ITOVEBI Film-coated tablet Ref.[115587] Active ingredients: Inavolisib

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 HbA_1C 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 HbA_1C:

^* 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 glucose-galactose 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'.

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.

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).

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

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:

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 national reporting system listed in Appendix V.

Not applicable.