Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
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.
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 using a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose (see section 5.1). If a CE-marked IVD is not available, an alternative validated test should be used. If a mutation is not detected in one specimen type, a mutation might be detected 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 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.
It is recommended that patients are treated with Itovebi until disease progression or unacceptable toxicity.
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.
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.
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 treatment b 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.
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.
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. |
| 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 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.
The safety and efficacy of Itovebi in children and adolescents aged 0–17 years have not been established. No data are available.
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).
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 patients with mild renal impairment (eGFR 60 to <90 mL/min). The safety and efficacy of Itovebi have not been 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 not been 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 swallowed whole and not chewed, crushed, dissolved, or divided.
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.
2 years.
This medicinal product does not require any special storage conditions.
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 local requirements.
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