4.1. Therapeutic indications

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

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

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

4.2. Posology and method of administration

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

Patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer should be selected for treatment with Itovebi based on the presence of one or more PIK3CA mutations in a tumour or plasma specimen, whichever is available, using a CE-marked in vitro diagnostic (IVD) medical device or a validated test. If a mutation is not detected in one specimen type, a mutation might be detected in the other specimen type, if available.

Posology

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 recommended dose of palbociclib is 125 mg taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. The recommended dose of fulvestrant is 500 mg administered 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 agonist in accordance with local clinical practice.

Duration of treatment

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

Delayed or missed doses

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 than 9 hours, the dose should be skipped for that day. On the next day, Itovebi should be taken at the usual time. If the patient vomits after taking the Itovebi dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time.

Dose modifications

Management of adverse reactions may require temporary interruption, dose reduction, or discontinuation of treatment with Itovebi. The recommended dose reduction guidelines for adverse reactions 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 dailya

a 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 evaluation of the patient by the treating physician. Dose modification guidance for specific adverse reactions is presented in Tables 2-4.

Hyperglycaemia

Table 2: Dose modification and management for hyperglycaemia

Fasting glucose levelsa

Recommendation

> ULN to 160 mg/dL

(> ULN to 8.9 mmol/L)

• No adjustment of Itovebi required.

• Consider dietary modifications (e.g., low carbohydrate diet) and ensure adequate hydration.

• Consider initiating or intensifying oral anti‑hyperglycaemic treatmentb for patients with risk factors for hyperglycaemiac.

> 160 to 250 mg/dL (> 8.9 – 13.9 mmol/L)

• Interrupt Itovebi until fasting glucose level decreases to ≤ 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 appropriate anti-hyperglycaemic treatment, consultation with a healthcare professional experienced in the treatment of hyperglycaemia is recommended.

> 250 to 500 mg/dL (> 13.9 – 27.8 mmol/L)

• Interrupt Itovebi.

• 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 dose level.

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

• If fasting glucose level > 250 to 500 mg/dL (> 13.9 – 27.8 mmol/L) recurs within 30 days, interrupt Itovebi until fasting glucose level decreases to ≤ 160 mg/dL (≤ 8.9 mmol/L). Resume Itovebi at one lower dose level (see Table 1).

> 500 mg/dL

(> 27.8 mmol/L)

• Interrupt Itovebi.

• Initiate or intensify anti-hyperglycaemic treatmentb.

• Assess for volume depletion and ketosis and administer appropriate 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) recurs within 30 days, permanently discontinue Itovebi.

ULN = upper limit of normal

a Fasting glucose levels (fasting plasma glucose [FPG] or fasting blood glucose [FBG]) should be checked prior to initiation of treatment. Fasting glucose levels referenced in this table reflect hyperglycaemia grading according 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 titration recommendations, 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 until recovery to Grade ≤ 1, then resume Itovebi at one lower dose level (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, until recovery to Grade ≤ 1.

• Resume Itovebi at the same dose level.

Grade 3, first event

• Interrupt Itovebi until recovery to Grade ≤ 1.

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

Grade 3, recurrent

OR

Grade 4, non‑life‑threatening

• Interrupt Itovebi until recovery to Grade ≤ 1.

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

Grade 4, life‑threatening

• Permanently discontinue Itovebi.

a Based on CTCAE version 5.0.

Special populations

Paediatric population

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

Elderly

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

Renal impairment

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, and with severe renal impairment (eGFR < 30 mL/min based on CKD-EPI) is 3 mg orally once daily. No dose adjustment is required in patients with mild renal impairment (eGFR 60 to < 90 mL/min).

Hepatic impairment

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 not been established in patients with moderate to severe hepatic impairment (see section 5.2).

Method of administration

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

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Hyperglycaemia

The safety and efficacy of Itovebi in patients with Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring ongoing anti‑hyperglycaemic therapy have not been studied as these patients were excluded from 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 diabetes mellitus. Patients with a history of diabetes mellitus may require intensified anti‑hyperglycaemic treatment and more frequent fasting glucose testing during Itovebi treatment. Treatment with Itovebi should not be initiated until fasting glucose levels are optimised. Consultation with a healthcare professional experienced in the treatment of hyperglycaemia should be considered before initiating Itovebi.

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

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

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

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 monitoring at home should be considered for patients who have risk factors for hyperglycaemia or who experience hyperglycaemia. Metformin premedication can be considered in patients with risk factors for hyperglycaemia. 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 initiating treatment with Itovebi

Test for fasting glucose levels (FPG or FBG) and HbA1C levels and optimise the patient's blood glucose level (see Table 2).

After initiating treatment with Itovebi

Monitor/self‑monitor fasting glucose once every 3 days for the first week (Day 1 to 7), then once every week for the next 3 weeks (Day 8 to 28), then once every 2 weeks for the next 8 weeks, then once every 4 weeks thereafter, and as clinically indicated*.

Consider monitoring/self‑monitoring fasting glucose levels more frequently as clinically indicated* in patients with risk factors for hyperglycaemia including, but are not limited to, (pre)diabetes, HbA1C ≥ 5.7%, BMI ≥ 30 kg/m2, ≥ 45 years of age, history of gestational diabetes, and family history of diabetes mellitus.

More frequent fasting glucose testing is required in patients with concomitant use of corticosteroids, intercurrent infections, or other conditions which may require intensified glycaemia management to prevent worsening of impaired glucose metabolism and potential complications, including diabetic ketoacidosis. Monitoring of HbA1C and ketones (preferably in blood), in addition to fasting glucose, is recommended in these patients.

Initiate or adjust anti‑hyperglycaemic treatment as required (see section 4.2).

HbA1C should be monitored every 3 months.

If hyperglycaemia develops after initiating treatment with Itovebi

Monitor fasting glucose more closely as clinically indicated*.

Based on the severity of the hyperglycaemia, Itovebi dosing may be interrupted, reduced, or discontinued as described in Table 2 (see section 4.2).

During anti‑hyperglycaemic treatment, fasting glucose levels should continue to be monitored at least once a week for 8 weeks, followed by once 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 of stomatitis, 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, prophylaxis containing 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 stomatitis and to avoid alcohol‑ or peroxide‑containing mouthwashes as they may exacerbate the condition (see section 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 limited in patients who previously received a CDK4/6 inhibitor as part of neoadjuvant or adjuvant treatment. Efficacy may be lower in such patients.

Lactose

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

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per film‑coated tablet, that is to say essentially 'sodium‑free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 likelihood of clinically relevant interactions between inavolisib and CYP inhibitors or inducers.

CYP substrates

Inavolisib induces CYP3A and is a time‑dependent inhibitor of CYP3A in vitro. Therefore, inavolisib should be used with caution in combination with sensitive CYP3A4 substrates with a narrow therapeutic 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 with a narrow therapeutic index (e.g., paclitaxel, warfarin, phenytoin, S‑mephenytoin) as inavolisib may decrease their systemic exposure and consequently lead to decreased efficacy.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Females

Patients should be advised to use effective non‑hormonal contraception during treatment with Itovebi and 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 a condom during treatment with Itovebi and for 1 week after the last dose of Itovebi.

Pregnancy

The pregnancy status of females of reproductive potential should be verified prior to initiating Itovebi therapy. 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 in animals have shown reproductive toxicity (see section 5.3). Itovebi is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast‑feeding

It is unknown whether inavolisib/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Itovebi and for 1 week after the last dose of Itovebi.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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. The adverse 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 breast cancer 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 organ class 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 frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on 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), not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

System organ class

Adverse reaction

Itovebi + palbociclib + fulvestrant

N=162

Frequency category

(all grades)

All grades (%)

Grade 3-4 (%)

Infections and infestations

Urinary tract infection

Very common

13

1.2*

Blood and lymphatic system disorders

Thrombocytopenia

Very common

48.1

14.2

Anaemia

Very common

37

6.2*

Metabolism and nutrition disorders

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

-

-

Nervous system disorders

Headache

Very common

21

0

Eye disorders

Dry eye

Common

8.6

0

Gastrointestinal disorders

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*

Vomiting

Very common

14.8

0.6*

Dysgeusia

Common

8.6

0

Dyspepsia

Common

8

0

Skin and subcutaneous tissue disorders

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

General disorders and administration site conditions

Fatigue

Very common

37.7

1.9*

Investigations

Alanine aminotransferase increased

Very common

17.3

3.7*

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 haemoglobin increased.

b Adverse reaction reported during post-marketing experience. The frequency category was estimated as the upper 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, and stomatitis.

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

Hyperglycaemia

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 in 38.3% and 5.6% of patients, respectively (based on CTCAE version 5.0). Among the patients who experienced hyperglycaemia, the rate of new onset of hyperglycaemia events was highest during the first 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 and experienced hyperglycaemia, 74.2% (72/97) received anti‑hyperglycaemic medicines including SGLT2 inhibitors, thiazolidinediones, and DPP‑4 inhibitors for prophylaxis or treatment of hyperglycaemia. All patients who received anti-hyperglycaemic medicines received metformin as a single agent or in combination with other anti‑hyperglycaemic medicines (i.e., insulin, DPP‑4 inhibitors, 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 was 8 days (range: 2 to 43 days).

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

Stomatitis

Stomatitis was reported in 51.2% of patients treated with Itovebi in combination with palbociclib and fulvestrant; 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 time to 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 to discontinuation of Itovebi in 0.6% of patients.

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

Diarrhoea

Diarrhoea was reported in 48.1% of patients treated with Itovebi in combination with palbociclib and fulvestrant; 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 time to 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 lead to discontinuation of Itovebi in any patients.

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

Elderly

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 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

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