Inavolisib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]
Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
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, 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
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
Patient Selection:
- Select patients for the treatment of HR-positive, HER2-negative, locally advanced or metastatic breast cancer with ITOVEBI based on the presence of one or more PIK3CA mutations in plasma specimens.
- Information on FDA-approved tests for the detection of PIK3CA mutations in breast cancer is available at: http://www.fda.gov/companiondiagnostics.
Recommended Evaluation Before Initiating ITOVEBI
- Evaluate fasting plasma glucose (FPG)/blood glucose (FBG) and hemoglobin A1C (HbA1C) and optimize blood glucose prior to starting ITOVEBI and at regular intervals during treatment.
Recommended Dosage
- The recommended dosage of ITOVEBI is 9 mg taken orally once daily, with or without food, until disease progression or unacceptable toxicity.
- Advise patients to take ITOVEBI at approximately the same time each day.
- Swallow ITOVEBI tablet(s) whole. Do not chew, crush, or split prior to swallowing.
- If a patient misses a dose, instruct the patient to take the missed dose as soon as possible within 9 hours. After more than 9 hours, instruct the patient to skip the dose and take the next dose at the scheduled time.
- If a patient vomits a dose, instruct patients not to take an additional dose on that day and resume the usual dosing schedule the next day.
- Administer ITOVEBI in combination with palbociclib and fulvestrant. The recommended dosage of palbociclib is 125 mg taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days. Refer to the Full Prescribing Information for palbociclib and fulvestrant for dosing information.
- For premenopausal and perimenopausal women, administer a luteinizing hormone-releasing hormone (LHRH) agonist in accordance with local clinical practice.
- For men, consider administering an LHRH agonist in accordance with local clinical practice.
Dosage Modifications for Adverse Reactions
- Dose modifications for adverse reactions followed a predefined stepwise approach. The recommended starting dose was 9 mg once daily. In cases requiring a first dose reduction due to adverse events, the dose was decreased to 6 mg once daily. If further reduction was necessary, a second dose reduction to 3 mg once daily was implemented.
- Permanently discontinue ITOVEBI if patients are unable to tolerate the second dose reduction.
- Recommended Dosage Modifications for Adverse Reactions:
- Prior to initiating treatment with ITOVEBI, fasting plasma glucose (FPG) or fasting blood glucose (FBG) and HbA1c levels should be assessed, and plasma/blood glucose levels optimized. After starting therapy, regular monitoring of FPG or FBG is advised, following the recommended schedule or as clinically indicated.
Dose Reduction for Adverse Reactions
- Prior to initiating treatment with ITOVEBI, fasting plasma glucose (FPG) or fasting blood glucose (FBG) and HbA1c levels should be assessed, and plasma/blood glucose levels optimized. After starting therapy, regular monitoring of FPG or FBG is advised, following the recommended schedule or as clinically indicated.
- For hyperglycemia, if fasting glucose levels (FPG or FBG) are > upper limit of normal (ULN) to 160 mg/dL (> ULN – 8.9 mmol/L), no dose adjustment is required. Dietary modifications, adequate hydration, and initiation or intensification of oral anti-hyperglycemic medications may be considered, particularly in patients at risk. If glucose levels rise to >160 to 250 mg/dL (>8.9–13.9 mmol/L), ITOVEBI should be withheld until levels are ≤160 mg/dL (≤8.9 mmol/L), while initiating or intensifying anti-hyperglycemic therapy; ITOVEBI may then be resumed at the same dose. Persistent glucose levels >200–250 mg/dL (>11.1–13.9 mmol/L) for ≥7 days despite treatment should prompt consultation with a specialist. For levels >250 to 500 mg/dL (>13.9–27.8 mmol/L), ITOVEBI must be withheld, and anti-hyperglycemic therapy initiated or intensified alongside appropriate hydration. If glucose levels normalize (≤160 mg/dL) within 7 days, treatment can be resumed at the same dose; if recovery takes ≥8 days, resume at one lower dose level. In case of recurrence within 30 days, withhold again and resume at a reduced dose. If glucose exceeds 500 mg/dL (>27.8 mmol/L), ITOVEBI should be withheld. Initiate or intensify therapy, assess for dehydration and ketosis, and hydrate as necessary. Upon normalization (≤160 mg/dL), resume ITOVEBI at one lower dose level; if recurrence occurs within 30 days, discontinue treatment permanently.
- For stomatitis, no dose adjustment is necessary for Grade 1 events; supportive care such as corticosteroid-containing mouthwash should be initiated as needed. In Grade 2 cases, withhold ITOVEBI until resolution to Grade ≤1, then resume at the same dose; if recurrent, resume at one lower dose. For Grade 3 stomatitis, withhold until resolution to Grade ≤1 and resume at a reduced dose. In cases of Grade 4 stomatitis, permanently discontinue ITOVEBI.
- For diarrhea, no adjustment is needed for Grade 1; initiate symptomatic treatment and monitor. In Grade 2 cases, withhold ITOVEBI until resolution to Grade ≤1, then resume at the same dose. If Grade 2 recurs, resume at one lower dose. For Grade 3 events, withhold until resolution to Grade ≤1 and resume at one lower dose. Grade 4 diarrhea warrants permanent discontinuation.
- Regarding hematologic toxicities, no adjustment is needed for Grade 1–3. Complete blood counts and clinical signs of hematologic toxicity should be monitored. In Grade 4 cases, withhold ITOVEBI until recovery to Grade ≤2 and resume at the same or reduced dose, depending on clinical judgment.
- For other adverse reactions, Grade 1 events do not require any modification. In Grade 2 events, ITOVEBI may be withheld until resolution to Grade ≤1 and then resumed at the same dose. For a first occurrence of Grade 3 toxicity, withhold treatment until recovery to Grade ≤1 and resume at the same or lower dose based on clinical evaluation. In recurrent Grade 3 events, withhold until resolution and resume at one lower dose. Grade 4 reactions require permanent discontinuation of ITOVEBI.
- Dosage Modification for Moderate Renal Impairment
The recommended starting dosage of ITOVEBI for patients with moderate renal impairment (eGFR 30 to < 60 mL/min based on CKD-EPI) is 6 mg orally once daily
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.
IV Compatibility
There is limited information regarding the compatibility of Inavolisib and IV administrations.
Overdosage
There is limited information regarding Inavolisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Inavolisib Pharmacology in the drug label.
Mechanism of Action
Inavolisib is an inhibitor of phosphatidylinositol 3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. In vitro, inavolisib induced the degradation of mutated PI3K catalytic alpha subunit p110α (encoded by the PIK3CA gene), inhibited phosphorylation of the downstream target AKT, reduced cellular proliferation, and induced apoptosis in PIK3CA-mutated breast cancer cell lines. In vivo, inavolisib reduced tumor growth in PIK3CA-mutated, estrogen receptor-positive, breast cancer xenograft models. The combination of inavolisib with palbociclib and fulvestrant increased tumor growth inhibition compared to each treatment alone or the doublet combinations.
Structure
The chemical name of inavolisib is (2S)-2- [ [ 2- [ ( 4S ) -4- ( difluoromethyl ) -2-oxo-oxazolidin-3-yl ] -5,6-dihydroimidazo [ 1,2-d ] - [ 1,4 ] benzoxazepin-9-yl ] amino ] propanamide. Inavolisib is a white to off-white, greyish pink, greyish orange, or greyish yellow powder or powder with lumps. Inavolisib demonstrates pH-dependent aqueous solubility; the greatest solubility is at low pH, and solubility decreases with increasing pH. The molecular formula for inavolisib is C18H19F2N5O4 and the molecular weight is 407.37 g/mol.
Inavolisib film-coated tablets are supplied for oral administration with two strengths that contain 3 mg and 9 mg of inavolisib. The tablets also contain lactose, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film-coating contains the following inactive ingredients: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol/polyethylene glycol, talc, iron oxide red, and iron oxide yellow (in the 9 mg tablet only).
Pharmacodynamics
Exposure-Response Relationships
- The exposure-response relationship for the efficacy of inavolisib has not been fully characterized. Inavolisib time course of pharmacodynamic response is unknown. Higher systemic exposure of inavolisib was associated with higher incidence of Grade ≥ 2 anemia, Grade ≥ 2 hyperglycemia, and inavolisib dosage modifications due to adverse reactions.
Cardiac Electrophysiology
- At the recommended approved dosage, a mean increase in the QTc interval of > 20 ms is unlikely.
Pharmacokinetics
Inavolisib pharmacokinetics are presented as geometric mean (geometric coefficient of variation [geo CV]%) following administration of the approved recommended dosage unless otherwise specified. The inavolisib steady-state AUC is 1,010 h*ng/mL (25%) and Cmax is 69 ng/mL (27%). Steady-state concentrations are predicted to be attained by day 5. Inavolisib accumulation is approximately 2-fold. Inavolisib steady-state AUC is proportional with dose from 6 to 12 mg (0.7 to 1.3 times the approved recommended dosage).
- Absorption:
- Inavolisib absolute oral bioavailability is 76%. Inavolisib steady-state median (min, max) time to maximum plasma concentration (Tmax) is 3 hours (0.5, 4 hours).
- Effect of Food:
- No clinically significant differences in inavolisib pharmacokinetics were observed following administration of inavolisib with a high-fat meal (approximately 1,000 calories, 50% fat).
- Distribution:
- Inavolisib apparent (oral) volume of distribution is 155 L (26%). Inavolisib plasma protein binding is 37% and is not concentration-dependent in vitro. Inavolisib blood-to-plasma ratio is 0.8.
- Elimination:
- Inavolisib elimination half-life is 15 hours (24%) with a total clearance of 8.8 L/hr (29%).
- Metabolism
- Inavolisib is primarily metabolized by hydrolysis. In vitro, inavolisib was minimally metabolized by CYP3A.
- Excretion:
- Following oral administration of a single radiolabeled dose, 49% of the administered dose was recovered in urine (40% unchanged) and 48% in feces (11% unchanged).
- Specific Populations:
- No clinically significant differences in the pharmacokinetics of inavolisib were observed based on age (27 to 85 years), sex, race (Asian or White), body weight (39 to 159 kg), or mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 × ULN or AST > ULN and total bilirubin ≤ ULN). The effect of moderate to severe hepatic impairment on inavolisib pharmacokinetics is unknown.
- Patients with Renal Impairment: Inavolisib AUC was 73% higher in patients with moderate renal impairment compared to patients with normal renal function (eGFR ≥ 90 mL/min). No clinically significant differences in the pharmacokinetics of inavolisib were observed in patients with mild renal impairment compared to patients with normal renal function. The effect of severe renal impairment (eGFR < 30 mL/min) on the pharmacokinetics of inavolisib is unknown.
- Drug Interaction Studies
- 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.
- Clinical Studies and Model-Informed Approaches
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with inavolisib have not been conducted. Inavolisib was not mutagenic in the bacterial reverse mutation (Ames) assay. Inavolisib was clastogenic in an in vitro human lymphocyte micronucleus assay. Inavolisib was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA break in a liver comet assay. Fertility studies with inavolisib have not been conducted. In repeat-dose toxicity studies, inavolisib was administered orally once daily for up to 3 months duration in rats and dogs. In male rats, dose-dependent atrophy of the prostate and seminal vesicle and decreased organ weights of the prostate, seminal vesicle, epididymis and testis were observed at doses ≥ 1.5 mg/kg/day (≥ 0.4 times the human exposure at the recommended dose of 9 mg/day based on AUC). In male dogs, focal inspissation of seminiferous tubule contents and multinucleated spermatids in the testis and epithelial degeneration/necrosis in the epididymis were observed following 4 weeks of dosing at ≥ 1.5 mg/kg/day (≥ 2 times the human exposure at the recommended dose of 9 mg/day based on AUC) and decreased sperm count was observed following 3 months of dosing at ≥ 1 mg/kg/day (≥ 1.2 times the human exposure at the recommended dose of 9 mg/day based on AUC). Findings in dogs were not observed following a recovery period. In female rats, atrophy in the uterus and vagina, decreased ovarian follicles, and findings suggestive of an interruption/alteration of the estrous cycle were observed following up to 3 months of dosing at doses ≥ 3 mg/kg/day (≥ 1.2 times the human exposure at the recommended dose of 9 mg/day based on AUC). Findings in the uterus, vagina, and estrous cycle observed in the 4-week toxicity study were not observed following recovery. Recovery was not assessed in the 3-month study in rats.
Animal Toxicology and/or Pharmacology:
Lens degeneration, characterized by lens fiber swelling, separation of lens fibers, and/or accumulation of subcapsular proteinaceous material, was observed in rats at an oral inavolisib dose of 10 mg/kg/day (6.3 times the human exposure at the recommended dose of 9 mg/day based on AUC). In dogs, lens fiber swelling and lens cortex vacuolation were observed at oral inavolisib doses ≥ 0.3 mg/kg/day (≥ 0.5 times the human exposure at the recommended dose based on AUC) and ≥ 1 mg/kg/day (≥ 1.2 times the human exposure at the recommended dose based on AUC), respectively. Lens degeneration was present in rats following a 4-week recovery period but was not present in dogs following a 12-week recovery period.
Clinical Studies
INAVO120
- INAVO120 (NCT04191499) was a randomized (1:1), double-blind, placebo-controlled trial evaluating the efficacy of ITOVEBI in combination with palbociclib and fulvestrant in adult patients with endocrine-resistant PIK3CA-mutated, HR-positive, HER2-negative (defined as IHC 0 or 1+, or IHC 2+/ISH-), locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for locally advanced or metastatic disease. Randomization was stratified by presence of visceral disease (yes or no), endocrine resistance (primary or secondary), and geographic region (North America/Western Europe, Asia, other).
- Primary endocrine resistance was defined as relapse while on the first 2 years of adjuvant endocrine therapy (ET) and secondary endocrine resistance was defined as relapse while on adjuvant ET after at least 2 years or relapse within 12 months of completing adjuvant ET.
- Patients were required to have HbA1C < 6% and fasting blood glucose < 126 mg/dL. The study excluded patients with Type 1 diabetes mellitus or Type 2 diabetes mellitus requiring ongoing anti-hyperglycemic treatment at the start of study treatment.
- PIK3CA mutation status was prospectively determined in a central laboratory using the FoundationOne® Liquid CDx assay on plasma-derived circulating tumor DNA (ctDNA) or in local laboratories using various validated polymerase chain reaction (PCR) or next-generation sequencing (NGS) assays on tumor tissue or plasma. All patients were required to provide both a freshly collected pre-treatment blood sample and a tumor tissue sample for central evaluation and determination of PIK3CA mutation(s) status.
- Patients received either ITOVEBI 9 mg (n=161) or placebo (n=164) orally once daily, in combination with palbociclib 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days, and fulvestrant 500 mg administered intramuscularly on Cycle 1, Days 1 and 15, and then on Day 1 of every 28-day cycle. Patients received treatment until disease progression or unacceptable toxicity. In addition, all pre/perimenopausal women and men received an LHRH agonist throughout therapy.
- The baseline demographic and disease characteristics were: median age 54 years (range: 27 to 79 years); 98% female, of which 39% were pre/perimenopausal; 59% White, 38% Asian, 2.5% unknown, 0.6% Black or African American; 6% Hispanic or Latino; and Eastern Cooperative Oncology Group (ECOG) performance status of 0 (63%) or 1 (36%). Tamoxifen (57%) and aromatase inhibitors (50%) were the most commonly used adjuvant endocrine therapies. Sixty-four percent of patients were considered to have secondary endocrine resistance. Eighty-three percent of patients had received prior chemotherapy (in the neo/adjuvant setting) and 1.2% of patients had been treated with a CDK4/6 inhibitor.
- The major efficacy outcome measure was investigator (INV)-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Additional efficacy outcome measures included overall survival (OS), INV-assessed objective response rate (ORR), and INV-assessed duration of response (DOR).
- INV-assessed progression-free survival (PFS) results were supported by consistent findings from a blinded independent central review (BICR). At the time of the PFS analysis, overall survival (OS) data were not mature, with 30% of deaths observed in the overall population. In the INAVO120 trial evaluating patients with locally advanced or metastatic breast cancer, the combination of ITOVEBI, palbociclib, and fulvestrant (N=161) demonstrated a median PFS of 15.0 months (95% CI: 11.3–20.5) compared to 7.3 months (95% CI: 5.6–9.3) with placebo, palbociclib, and fulvestrant (N=164). The hazard ratio for disease progression or death was 0.43 (95% CI: 0.32–0.59; p < 0.0001). Objective response rate (ORR), based on confirmed complete or partial responses (per RECIST v1.1 and investigator assessment), was 58% (94/161; 95% CI: 50–66%) in the ITOVEBI arm versus 25% (41/164; 95% CI: 19–32%) in the placebo arm. Among responders, the median duration of response (DOR) was 18.4 months (95% CI: 10.4–22.2) with ITOVEBI and 9.6 months (95% CI: 7.4–16.6) with placebo.
How Supplied
Inavolisib is supplied in the following strengths and package configurations:
Storage
•Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F) [see USP Controlled Room Temperature].
Images
Drug Images
{{#ask: Page Name::Inavolisib |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
- NDC 50242-079-08
Itovebi™ (inavolisib) Tablets
9 mg
Swallow tablets whole.
DO NOT chew, crush, or split tablets.
28 Tablets
Rx only Genentech
11026284
- NDC 50242-084-08
Itovebi™ (inavolisib) Tablets
3 mg
Swallow tablets whole.
DO NOT chew, crush, or split tablets.
28 Tablets
Rx only Genentech
11026285
{{#ask: Label Page::Inavolisib |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Hyperglycemia:
- Advise patients that ITOVEBI may cause hyperglycemia and the need to monitor fasting glucose levels periodically during therapy. Advise patients to contact their healthcare provider immediately for signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often, blurred vision, mental confusion, difficulty breathing, or increased appetite with weight loss).
- Stomatitis:
- Advise patients that ITOVEBI may cause stomatitis, which may be severe, and to notify their healthcare provider if they develop symptoms of stomatitis (e.g., painful redness, swelling, or sores in the mouth).
- Diarrhea:
- Advise patients that ITOVEBI may cause diarrhea, which may be severe, and to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking ITOVEBI.
- Embryo-Fetal Toxicity:
- Inform pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. 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.
- Refer to the Full Prescribing Information of palbociclib and fulvestrant for pregnancy and contraception information.
- Lactation:
- Advise women not to breastfeed during treatment with ITOVEBI and for 1 week after the last dose. Refer to the Full Prescribing Information of palbociclib and fulvestrant for lactation information.
- Infertility:
- Advise females and males of reproductive potential that ITOVEBI may impair fertility. Refer to the Full Prescribing Information of palbociclib and fulvestrant for infertility information.
- Dosing:
- Instruct patients to take ITOVEBI at approximately the same time each day. Instruct patients that if a dose of ITOVEBI is missed, to take the missed dose as soon as possible within 9 hours. After more than 9 hours, skip the dose and take the next dose at the scheduled time. Instruct patients that if vomiting occurs after taking the ITOVEBI dose, do not take an additional dose on that day. Resume the usual dosing schedule the next day.
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
ITOVEBI
Look-Alike Drug Names
There is limited information regarding Inavolisib Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.