action, inavolisib inhibits the activity of downstream PI3K pathway targets, including

AKT, resulting in reduced cellular proliferation and induction of apoptosis in PIK3CA-mutated breastcancer cell lines.

Locally advanced or metastatic breast cancer

The patients in this setting, based on data from the INAVO120 study, are defined asendocrine-resistant patients (disease recurrence on or within 12 months of adjuvant endocrinetreatment completion) who have not received prior treatment for their locally advanced or metastaticdisease.

INAVO120

The efficacy of Itovebi in combination with palbociclib and fulvestrant was evaluated in a Phase 3,randomised, double-blind, placebo-controlled study in adult patients with PIK3CA-mutated,

HR-positive, HER2-negative, locally advanced or metastatic breast cancer whose disease progressedduring or within 12 months of completing adjuvant endocrine therapy (endocrine-resistant) and whohave not received prior systemic therapy for locally advanced or metastatic disease. The studyincluded patients who received prior (neo)adjuvant endocrine therapy including a CDK4/6 inhibitor ifthe progression event was  12 months since completion of the CDK4/6 inhibitor portion of(neo)adjuvant therapy, and who had HbA1C < 6% and fasting blood glucose < 126 mg/dL. The studyexcluded patients with Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring ongoinganti-hyperglycaemic therapy at the start of study treatment, patients who received prior treatment withfulvestrant (except as part of neoadjuvant therapy with treatment duration ≤ 6 months), and patientswith known and untreated, or active CNS metastases (progressing or requiring anticonvulsants orcorticosteroids for symptomatic control).

PIK3CA mutation status was prospectively determined through testing of plasma-derived circulatingtumour DNA (ctDNA) using a next-generation sequencing (NGS) assay (FoundationOne® Liquid CDxassay or PredicineCARETM) performed at a central laboratory (87.4%), or in local laboratories (12.6%)using various validated polymerase chain reaction (PCR) or NGS assays on tumour tissue or plasma.

The following PIK3CA mutations at the indicated amino acid positions were eligible for inclusion:

H1047D/I/L/N/P/Q/R/T/Y, G1049A/C/D/R/S, E545A/D/G/K/L/Q/R/V, E453A/D/G/K/Q/V,

E542A/D/G/K/Q/R/V, K111N/R/E, Q546E/H/K/L/P/R, G106A/D/R/S/V, N345D/H/I/K/S/T/Y,

G118D, C420R, R88Q, and M1043I/T/V. At least one eligible PIK3CA mutation was identified in atleast one of these amino acid positions in each of the enrolled patient specimens. Based on resultsfrom the central FoundationOne® Liquid CDx assay, the most common PIK3CA alterations were shortvariants at amino acids H1047 (n=115, 42.6%), E545 (n=58, 21.5%), and E542 (n=39, 14.4%). Therewere 25 patients whose specimens harboured more than one PIK3CA alterations (i.e., multiple

PIK3CA mutations), and 33 with less common PIK3CA alterations.

A total of 325 patients were randomised 1:1 to receive either Itovebi 9 mg (n=161) or placebo (n=164)orally once daily, in combination with palbociclib and fulvestrant, until disease progression orunacceptable toxicity. In addition, pre/perimenopausal women and men received an LHRH agonistthroughout therapy. Randomisation was stratified by presence of visceral disease (yes or no),endocrine resistance (primary or secondary), and geographic region (North America/Western Europe,

Asia, other).

The baseline demographic and disease characteristics were: median age 54 years (range: 27 to79 years, 18.2% were ≥ 65 years of age); 98.2% female; 38.2% pre/perimenopausal; 58.8% White,38.2% Asian, 2.5% unknown, 0.6% Black or African American; 6.2% Hispanic or Latino; and Eastern

Cooperative Oncology Group (ECOG) performance status of 0 (63.4%) or 1 (36.3%). Tamoxifen(56.9%) and aromatase inhibitors (50.2%) were the most commonly used adjuvant endocrinetherapies. Three (0.9%) patients received prior CDK4/6 inhibitor therapy. The demographics andbaseline disease characteristics were balanced and comparable between study arms.

The primary efficacy outcome measure was investigator (INV)-assessed progression-free survival(PFS) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. The secondaryefficacy outcome measures included overall survival (OS), objective response rate (ORR), best overallresponse (BOR), clinical benefit rate (CBR), duration of response (DOR), and time to confirmeddeterioration (TTCD) in pain, physical function, role function, and global health status/health-relatedquality of life (HRQoL).

Efficacy results are summarised in Table 7, Figure 1, and Figure 2. INV-assessed PFS results weresupported by consistent results from blinded independent central review (BICR) assessment.

Table 7: Efficacy results in patients with locally advanced or metastatic breast cancer in

INAVO120

Itovebi + palbociclib Placebo + palbociclib

Efficacy endpoint + fulvestrant + fulvestrant

N=161 N=164

INV-assessed progression-free survivala

Patients with event, n (%) 82 (50.9) 113 (68.9)

Median, months (95% CI) 15 (11.3, 20.5) 7.3 (5.6, 9.3)

Hazard ratio (95% CI) 0.43 (0.32, 0.59)p-value < 0.0001

Overall survivalb,c

Patients with event, n (%) 72 (44.7) 82 (50)

Median, months (95% CI) 34 (28.4, 44.8) 27 (22.8, 38.7)

Hazard ratio (95% CI) 0.67 (0.48, 0.94)p-value 0.0190

Objective response rateb,d

Patients with CR or PR, n (%) 101 (62.7) 46 (28)95% CI (54.8, 70.2) (21.3, 35.6)p-value <0.0001

Duration of responseb

Median DOR, months (95% 19.2 (14.7, 28.3) 11.1 (8.5, 20.2)

CI)

CI = confidence interval; CR = complete response; PR = partial responsea Per RECIST version 1.1. Based on primary analysis (clinical cutoff date: 29 September 2023).b Based on final overall survival analysis (clinical cutoff date: 15 November 2024).c The prespecified boundary for statistical significance was p < 0.0469.

d Per RECIST version 1.1. ORR is defined as the proportion of patients with a CR or PR on two consecutiveoccasions ≥ 4 weeks apart, as determined by the investigator.

Figure 1 INV-assessed progression-free survival in patients with locally advanced ormetastatic breast cancer in INAVO120

Figure 2 Overall survival in patients with locally advanced or metastatic breast cancer in

INAVO120

The European Medical Agency has waived the obligation to submit the results of studies with Itovebiin all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatricuse).

The pharmacokinetics of inavolisib were characterised in healthy subjects and in patients with locallyadvanced or metastatic PIK3CA-mutated solid tumours, including breast cancer, under an oral dosingregimen ranging from 6 mg to 12 mg daily and in healthy subjects at 9 mg single dose.

Inavolisib pharmacokinetics are presented as geometric mean (geometric coefficient of variation [geo

CV]%) following administration of the approved recommended dosage unless otherwise specified.

Based on population pharmacokinetics analysis, the inavolisib steady-state AUC was 1 019 h*ng/mL(29%) and Cmax was 67 ng/mL (28%). Steady-state concentrations were predicted to be attained byday 5.

With 9 mg once daily dosing, the geometric mean accumulation ratio was about 2-fold.

The time to maximum plasma concentration (Tmax) was reached after a median of 3 hours (range: 0.5to 4 hours) at steady state following 9 mg daily dosing of inavolisib, under fasted conditions.

The absolute oral bioavailability of inavolisib was 76%.

No clinically significant effect of food on inavolisib exposure was observed. The geometric mean ratio(GMR) (90% CI) for AUC0-24 comparing the fed to the fasted state was 0.895 (0.737 - 1.09) after asingle dose and 0.876 (0.701 - 1.09) at steady state. The GMR (90% CI) for Cmax comparing the fed tothe fasted state was 0.925 (0.748 - 1.14) after a single dose and 0.910 (0.712 - 1.16) at steady state.

Plasma protein binding of inavolisib in humans is 37% and did not appear to beconcentration-dependent over the concentration range tested (0.1 - 10 μM). In humans, the estimatedsteady state oral volume of distribution is 155 L (26%) based on population pharmacokineticsanalysis.

Following oral administration of a single radio-labeled 9 mg dose of inavolisib to healthy subjects,parent drug was the most prominent drug-related compound in plasma and urine. Hydrolysis was themajor metabolic pathway. No specific hydrolysis enzymes involved in the metabolism of inavolisibwere identified.

Following oral administration of a single radio-labeled 9 mg dose of inavolisib to healthy subjects,48.5% of the administered dose was recovered in urine (40.4% unchanged) and 48% in faeces (10.8%unchanged).

In clinical studies, based on population pharmacokinetics analysis, the geometric mean of theindividual elimination half-life estimates for inavolisib was 15 hours (24%) following a single 9 mgdose. The estimated total clearance of inavolisib is 8.8 L/hr (29%).

Limited data suggest dose proportionality within the dose range tested (6 to 12 mg) for single-dose

Cmax and AUC0-24 and steady-state AUC0-24; however, for steady-state Cmax, the data suggest non-proportionality.

Clinical study results indicated that the predominant metabolites of inavolisib are not mediated by

CYP enzymes, suggesting a low likelihood of clinically relevant interactions between inavolisib and

CYP inhibitors or inducers. Moreover, in vitro results indicated that inavolisib does not inhibit

CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 enzymes.

In vitro studies have shown that inavolisib does not appear to have the potential to inhibit any of therelevant drug transporters tested. Furthermore, inavolisib is a substrate of P-glycoprotein (P-gp) andbreast cancer resistance protein (BCRP) in vitro. However, based on the overall pharmacokineticcharacteristics of inavolisib, inhibitors or inducers of P-gp and/or BCRP are not expected to cause aclinically relevant drug-drug interaction with inavolisib.

No clinically relevant differences in inavolisib pharmacokinetics were noted between patients 65 yearsof age and older and those under 65 years based on population pharmacokinetic analysis. Of the162 patients who received Itovebi in the INAVO120 study, 24 patients were ≥ 65 years of age.

Population pharmacokinetic analyses indicated that mild renal impairment is not a clinically relevantcovariate on inavolisib exposure. The pharmacokinetics of inavolisib in patients with mild renalimpairment (eGFR 60 to < 90 mL/min) were similar to those in patients with normal renal function.

Inavolisib AUC and Cmax were 73% and 11% higher in patients with moderate renal impairmentcompared to patients with normal renal function (eGFR ≥ 90 mL/min), respectively. The effect ofsevere renal impairment on inavolisib pharmacokinetics has not been established.

Population pharmacokinetic analyses indicated that mild hepatic impairment is not a clinically relevantcovariate on inavolisib exposure. The pharmacokinetics of inavolisib in patients with mild hepaticimpairment (total bilirubin > ULN to ≤ 1.5 × ULN or AST > ULN and total bilirubin ≤ ULN) weresimilar to those in patients with normal hepatic function. The effect of moderate to severe hepaticimpairment on inavolisib pharmacokinetics has not been studied.

Inavolisib was not mutagenic in the bacterial mutagenesis assay.

Inavolisib showed clastogenicity in vitro; however, there was no evidence of inavolisib-induced invivo genotoxicity (clastogenicity, aneugenicity, or DNA damage) in the micronucleus and comet studyin rats at doses up to a maximum tolerated dose (MTD) of 16 times the exposure at a clinical dose of9 mg.

No carcinogenicity studies with inavolisib have been conducted.

Developmental toxicity

An embryo-foetal development study in Sprague-Dawley rats identified inavolisib-relateddose-dependent effects on embryo-foetal development that included decreases in foetal body weightand placental weight, post-implantation loss, lower foetal viability, and teratogenicity (foetal external,visceral, and skeletal malformations), with the maternal exposure at NOAEL being 0.2 times theexposure at a clinical dose of 9 mg.

No dedicated fertility studies with inavolisib have been conducted.

In male rats, dose-dependent atrophy of the prostate and seminal vesicle and decreased organ weightswithout microscopic correlate in the epididymis and testis were observed (at ≥ NOAEL of 0.4 timesthe exposure at a clinical dose of 9 mg). These findings were reversible. In male dogs, focalinspissation of seminiferous tubule contents and multinucleated spermatids in the testis and epithelialdegeneration/necrosis in the epididymis were observed following 4 weeks of dosing (at ≥ 2 times theexposure at a clinical dose of 9 mg). Following 3 months of dosing at up to 1.2 times the exposure at aclinical dose of 9 mg, a reversible decrease in total sperm count was observed with a no observedadverse effect level (NOAEL) of 0.4 times the exposure at a clinical dose of 9 mg but there were noinavolisib-related microscopic findings in the testes or epididymides or effects on sperm concentration,motility, or morphology.

In female rats, minimal to mild atrophy in the uterus and vagina, decreased ovarian follicles, andfindings suggestive of an interruption/alteration of the oestrus cycle were observed (at ≥ 1.2 times theexposure at a clinical dose of 9 mg), with a NOAEL of 0.5 times the exposure at a clinical dose of9 mg. These findings were not observed following the recovery period in the 4-week toxicity study.

Recovery was not assessed in the 3-month study in rats.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use, included inflammation in dogs andeye lens degeneration in rats. The inflammation is consistent with the anticipated pharmacologiceffects of PI3K inhibition, was generally dose-dependent and reversible. Minimal lens fiberdegeneration observed in some rats (at ≥ 3.6 times the exposure at a clinical dose of 9 mg) wasconsidered irreversible.

Itovebi 3 mg and 9 mg tablet core

Lactose monohydrate

Magnesium stearate (E470b)

Microcrystalline cellulose (E460)

Sodium starch glycolate

Itovebi 3 mg film-coating

Polyvinyl alcohol, partially hydrolysed

Titanium dioxide (E 171)

Macrogol

Talc (E 553b)

Iron oxide red (E 172)

Itovebi 9 mg film-coating

Polyvinyl alcohol, partially hydrolysed

Titanium dioxide (E 171)

Macrogol

Talc (E 553b)

Iron oxide red (E 172)

Iron oxide yellow (E 172)

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from moisture.

Alu/Alu (aluminium/aluminium) perforated unit-dose blisters in cartons of 28 × 1 film-coated tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/25/1942/001

EU/1/25/1942/002

Date of first authorisation: 18 July 2025

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.