ITOVEBI

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. 9 mmol/L) • No adjustment of Itovebi required.

, low carbohydrate diet) and ensure adequate hydration. • Consider initiating or intensifying oral anti-hyperglycaemic treatmentb for patients with risk factors for hyperglycaemiac. 9 mmol/L). • Initiate or intensify anti-hyperglycaemic treatmentb.

• Resume Itovebi at the same dose level. 9 mmol/L) for 7 days under appropriate anti- hyperglycaemic treatment, consultation with a healthcare professional experienced in the treatment of hyperglycaemia is recommended. 8 mmol/L) • Interrupt Itovebi.

• Initiate or intensify anti-hyperglycaemic treatmentb. • Administer appropriate hydration if required. 9 mmol/L) within 7 days, resume Itovebi at the same dose level. 9 mmol/L) in ≥ 8 days, resume Itovebi at one lower dose level (see Table 1).

9 mmol/L). Resume Itovebi at one lower dose level (see Table 1). 8 mmol/L) • Interrupt Itovebi. • Initiate or intensify anti-hyperglycaemic treatmentb. • Assess for volume depletion and ketosis and administer appropriate hydration. 9 mmol/L), resume Itovebi at one lower dose level (see Table 1).

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.

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. 8. 4 for risk factors for hyperglycaemia.

Stomatitis Table 3:

Dose modification and management for stomatitis Gradea Recommendation Grade 1 • No adjustment of Itovebi required. , 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, […]

8%), and urinary tract infection (13%). 2%). 1% of patients. 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.

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. 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. 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).

2% (72/97) received anti-hyperglycaemic medicines including SGLT2 inhibitors, thiazolidinediones, and DPP-4 inhibitors for prophylaxis or treatment of hyperglycaemia. 4). 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).

2% of patients. 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 […]

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. 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.

, insulin, sulfonylureas) should be considered when used to manage hyperglycaemia prior to Itovebi being interrupted or discontinued. , 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.

, 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*.

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. 2). HbA1C should be monitored every 3 months. Monitor fasting glucose more closely as clinically indicated*. 2). If hyperglycaemia develops after initiating treatment with Itovebi 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. 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.

2% of patients, respectively. 8). , 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 […]

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