Inavolisib

Inavolisib
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh

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Overview

Inavolisib is a phosphoinositide 3-kinase inhibitors that is FDA approved for the treatment of Inavolisib is a phosphoinositide 3-kinase inhibitor that is FDA approved 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 breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.. Common adverse reactions include Common adverse reactions include decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

HR-positive, HER2-negative, locally advanced or metastatic breast cancer with the presence of one or more PIK3CA mutations in plasma specimens Recommended dosage of Inavolisib is 9 mg taken orally once daily, with or without food, until disease progression or unacceptable toxicity.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Inavolisib in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Inavolisib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Inavolisib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Inavolisib in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Inavolisib in pediatric patients.

Contraindications

None.

Warnings

•Hyperglycemia

  •Severe hyperglycemia can occur in patients treated with Inavolisib. Increased fasting glucose occurred in 85% of patients treated with Inavolisib, including 22% of patients with Grade 2 (FPG > 160 to 250 mg/dL), 12% with Grade 3 (FPG > 250 to 500 mg/dL), and 0.6% with Grade 4 (FPG > 500 mg/dL) events. Among patients with hyperglycemia, the median time to first onset was 7 days (range: 2 to 955 days). Hyperglycemia led to dose interruption in 28%, to dose reduction in 2.5%, and to discontinuation of Inavolisib in 1.2% of patients. The safety of ITOVEBI in patients with Type 1 diabetes mellitus, or Type 2 diabetes mellitus requiring ongoing anti-hyperglycemic treatment have not been studied. Before initiating treatment with Inavolisib, test fasting glucose levels (FPG or FBG), HbA1C levels, and optimize fasting glucose. After initiating treatment with Inavolisib, or in patients who experience hyperglycemia after initiating treatment with Inavolisib, monitor or self-monitor fasting glucose levels 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. Monitor HbA1C every 3 months and as clinically indicated. Manage hyperglycemia with anti-hyperglycemic medications as clinically indicated. During treatment with anti-hyperglycemic medication, continue monitoring fasting glucose levels. Patients with a history of well-controlled Type 2 diabetes mellitus may require intensified anti-hyperglycemic treatment and close monitoring of fasting glucose levels. Based on the severity of the hyperglycemia, ITOVEBI may require dose interruption, reduction, or discontinuation.

•Stomatitis

  •Severe stomatitis can occur in patients treated with INAVOLISIB. Stomatitis occurred in 51% of patients treated with INAVOLISIB in combination with palbociclib and fulvestrant, including Grade 3 events in 6% of patients. The median time to first onset was 13 days (range: 1 to 610 days). Stomatitis led to interruption of INAVOLISIB in 10%, to dose reduction in 3.7%, and to discontinuation of INAVOLISIB in 0.6% of patients. Monitor patients for signs and symptoms of stomatitis. Withhold, reduce dose, or permanently discontinue INAVOLISIB based on severity.

•Diarrhea

  •Severe diarrhea, including dehydration and acute kidney injury, can occur in patients treated with Inavolisib. Diarrhea occurred in 48% of patients treated with Inavolisib in combination with palbociclib and fulvestrant, including Grade 3 events in 3.7% of patients. The median time to first onset was 15 days (range: 2 to 602 days). Anti-diarrheal medicines were used in 28% (46/162) of patients who received ITOVEBI in combination with palbociclib and fulvestrant to manage symptoms. Dose interruptions were required in 7% of patients, and dose reductions occurred in 1.2% of patients. Monitor patients for signs and symptoms of diarrhea. Advise patients to increase oral fluids and start anti-diarrheal treatment at the first sign of diarrhea while taking ITOVEBI. Withhold, reduce dose, or permanently discontinue ITOVEBI based on severity 

•Embryo-Fetal Toxicity

  •Based on findings in animals and its mechanism of action, INAVOLISIB can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of inavolisib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and alterations to growth at maternal exposures approximately equivalent to the human exposure at the recommended dose of 9 mg/day based on area under the curve (AUC). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with INAVOLISIB and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with INAVOLISIB and for 1 week after the last dose.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of INAVOLISIB was evaluated in a randomized, double-blind, placebo-controlled study (INAVO120) in 324 patients with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer. Patients received either INAVOLISIB 9 mg (n=162) or placebo (n=162) with palbociclib and fulvestrant. The median duration of treatment with INAVOLISIB was 9 months (range: 0 to 39 months) in the INAVOLISIB with palbociclib and fulvestrant arm. Serious adverse reactions occurred in 24% of patients who received INAVOLISIB with palbociclib and fulvestrant. Serious adverse reactions in ≥ 1% of patients included anemia (1.9%), diarrhea (1.2%), and urinary tract infection (1.2%). Fatal adverse reactions occurred in 3.7% of patients who received INAVOLISIB with palbociclib and fulvestrant, including (0.6% each) acute coronary syndrome, cerebral hemorrhage, cerebrovascular accident, COVID-19 infection, and gastrointestinal hemorrhage. Permanent discontinuation of INAVOLISIB due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of INAVOLISIB included hyperglycemia (1.2%), and (0.6% each) stomatitis, gastric ulcer, intestinal perforation, anal abscess, increased ALT, decreased weight, bone pain, musculoskeletal pain, transitional cell carcinoma, and acute kidney injury. Dosage interruptions of INAVOLISIB due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included hyperglycemia (28%), neutropenia (23%), COVID-19 infection (16%), stomatitis (10%), diarrhea (7%), thrombocytopenia (4.9%), anemia (4.3%), upper respiratory tract infection (4.3%), decreased white blood cell count (3.7%), pyrexia (3.1%), nausea (2.5%), and fatigue (2.5%). Dose reductions of INAVOLISIB due to adverse reactions occurred in 14% of patients. Adverse reactions which required dose reduction of INAVOLISIB in ≥ 2% of patients were stomatitis (3.7%) and hyperglycemia (2.5%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.

•Gastrointestinal Disorders

  •Stomatitis
  •Diarrhea
  •Nausea
  •Vomiting

•General Disorders and Administration Site Conditions

  •Fatigue

•Skin and Subcutaneous Tissue Disorders

  •Rash
  •Alopecia
  •Dry skin

•Metabolism and Nutrition Disorders

  •Decreased appetite	

•Infections and Infestations

  •COVID-19 infection
  •Urinary tract infection
  

•Nervous System Disorders

  •Headache

•Investigations

  •Decreased weight

Postmarketing Experience

There is limited information regarding Inavolisib Postmarketing Experience in the drug label.

Drug Interactions

•Clinical Studies and Model-Informed Approaches

  •Proton Pump Inhibitors: No clinically significant difference in steady-state inavolisib pharmacokinetics were observed based upon concomitant use of a proton pump inhibitor (lansoprazole, omeprazole, esomeprazole, pantoprazole, or rabeprazole).

•In Vitro Studies

  •CYP450 Enzymes: Inavolisib induces CYP3A and CYP2B6. Inavolisib is a time-dependent inhibitor of CYP3A. Inavolisib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
  •Transporter Systems: Inavolisib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2K, OAT1, OAT2. Inavolisib does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C •Risk Summary

  •Based on animal data and its mechanism of action, ITOVEBI can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ITOVEBI in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of inavolisib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and alterations to growth at maternal exposures approximately equivalent to the human exposure at the recommended dose of 9 mg/day based on AUC. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

•Animal Data

  •In an embryo-fetal development study, pregnant rats received oral doses of inavolisib up to 6 mg/kg/day during the period of organogenesis. Administration of doses ≥ 2 mg/kg/day resulted in decreases in fetal body weight and placental weight, post-implantation loss, lower fetal viability, fetal malformations (including kyphosis of vertebral column, fused thoracic arch, microphthalmia) and variations (including dilated renal pelvis, short supernumerary rib, wavy rib). At a dose of 2 mg/kg/day, maternal exposures were 0.9 times the human exposure at the recommended dose of 9 mg/day based on AUC.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Inavolisib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Inavolisib during labor and delivery.

Nursing Mothers

There are no data on the presence of inavolisib or its metabolites in human milk, its effects on milk production or a breastfed child. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women to not breastfeed during treatment with INAVOLISIB and for 1 week after the last dose.

Pediatric Use

The safety and efficacy of inavolisib in pediatric patients have not been established.

Geriatic Use

Of the 162 patients who received inavolisib in INAVO120, 15% were ≥ 65 years of age, and 3% were ≥ 75 years of age. Dosage modifications or interruptions of inavolisib due to adverse reactions occurred at a higher incidence for patients ≥ 65 years of age compared to younger patients (79% versus 68%, respectively). Clinical studies of inavolisib did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients.

Gender

There is no FDA guidance on the use of Inavolisib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Inavolisib with respect to specific racial populations.

Renal Impairment

Reduce the dosage in patients with moderate renal impairment (eGFR 30 to < 60 mL/min based on CKD-EPI). No dosage modification is recommended in patients with mild renal impairment (eGFR 60 to < 90 mL/min). Inavolisib has not been evaluated in patients with severe renal impairment (eGFR < 30 mL/min).

Hepatic Impairment

There is no FDA guidance on the use of Inavolisib in patients with hepatic impairment.

Females of Reproductive Potential and Males

INAVOLISIB can cause fetal harm when administered to a pregnant woman.

•Pregnancy Testing

  •Verify pregnancy status in females of reproductive potential prior to initiating treatment with INAVOLISIB.

•Contraception

  •Advise females of reproductive potential to use effective non-hormonal contraception during treatment with INAVOLISIB and for 1 week after the last dose.

•Infertility

  •Based on animal studies, INAVOLISIB may impair fertility in females and males of reproductive potential.

Immunocompromised Patients

There is no FDA guidance one the use of Inavolisib in patients who are immunocompromised.

Administration and Monitoring

Administration

Oral

Monitoring

•Hyperglycemia:

  •ITOVEBI can cause hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated. Interrupt, reduce dose, or discontinue ITOVEBI if severe hyperglycemia occurs. 

•Stomatitis:

  •ITOVEBI can cause severe stomatitis. Consider treating with a corticosteroid-containing mouthwash if stomatitis occurs. Monitor patients for signs and symptoms of stomatitis. Withhold, reduce dose, or permanently discontinue ITOVEBI based on severity. 

•Diarrhea:

  •ITOVEBI can cause diarrhea, which may be severe, and result in dehydration and acute kidney injury. Advise patients to start anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if severe diarrhea occurs. Interrupt, reduce dose, or discontinue ITOVEBI if severe diarrhea occurs. 

•Embryo-Fetal Toxicity:

  •ITOVEBI can cause fetal harm.  Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ITOVEBI and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ITOVEBI and for 1 week after the last dose.

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Mechanism of Action

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Images

Drug Images

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Patient Counseling Information

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Precautions with Alcohol

Alcohol-Inavolisib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

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Look-Alike Drug Names

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Drug Shortage Status

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References

The contents of this FDA label are provided by the National Library of Medicine.