The following Structured Product Label (SPL) was submitted to the FDA by Novartis Pharmaceuticals Corporation for the product Vijoice (NDC 0078-1021). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 recommended dosage, 2.2 administration, 2.3 dosage modifications for adverse reactions, 3 dosage forms and strengths, 4 contraindications, 5.1 severe hypersensitivity, 5.2 severe cutaneous adverse reactions, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
VIJOICE is indicated for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy.
This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Adult Patients
The recommended dosage of VIJOICE in adult patients is 250 mg orally, once daily, administered as recommended [see Dosage and Administration (2.2)] until disease progression or unacceptable toxicity.
Pediatric Patients (2 to less than 18 years of age)
The recommended initial dosage of VIJOICE in pediatric patients is 50 mg orally, once daily, administered as recommended [see Dosage and Administration (2.2)] until disease progression or unacceptable toxicity.
Consider a dose increase to 125 mg once daily in pediatric patients ≥ 6 years old for response optimization (clinical/radiological) after 24 weeks of treatment with VIJOICE at 50 mg once daily. When a pediatric patient turns 18 years old, consider a gradual dose increase up to 250 mg. Recommended dose increases by age group are listed in Table 1.
| *A recommended increased dose has not been established. | ||
| Patient age (years) | Initial dose | Dose increase |
| 2 to < 6 | 50 mg | Not applicable* |
| 6 to < 18 | 50 mg | 125 mg |
Take VIJOICE with food at approximately the same time each day.
No tablet should be used if it is broken, cracked, or otherwise damaged at the time of opening the blister pack.
Swallow VIJOICE tablets whole. Do not split or chew.
If a dose of VIJOICE is missed, it can be taken with food within 9 hours after the time it is usually taken. After more than 9 hours, skip the dose for that day. The next day, take VIJOICE at the usual time.
If the patient vomits after taking the dose, advise the patient not to take an additional dose on that day, and to resume the dosing schedule the next day at the usual time.
Preparation and Administration for Patients Who Have Difficulty Swallowing Tablets
The recommended VIJOICE dose reductions for adverse reactions in adult and pediatric patients are listed in Table 2 and Table 3, respectively.
| VIJOICE dose level | Dose and schedule |
| First-dose reduction | 125 mg once daily |
| Second-dose reduction | 50 mg once daily |
| Action | VIJOICE dose prior to dose reduction | |
| 125 mg once daily | 50 mg once daily | |
| Dose reduction | 50 mg once daily | Not applicable |
Discontinue VIJOICE in adults or pediatric patients who cannot tolerate 50 mg daily.
Tables 4, 5, 6, 7, 8, and 9 summarize recommendations for dose interruption, reduction, or discontinuation of VIJOICE in the management of specific adverse reactions.
Cutaneous Adverse Reactions
If a severe cutaneous adverse reaction (SCAR) is confirmed, permanently discontinue VIJOICE. Do not reintroduce VIJOICE in patients who have experienced previous SCAR during VIJOICE treatment [see Warnings and Precautions (5.2)].
| aGrading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. bFor all grades of rash, consider consultation with a dermatologist. cAntihistamines administered prior to rash onset may decrease incidence and severity of rash. | |
| [see Warnings and Precautions (5.1, 5.2)] | |
| Gradea,b | Recommendation for adult and pediatric patientsc |
| Grade 1 (< 10% body surface area (BSA) with active skin toxicity) | No VIJOICE dosage modification is required unless the etiology is determined to be SCAR. Initiate topical corticosteroid treatment. Consider adding oral antihistamine to manage symptoms. If active rash is not improved within 28 days of appropriate treatment, add a low dose systemic corticosteroid. If the etiology is determined to be SCAR, permanently discontinue VIJOICE. |
| Grade 2 (10% to 30% BSA with active skin toxicity) | No VIJOICE dosage modification is required unless the etiology is determined to be SCAR. Initiate or intensify topical corticosteroid and oral antihistamine treatment. Consider low dose systemic corticosteroid treatment. If rash improves to Grade ≤ 1 within 10 days, systemic corticosteroid may be discontinued. If the etiology is determined to be SCAR, permanently discontinue VIJOICE. |
| Grade 3 (e.g., severe rash not responsive to medical management) (> 30% BSA with active skin toxicity) | Interrupt VIJOICE and initiate or intensify topical/systemic corticosteroid and oral antihistamine treatment. If the etiology is determined to be SCAR, permanently discontinue VIJOICE. For rashes other than SCAR Adult Patients:
|
| Grade 4 (e.g., severe bullous, blistering or exfoliating skin conditions) (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences) | Permanently discontinue VIJOICE. |
Hyperglycemia
Before initiating treatment with VIJOICE, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with VIJOICE, monitor fasting glucose (FPG or fasting blood glucose) at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. In patients with risk factors for hyperglycemia, monitor fasting glucose more closely and as clinically indicated [see Warnings and Precautions (5.3)].
| Abbreviation: ULN, upper limit of normal. aFPG/Fasting Blood Glucose/Grade levels reflect hyperglycemia grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. bInitiate applicable anti-hyperglycemic medications, including metformin in adult and pediatric patients ≥ 10 years, SGLT2 inhibitors or insulin sensitizers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors) in adult patients, and review respective prescribing information for dosing and dose titration recommendations, including local hyperglycemic treatment guidelines [see Warnings and Precautions (5.3)]. | |
| [see Warnings and Precautions (5.3)] | |
| Fasting plasma glucose (FPG)/Fasting blood glucose valuesa | Recommendation for adult and pediatric patients |
| Dose modifications and management should only be based on fasting glucose values (FPG or fasting blood glucose). | |
| Grade 1 Fasting glucose > ULN -160 mg/dL or > ULN -8.9 mmol/L | No VIJOICE dosage modification is required. Initiate or intensify oral anti-hyperglycemic treatmentb. |
| Grade 2 Fasting glucose > 160 - 250 mg/dL or > 8.9 - 13.9 mmol/L | No VIJOICE dosage modification is required. Initiate or intensify oral anti-hyperglycemic treatmentb. Adult Patients:
|
| Grade 3 Fasting glucose > 250 - 500 mg/dL or > 13.9 - 27.8 mmol/L | Interrupt VIJOICE. Initiate or intensify oral anti-hyperglycemic treatmentb and consider additional anti-hyperglycemic medications for 1-2 days until hyperglycemia improves, as clinically indicated. Administer intravenous hydration and consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances). Adult Patients:
|
| Grade 4 Fasting glucose > 500 mg/dL or ≥ 27.8 mmol/L | Interrupt VIJOICE.
Initiate or intensify appropriate oral anti-hyperglycemic treatmentb. Administer intravenous hydration and consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances). Re-check fasting glucose within 24 hours and as clinically indicated.
|
Pneumonitis
| aGrading according to CTCAE Version 5.0. | |
| [see Warnings and Precautions (5.4)] | |
| Gradea | Recommendation for adult and pediatric patients |
| Any Grade | • Interrupt VIJOICE if pneumonitis is suspected. • Permanently discontinue VIJOICE if pneumonitis is confirmed. |
Diarrhea
In pediatric patients, consider consultation with a physician with experience in the treatment of gastrointestinal conditions.
| aGrading according to CTCAE Version 5.0. | |
| [see Warnings and Precautions (5.5)] | |
| Gradea | Recommendation for adult and pediatric patients |
| Grade 1 | No VIJOICE dosage modification is required. Initiate appropriate medical therapy and monitor as clinically indicated. |
| Grade 2 | Interrupt VIJOICE dose until improvement to Grade ≤ 1, then resume VIJOICE at the same dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Adult Patients:
|
| Grade 3 | Interrupt VIJOICE dose until improvement to Grade ≤ 1. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Adult Patients:
|
| Grade 4 | Permanently discontinue VIJOICE. |
Pancreatitis
| aGrading according to CTCAE Version 5.0. | |
| Gradea | Recommendation for adult and pediatric patients |
| Grade 2 | Interrupt VIJOICE dose until improvement to Grade < 2. Adult Patients:
|
| Grade 3 | Adult Patients:
|
| Grade 4 | Permanently discontinue VIJOICE. |
Other Adverse Reactions
| aGrading according to CTCAE Version 5.0. bFor Grade 2 total bilirubin elevation in adult patients, interrupt VIJOICE dose until improvement to Grade ≤ 1. If improvement occurs in ≤ 14 days, resume at the same dose level. If improvement occurs in > 14 days, resume VIJOICE at the next lower dose level. cFor Grade 2 total bilirubin elevation in pediatric patients, interrupt VIJOICE dose until improvement to Grade ≤ 1. If improvement occurs in ≤ 14 days, resume at the same dose level. If improvement occurs in > 14 days, resume VIJOICE at 50 mg. | |
| Gradea | Recommendation for adult and pediatric patients |
| Grade 1 or 2b,c | No VIJOICE dosage modification is required. Initiate appropriate medical therapy and monitor as clinically indicatedb,c. |
| Grade 3 | Interrupt VIJOICE dose until improvement to Grade ≤ 1. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Adult Patients:
|
| Grade 4 | Permanently discontinue VIJOICE. |
Tablets: 50 mg, 125 mg, and 200 mg alpelisib
50 mg: Light yellow, unscored, round and curved with beveled edges film-coated tablet, debossed with “C7” on one side and “NVR” on the other side.
125 mg: Dark yellow, unscored, ovaloid and curved with beveled edges film-coated tablet, debossed with “Y7” on one side and “NVR” on the other side.
200 mg: Pale yellow, unscored, ovaloid and curved with beveled edges film-coated tablet, debossed with “CL7” on one side and “NVR” on the other side.
VIJOICE is contraindicated in patients with severe hypersensitivity to alpelisib or any of its ingredients [see Warnings and Precautions (5.1)].
Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.
Permanently discontinue VIJOICE in the event of severe hypersensitivity [see Contraindications (4)].
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.
If signs or symptoms of SCARs occur, interrupt VIJOICE until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.
If a SCAR is confirmed, permanently discontinue VIJOICE.
If a SCAR is not confirmed, VIJOICE may require dose modifications, topical corticosteroids, or oral antihistamine treatment, as described in Table 4 [see Dosage and Administration (2.3)].
Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or fatal cases of ketoacidosis, has occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.
In the EPIK-P1 study, Grade 1 or 2 hyperglycemia was reported in 12% of patients treated with VIJOICE [see Adverse Reactions (6.1)].
Before initiating treatment with VIJOICE, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with VIJOICE, monitor fasting glucose (FPG or fasting blood glucose) at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. Monitor fasting glucose more frequently for the first few weeks during treatment with VIJOICE in patients with risk factors for hyperglycemia, such as obesity (BMI ≥ 30), elevated FPG, HbA1c at the upper limit of normal or above, use of concomitant systemic corticosteroids, or age ≥ 75 [see Use in Specific Populations (8.5)].
If a patient experiences hyperglycemia after initiating treatment with VIJOICE, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with anti-hyperglycemic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.
The safety of VIJOICE in patients with Type 1 and uncontrolled Type 2 diabetes has not been established. Patients with a history of diabetes mellitus may require intensified hyperglycemic treatment. Closely monitor patients with diabetes.
Interrupt, reduce the dose, or permanently discontinue VIJOICE based on the severity as decribed in Table 5 [see Dosage and Administration (2.3)].
Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, has occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.
In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt VIJOICE immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms, such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations.
Permanently discontinue VIJOICE in all patients with confirmed pneumonitis [see Dosage and Administration (2.3)].
Severe diarrhea, including cases resulting in dehydration and acute kidney injury, has occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting.
In the EPIK-P1 study, 16% of patients experienced Grade 1 diarrhea during treatment with VIJOICE [see Adverse Reactions (6.1)].
Interrupt, reduce the dose or permanently discontinue VIJOICE based on severity [see Dosage and Administration (2.3)].
Based on findings in animals and its mechanism of action, VIJOICE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant animals during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at doses that were approximately equivalent to the recommended pediatric and adult doses. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VIJOICE and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with VIJOICE and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
The following clinically significant adverse reactions are discussed elsewhere in the labeling:
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 VIJOICE was evaluated in EPIK-P1 (NCT04285723), a single-arm clinical study in patients who were treated as part of an expanded access program for compassionate use. Fifty-seven patients 2 years of age and older with severe or life-threatening PIK3CA-Related Overgrowth Spectrum (PROS) received VIJOICE based on age at dosages ranging from 50 mg to 250 mg orally once daily [see Clinical Studies (14)]. Among patients who received VIJOICE, 95% were exposed for 6 months or longer and 79% were exposed for greater than one year.
The median age of patients who received VIJOICE was 14 years (range, 2 to 50); 58% were female; 12% were White and race was not reported for 88%.
Serious adverse reactions occurred in 12% of patients who received VIJOICE. Serious adverse reactions occurring in two or more patients included dehydration (n = 2) and cellulitis (n = 2).
Dosage interruption of VIJOICE due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption in two or more patients included dizziness (n = 2) and vomiting (n = 2). Dose reductions of VIJOICE due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dose reduction included alopecia, memory impairment, and soft tissue infection.
The most common adverse reactions (≥ 10%) were diarrhea, stomatitis, and hyperglycemia. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were increased glucose, decreased hemoglobin, decreased phosphate, increased bilirubin, decreased sodium, and decreased platelets.
Adverse reactions and laboratory abnormalities are listed in Table 10 and Table 11, respectively.
| Grading according to CTCAE Version 4.03. aStomatitis: including stomatitis and aphthous ulcer. | ||
| VIJOICE
N = 57 | ||
| Adverse reactions | ||
| All Grades (%) | Grade 3 or 4 (%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 16 | 0 |
| Stomatitisa | 16 | 0 |
| Metabolism and nutrition disorders | ||
| Hyperglycemia | 12 | 0 |
| Skin and subcutaneous tissue disorders | ||
| Eczema | 7 | 0 |
| Dry skin | 7 | 0 |
| Alopecia | 5 | 0 |
| Nervous system disorders | ||
| Headache | 5 | 0 |
| Infections and infestations | ||
| Cellulitis | 5 | 3.5 |
Clinically relevant adverse reactions in < 5% of patients who received VIJOICE included nausea, vomiting, dehydration, and mucosal dryness.
| Grading according to CTCAE Version 4.03. Abbreviation: N/A, not available. aThe denominator used to calculate the rate varied from 9 to 50 based on the number of patients with a baseline value and at least one post-treatment value. bNo Grade 4 laboratory abnormalities were reported. cGlucose increase is an expected laboratory abnormality of PI3K inhibition. dNo CTCAE grade available. For HbA1c, baseline values increasing post-treatment to a value above the upper limit of the normal range (≥ 5.7%) are considered increased. | ||
| Laboratory abnormality | VIJOICEa N = 57 | |
| All Grades % | Grade 3 or 4 % | |
| Chemistry | ||
| Decreased calcium (corrected) | 60 | 0 |
| Decreased phosphate | 59 | 5b |
| Increased glucosec | 56 | 11b |
| Increased glycosylated hemoglobin (HbA1c)d | 38d | N/Ad |
| Increased creatinine | 31 | 0 |
| Increased bilirubin | 29 | 2b |
| Increased potassium | 24 | 0 |
| Increased triglycerides | 19 | 0 |
| Decreased magnesium | 18 | 0 |
| Increased aspartate aminotransferase (AST) | 17 | 0 |
| Increased cholesterol | 13 | 0 |
| Decreased albumin | 13 | 0 |
| Decreased sodium | 12 | 2b |
| Decreased potassium | 12 | 0 |
| Increased gamma glutamyl transferase (GGT) | 11 | 0 |
| Increased alanine aminotransferase (ALT) | 10 | 0 |
| Hematology | ||
| Decreased leukocyte | 22 | 0 |
| Decreased hemoglobin | 20 | 6b |
| Decreased lymphocyte | 20 | 0 |
| Decreased neutrophil | 19 | 0 |
| Increased lymphocyte | 17 | 0 |
| Decreased platelets | 14 | 2b |
The following adverse reactions have been identified with VIJOICE use in patients with PROS in an expanded access program for compassionate use. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Metabolism and nutrition disorders: Decreased appetite.
Skin and subcutaneous tissue disorders: Pruritus, rash (including rash maculo-papular, rash erythematous, rash papular, and rash pruritic), acne (including dermatitis acneiform).
CYP3A4 Inducers
Avoid coadministration of VIJOICE with strong CYP3A4 inducers.
Alpelisib is metabolized by CYP3A4. Concomitant use of VIJOICE with a strong CYP3A4 inducer may decrease alpelisib concentration [see Clinical Pharmacology (12.3)], which may decrease alpelisib activity.
Breast Cancer Resistance Protein Inhibitors (BCRP)
Avoid the use of BCRP inhibitors in patients treated with VIJOICE. If unable to use alternative drugs, when VIJOICE is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions.
Alpelisib is transported by BCRP. Concomitant use of VIJOICE with a BCRP inhibitor may increase alpelisib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.
CYP2C9 Substrates
Closely monitor CYP2C9 substrates where minimal concentration changes of the CYP2C9 substrate may reduce activity when used concomitantly with VIJOICE.
Alpelisib induces CYP2C9. Concomitant use of VIJOICE with CYP2C9 substrates may reduce exposure of these drugs, which may reduce activity [see Clinical Pharmacology (12.3)].
Risk Summary
Based on animal data and mechanism of action, VIJOICE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at doses described below (see Data). Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.
Data
Animal Data
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of alpelisib during the period of organogenesis. In the rat study, animals were dosed at 3, 10, or 30 mg/kg/day from gestation day 6 to 17; and in the rabbit study, animals were dosed at 3, 15, 25, and 30 mg/kg/day from gestation day 7 to 20.
In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3.6 to 1.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). At a dose of 10 mg/kg/day (approximately 1.2 to 0.4 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA), toxicities included reduced fetal weight and increased incidences of skeletal malformations (bent scapula and thickened or bent long bones) and fetal variations (enlarged brain ventricle, decreased bone ossification).
In a pilot embryo-fetal development study in rabbits, a dose of 30 mg/kg/day (approximately 7 to 2.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients based on BSA) resulted in no viable fetuses (post-implantation loss). Doses ≥ 15 mg/kg/day (approximately 3.5 to 1.1 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA) resulted in increased embryo-fetal deaths, reduced fetal weights, and malformations, mostly related to the tail and head.
Risk Summary
There are no data on the presence of alpelisib in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with VIJOICE and for 1 week after the last dose.
Pregnancy Testing
Verify the pregnancy status in females of reproductive potential prior to initiating VIJOICE.
Contraception
Females
VIJOICE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with VIJOICE and for 1 week after the last dose.
Males
Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with VIJOICE and for 1 week after the last dose.
Infertility
Based on findings from animal studies, VIJOICE may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of VIJOICE have been established in pediatric patients 2 to less than 18 years of age with PROS based on results from a single-arm clinical study of VIJOICE (EPIK-P1) that enrolled 39 pediatric patients: 11 patients aged 2 to 5 years, 12 patients aged 6 to 11 years, and 16 patients aged 12 to less than 18 years of age [see Adverse Reactions (6.1) and Clinical Studies (14)].
The safety and effectiveness of VIJOICE in pediatric patients below the age of 2 years have not been established.
Although there were no new safety signals observed in pediatric patients, there is insufficient data to determine whether VIJOICE has an adverse impact on growth and development in pediatric patients with PROS. Based on the animal toxicity data (described below), regular monitoring of growth and development in pediatric patients treated with VIJOICE is recommended.
Animal Toxicity Data
In a 4-week general toxicology study, rats administered alpelisib had growth plate thickening and decreased trabeculae of the knee joint, dentin thinning, and degenerative odontoblasts at the dose of 30 mg/kg/day (approximately 2.8 to 1.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). Dentin thinning/irregular dentin was also observed in the 13-week toxicology study in rats at the high dose of 20 mg/kg/day (approximately 2 to 0.8 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA).
There were no adult patients aged 65 years of age or older who received VIJOICE in EPIK-P1.
There is limited experience of overdose with alpelisib in clinical trials.
In cases where accidental overdosage of alpelisib was reported in the clinical studies, the adverse reactions associated with the overdose were consistent with the known safety profile of alpelisib and included hyperglycemia, nausea, asthenia, and rash.
Initiate general symptomatic and supportive measures in all cases of overdosage where necessary. There is no known antidote for VIJOICE.
VIJOICE (alpelisib) is a kinase inhibitor. The chemical name of alpelisib is (2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide. Alpelisib is a white to almost white powder. The molecular formula for alpelisib is C19H22F3N5O2S and the relative molecular mass is 441.47 g/mol. The chemical structure of alpelisib is shown below:
Alpelisib Structural Formula (Vijoice 01)
VIJOICE film-coated tablets are supplied for oral administration with three strengths that contain 50 mg, 125 mg and 200 mg of alpelisib. The tablets also contain hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate. The film-coating contains hypromellose, iron oxide red (applicable only to 50 mg and 200 mg strengths), iron oxide yellow, macrogol/polyethylene glycol (PEG) 4000, talc, and titanium dioxide.
Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors in in vitro and in vivo models.
Activating mutations in PIK3CA have been found to induce a spectrum of overgrowths and malformations comprising a wide group of clinically recognizable disorders commonly known as PROS.
In an inducible mouse model of Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal syndrome (CLOVES), a phenotype of PROS, alpelisib inhibition of the PI3K pathway resulted in the prevention or improvement of organ abnormalities associated with the disease, depending on when alpelisib treatment was started. These findings were reversed after withdrawal of alpelisib.
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of VIJOICE have not been characterized.
Cardiac Electrophysiology
At a dose of 300 mg, alpelisib does not prolong the QT interval to any clinically relevant extent in the oncology setting. VIJOICE is not approved for use in the oncology setting.
The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors and are presented as mean (% CV) under fed conditions unless otherwise specified. Steady-state alpelisib maximum plasma concentration (Cmax) and area under the curve (AUC) increased proportionally over the dose range of 30 mg (0.6 times the lowest approved recommended dosage) to 450 mg (1.8 times the highest approved recommended dosage) under fed conditions. The mean accumulation of alpelisib is 1.3 to 1.5 and steady-state plasma concentrations are reached within 3 days following daily dosage.
Absorption
The median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours.
Effect of food
A high-fat high-calorie meal (985 calories with 58.1 g of fat) increased alpelisib AUC by 73% and Cmax by 84%, and a low-fat low-calorie meal (334 calories with 8.7 g of fat) increased alpelisib AUC by 77% and Cmax by 145% following a single alpelisib dose of 300 mg. No clinically relevant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.
Distribution
The apparent volume of distribution of alpelisib at steady-state is 114 L (46%). Protein binding of alpelisib is 89% and is independent of concentration.
Elimination
The half-life of alpelisib is predicted to be 8 to 9 hours. The clearance of alpelisib is 9.2 L/hr (21%) under fed conditions.
Metabolism
Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis and to a lesser extent by CYP3A4, in vitro.
Excretion
Following a single oral dose of 400 mg (1.6 times the highest approved recommended dosage) radiolabeled alpelisib under fasted condition, 81% of the administered dose was recovered in feces (36% unchanged) and 14% (2% unchanged) in urine. CYP3A4-mediated metabolites (12%) and glucuronides amounted to approximately 15% of the dose.
Specific Populations
No clinically significant differences in the pharmacokinetics of alpelisib were predicted based on age (21 to 87 years), sex, race/ethnicity (Japanese or Caucasian), body weight (37 to 181 kg), mild to moderate renal impairment (CLcr 30 to < 90 mL/min based on the Cockcroft-Gault formula), or mild to severe hepatic impairment (Child-Pugh Class A, B, and C). The effect of severe renal impairment (CLcr < 30 mL/min) on the pharmacokinetics of alpelisib is unknown.
Pediatric Patients
The pharmacokinetics of VIJOICE in pediatric patients have not been evaluated.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Acid Reducing Agents: No clinically significant differences in the pharmacokinetics of alpelisib were observed when used concomitantly with ranitidine (H2 receptor antagonist) and administered with food as directed.
Concomitant use of ranitidine decreased alpelisib AUC approximately 30% and Cmax by 51% with a single 300 mg oral dose (1.2 times the highest approved recommended dosage) of alpelisib under the fasted state. In the presence of a low-fat low-calorie meal, AUC was decreased by 21% and Cmax by 36% with ranitidine.
CYP3A4 Substrates: No clinically significant differences in pharmacokinetics of everolimus (a substrate of CYP3A4 and P-gp) were observed when used concurrently with alpelisib.
In Vitro Studies
Effect of Alpelisib on CYP Enzymes: Alpelisib inhibits CYP3A4 in a time-dependent manner and induces CYP2B6, CYP2C9 and CYP3A4.
Effect of Transporter on Alpelisib: Alpelisib is a substrate of BCRP.
Effect of Alpelisib on Transporters: Alpelisib is an inhibitor of P-gp. Alpelisib has a low potential to inhibit BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, OCT2, MATE1, and MATE2K at clinically relevant concentrations.
Carcinogenicity studies have not been conducted with alpelisib.
Alpelisib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, or aneugenic or clastogenic in human cell micronucleus and chromosome aberration tests in vitro. Alpelisib was not genotoxic in an in vivo rat micronucleus test.
In a fertility and early embryonic development study in rats, female animals were administered alpelisib doses of 3, 10, and 20 mg/kg/day orally. Animals were dosed for 4-weeks prior to pairing, during the mating period, and up to Gestation Day 6. At the dose of 20 mg/kg/day, alpelisib increased pre- and post-implantation losses, leading to reduced numbers of implantation sites and live embryos. These findings were observed at doses approximately 2.4 to 0.8 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on body surface areas (BSA). In a repeated-dose toxicity study in rats, adverse effects in female reproductive organs included vaginal atrophy and estrous cycle variations in rats at doses ≥ 6 mg/kg/day (approximately 0.7 to 0.2 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). In a male fertility study, alpelisib administered orally at doses of 3, 10 and 20 mg/kg/day for up to 99 days (10-weeks prior to pairing, during mating period and continuing during post-pairing) to male rats, resulted in reduced weights of seminal vesicles and prostate, which correlated with atrophy and/or reduced secretion in prostate and seminal vesicles at ≥ 10 mg/kg/day (approximately 1.2 to 0.4 times the initial recommended doses of 50 mg and 250 mg in pediatric and adult patients, respectively, based on BSA). No adverse effects on male fertility parameters were observed at doses up to 20 mg/kg/day.
The efficacy of VIJOICE was assessed in EPIK-P1 (NCT04285723), a single-arm clinical study in patients who were treated as part of an expanded access program for compassionate use which enrolled patients across seven sites in five countries (France, Spain, US, Ireland and Australia). Eligible patients 2 years of age and older with PIK3CA-Related Overgrowth Spectrum (PROS) who received VIJOICE had clinical manifestations of PROS that were assessed by the treating physician as severe or life-threatening and necessitating systemic treatment and had documented evidence of mutation in the PIK3CA gene. Patients received VIJOICE at dosages based on age ranging from 50 mg to 250 mg orally once daily.
The efficacy of VIJOICE was evaluated in a total of 37 patients with at least one target lesion identified on imaging performed within 24 weeks prior to receipt of the first dose of VIJOICE. The median age of patients was 14 years (range: 2 to 38); 22% of patients were 2 to 5 years, 22% were 6 to 11 years, 27% were 12 to less than 18 years of age, and 30% were ≥ 18 years; 57% were female, 11% were White and race was not reported for 89%. Ninety-two percent of patients had congenital overgrowth and 8% had early childhood-onset. Patients had heterogeneous manifestations of PROS, including CLOVES, (81%), Megalencephaly-Capillary Malformation Polymicrogyria (MCAP; 8%), Klippel-Trenaunay Syndrome (KTS; 2.7%), Facial Infiltrating Lipomatosis (FIL; 8%), and Other (5%). Five percent (5%) of patients had concurrent manifestations of CLOVES and MCAP.
The major efficacy outcome measure for the study was the proportion of patients with radiological response at Week 24 as determined by blinded independent central review (BICR), defined as a ≥ 20% reduction from baseline in the sum of measurable target lesion volume (1 to 3 lesions) confirmed by at least one subsequent imaging assessment, in the absence of a ≥ 20% increase from baseline in any target lesion, progression of non-target lesions, or appearance of a new lesion. An additional efficacy outcome measure was duration of response, defined as the time from the first documented response to the date of the first documented disease progression or death due to any cause.
Efficacy results are presented in Table 12.
| Abbreviation: +: censored observation. aConfirmed response as determined by blinded independent central review (BICR). bPatients without any response assessment at Week 24 were considered non-responders. | |
| Efficacy parameters | All patients N = 37 |
| Response ratea,b | |
| Responders, n (%) 95% CI | 10 (27) (14, 44) |
| Duration of response (DOR) | |
| Median in months (range) | NR (0.9+, 42.9+) |
| % ≥ 6 months | 70 |
| % ≥ 12 months | 60 |
VIJOICE (alpelisib) 50 mg, 125 mg, and 200 mg film-coated tablets are available in blister packs based on daily dose as described in Table 13.
| Daily dose | Each child-resistant carton contains | Each blister pack contains | NDC |
| 50 mg daily dose | One 28-day supply blister pack | 28 tablets; 50 mg alpelisib per tablet | NDC 0078-1021-84 |
| 125 mg daily dose | One 28-day supply blister pack | 28 tablets; 125 mg alpelisib per tablet | NDC 0078-1028-84 |
| 250 mg daily dose | Two 14-day supply blister packs (56 tablets total) | 14 tablets: 200 mg alpelisib per tablet, and 14 tablets: 50 mg alpelisib per tablet | NDC 0078-1035-02 |
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
Advise the patient and their caregivers to read the FDA-approved patient labeling (Patient Information).
Severe Hypersensitivity
Inform patients and their caregivers of the signs and symptoms of hypersensitivity. Advise patients and their caregivers to contact their healthcare provider immediately for signs and symptoms of hypersensitivity [see Warnings and Precautions (5.1)].
Severe Cutaneous Adverse Reactions
Inform patients and their caregivers of the signs and symptoms of severe cutaneous adverse reactions (SCARs). Advise patients and their caregivers to contact their healthcare provider immediately for signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy) [see Warnings and Precautions (5.2)].
Hyperglycemia
Advise patients and their caregivers of the possibility of developing hyperglycemia and the need to monitor fasting glucose periodically during therapy. Advise patients and their caregivers of the signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss) [see Warnings and Precautions (5.3)].
Pneumonitis
Inform patients and their caregivers of the possibility of developing pneumonitis and to immediately report new or worsening respiratory symptoms [see Warnings and Precautions (5.4)].
Diarrhea
Advise patients and their caregivers that VIJOICE may cause diarrhea, which may be severe in some cases. Inform patients and their caregivers to start anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking VIJOICE [see Warnings and Precautions (5.5)].
Alopecia
Advise patients and caregivers that VIJOICE may cause alopecia [see Adverse Reactions (6.1)].
Embryo-Fetal Toxicity
Lactation
Advise women not to breastfeed during treatment with VIJOICE and for 1 week after the last dose [see Use in Specific Populations (8.2)].
Infertility
Advise males and females of reproductive potential that VIJOICE may impair fertility [see Use in Specific Populations (8.3)].
Drug Interactions
Advise patients and their caregivers to inform their healthcare providers of all concomitant medications, herbal and dietary supplements [see Drug Interactions (7.1, 7.2)].
Dosing
Instruct patients and their caregivers of the following:
Distributed by
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2022-27
Vijoice™
(alpelisib) tablets
NDC 0078-1021-84
50 mg daily dose
Take one 50 mg tablet once daily
Rx only
Recommended Dosage: Take one 50 mg tablet once daily with food.
Swallow tablets whole. DO NOT chew, crush, or split tablets.
See prescribing information for complete dosage information and
instruction for patients who are unable to swallow whole tablets.
28-Day Supply
Contains: One blister pack containing 28 tablets
NOVARTIS
Principal Display Panel Vijoice™ (alpelisib) Tablets Ndc 0078-1021-84 50 mg Daily Dose Take One 50 mg Tablet Once Daily Rx Only Recommended Dosage: Take One 50 mg Tablet Once Daily With Food. Swallow Tablets Whole. Do Not Chew, Crush, Or Split Tablets. See Prescribing Information For Complete Dosage Information And Instruction For Patients Who Are Unable To Swallow Whole Tablets. 28-day Supply Contains: One Blister Pack Containing 28 Tablets Novartis (Vijoice 02)
Vijoice™
(alpelisib) tablets
NDC 0078-1028-84
125 mg daily dose
Take one 125 mg tablet once daily
Rx only
Recommended Dosage: Take one 125 mg tablet once daily with
food. Swallow tablets whole. DO NOT chew, crush, or split tablets. See
prescribing information for complete dosage information and
instruction for patients who are unable to swallow whole tablets.
28-Day Supply
Contains: One blister pack containing 28 tablets
NOVARTIS
Principal Display Panel Vijoice™ (alpelisib) Tablets Ndc 0078-1028-84 125 mg Daily Dose Take One 125 mg Tablet Once Daily Rx Only Recommended Dosage: Take One 125 mg Tablet Once Daily With Food. Swallow Tablets Whole. Do Not Chew, Crush, Or Split Tablets. See Prescribing Information For Complete Dosage Information And Instruction For Patients Who Are Unable To Swallow Whole Tablets. 28-day Supply Contains: One Blister Pack Containing 28 Tablets Novartis (Vijoice 03)
Vijoice™
(alpelisib) tablets
NDC 0078-1035-02
250 mg daily dose
Take one 200 mg tablet and one 50 mg tablet once daily
Rx only
Recommended Dosage: Take one 200 mg tablet and one 50 mg
tablet once daily with food. Swallow tablets whole. DO NOT chew,
crush, or split tablets. See prescribing information for complete
dosage information and instruction for patients who are unable to
swallow whole tablets.
28-Day Supply (56 Tablets)
Contains: Two 14-day blister packs each containing 28 tablets:
200 mg
14 tablets per pack
50 mg
14 tablets per pack
NOVARTIS
Principal Display Panel Vijoice™ (alpelisib) Tablets Ndc 0078-1035-02 250 mg Daily Dose Take One 200 mg Tablet And One 50 mg Tablet Once Daily Rx Only Recommended Dosage: Take One 200 mg Tablet And One 50 mg Tablet Once Daily With Food. Swallow Tablets Whole. Do Not Chew, Crush, Or Split Tablets. See Prescribing Information For Complete Dosage Information And Instruction For Patients Who Are Unable To Swallow Whole Tablets. 28-day Supply (56 Tablets): Contains: Two 14-day Blister Packs Each Containing 28 Tablets: 200 mg 14 Tablets Per Pack 50 mg 14 Tablets Per Pack Novartis (Vijoice 04)
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