ITOVEBI (inavolisib) and the Risk of Life-Threatening Ketoacidosis

Two cases of life-threatening or fatal ketoacidosis have been reported in diabetic patients treated with ITOVEBI in the post-market setting.
 

Audience

Healthcare professionals involved in the treatment of breast cancer, including medical oncologists, surgical oncologists (Quebec), and oncology nurses and pharmacists.
 

Key messages

• Two cases of life-threatening or fatal ketoacidosis have been reported in diabetic patients treated with ITOVEBI (inavolisib) in the post-market setting.
  
• Hyperglycemia, a defining feature of ketoacidosis, is a known risk associated with ITOVEBI.
  
• Healthcare professionals are advised that:
  • ITOVEBI should NOT be administered to patients until their blood glucose levels are well-controlled and stable.
  • Fasting blood glucose and HbA1C levels should be tested in all patients before and during treatment with ITOVEBI. Fasting blood glucose levels should be monitored or self-monitored more frequently in patients with risk factors for hyperglycemia, as clinically indicated.
  • Dose modification guidelines in the Canadian Product Monograph (CPM) should be followed if hyperglycemia occurs during treatment with ITOVEBI.
• The CPM for ITOVEBI has been updated to include these warnings and recommendations.
   

Background

ITOVEBI is a PI3K-alpha inhibitor indicated, in combination with palbociclib and fulvestrant, for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, following recurrence on or after completing adjuvant endocrine treatment.

Hyperglycemia is a known risk associated with PI3K/AKT inhibitors due to disruption of the insulin signaling pathway. Ketoacidosis, a rare but serious complication of hyperglycemia, has been associated with PI3K-alpha and AKT inhibitors.

Ketoacidosis is a medical emergency characterized by hyperglycemia, electrolyte abnormalities, metabolic acidosis, and ketonemia. The mainstays of ketoacidosis treatment include restoration of circulating volume, insulin therapy, electrolyte replacement, and treatment of any underlying precipitating event. Without optimal treatment, ketoacidosis could result in morbidity and mortality.

Hyperglycemia is an identified risk associated with ITOVEBI and is included in the Serious Warnings and Precautions Box of the Canadian Product Monograph (CPM). In the Phase III trial INAVO120 (WO41554, NCT04191499), no cases of ketoacidosis were reported. However, two cases of ketoacidosis with serious outcomes have been reported in patients receiving ITOVEBI in the post-market setting. One patient with both renal impairment and uncontrolled Type 2 diabetes developed ketoacidosis with a fatal outcome. Another patient with Type 2 diabetes receiving insulin developed life-threatening ketoacidosis.

The safety of ITOVEBI in patients with Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring ongoing anti-hyperglycemic treatment has not been studied in clinical trials.
 

Information for consumers

ITOVEBI (inavolisib) is a prescription medicine used with palbociclib and fulvestrant to treat breast cancer in adults.

ITOVEBI can cause hyperglycemia (high blood sugar). Two cases of ketoacidosis, which is a serious and life-threatening complication of hyperglycemia, have been reported in patients treated with ITOVEBI. Ketoacidosis happens when the body cannot use sugar properly and starts breaking down fat for energy. This causes the body to make ketones, which can build up and make the blood acidic.

Healthcare professionals should test their patients’ blood sugar levels before and during treatment with ITOVEBI. Patients with diabetes or who have a history of diabetes, who are taking medications called corticosteroids, who have an infection, or who have other risk factors for hyperglycemia may need to check or have their blood sugar levels checked more often. Patients should stay well-hydrated before and during treatment with ITOVEBI.

Patients should stop taking ITOVEBI and seek immediate medical attention if they experience signs of ketoacidosis, such as feeling very thirsty, urinating often, nausea, feeling weak, fruity-scented breath, trouble breathing or confusion. Patients should consult with their healthcare professional if they have any questions or concerns about this information.
 

Information for healthcare professionals

Healthcare professionals are advised that:

• ITOVEBI should NOT be administered to patients until their blood glucose levels are well-controlled and stable.
• Fasting blood glucose and HbA1C levels should be tested in all patients before and during treatment with ITOVEBI.
• Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of fasting glucose levels, as clinically indicated. Consultation with a healthcare professional experienced in the treatment of hyperglycemia should be considered before initiating ITOVEBI.
• More frequent fasting glucose testing is required in patients receiving corticosteroids, experiencing intercurrent infections, or with other conditions that may require intensified glycemia management, in order to prevent worsening of impaired glucose metabolism and potential complications, including ketoacidosis. Monitoring of HbA1C and ketones (preferably in blood), in addition to fasting glucose, is recommended in these patients.
• In patients who experience hyperglycemia, dose modification guidelines in the CPM should be followed.
  
  

Action taken by Health Canada

Health Canada, in collaboration with Hoffmann-La Roche Limited, has updated the CPM for ITOVEBI to include this new information.

Health Canada is communicating this important safety information to healthcare professionals and Canadians via the Recalls and Safety Alerts Database on the Healthy Canadians Web Site. This communication will be further distributed through the MedEffect™ e-Notice email notification system.
 

Report health or safety concerns

Managing marketed health product-related side effects depends on healthcare professionals and consumers reporting them. Any case of ketoacidosis or other serious or unexpected side effects in patients receiving ITOVEBI should be reported to Hoffmann-La Roche Limited or Health Canada. 

 

Hoffmann-La Roche Limited
Medical Information Department
7070 Mississauga Road
Mississauga, Ontario, L5N 5M8
Toll free: 1-888-762-4388
Fax: 905-542-5864
E-mail: mississauga.canada_medinfo@roche.com
 

To correct your mailing address or fax number, contact Hoffmann-La Roche Limited.
 

You can report any suspected adverse reactions associated with the use of health products to Health Canada by:

• Calling toll-free at 1-866-234-2345; or
• Visiting MedEffect Canada's Web page on Adverse Reaction Reporting (https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/adverse-reaction-reporting.html) for information on how to report online, by mail or by fax.
   

For other health product inquiries related to this communication, contact Health Canada at:

Marketed Health Products Directorate
E-mail: mhpd-dpsc@hc-sc.gc.ca
Telephone: 613-954-6522
Fax: 613-952-7738
 

Original signed by

Daniel P. Edgcumbe, MB BChir
Vice President, Medical & Regulatory Affairs
Hoffmann-La Roche Limited