Important Safety Information:

VIJOICE® (alpelisib) tablets is contraindicated in patients with severe hypersensitivity to alpelisib or any of its ingredients...

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Indication: VIJOICE® (alpelisib) tablets 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 confirmatory trials.

PROS & PIK3CA Mutations

PROS Disorders

PIK3CA-Related Overgrowth Spectrum (PROS) is a spectrum of diverse overgrowth disorders caused by PIK3CA mutations1

Disorders now recognized to be part of PROS include1-3:

  • KTS (Klippel-Trenaunay Syndrome)
  • CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal)
  • ILM (Isolated Lymphatic Malformation)
  • MCAP or M-CM (Megalencephaly-Capillary Malformation)
  • HME (HemiMegalEncephaly)/DMEG (Dysplastic MEGalencephaly)/Focal cortical dysplasia type II
  • HHML (HemiHyperplasia-Multiple Lipomatosis)
  • FIL (Facial Infiltrating Lipomatosis)
  • FAVA (FibroAdipose Vascular Anomaly)
  • Macrodactyly
  • Muscular HH (HemiHyperplasia)
  • FAO (FibroAdipose hyperplasia or Overgrowth)
  • CLAPO syndrome (Capillary malformation of the lower lip, Lymphatic malformation of the face and neck, Asymmetry of the face and limbs, and Partial or generalized Overgrowth)
  • Epidermal nevus, benign lichenoid keratosis, or seborrheic keratosis
  • Other disorders may be identified and characterized as PROS

Patients with CLOVES syndrome, MCAP or M-CM, KTS, FIL, and 2 patients with unspecified PROS disorders were included in the study.

Despite the range of presentation, PROS disorders have clinical commonalities1

Clinical hallmarks of PROS include congenital or early childhood onset, sporadic and mosaic overgrowth, and a progressive course of disease.

Features of PROS disorders broadly include the following types of overgrowth:

Abnormal growth icon

Abnormal growth

Vascular malformations icon

Vascular malformations

Lymphatic malformations icon

Lymphatic malformations

Skin lesions icon

Skin lesions


PROS and its associated overgrowth can have a substantial effect on patients’ lives4-7

Patients with PROS experience a variety of signs and symptoms related to their disorders. These manifestations can cause severe medical complications, disfigurements, and functional complications that interfere with daily living.

Vascular complications, including disseminated intravascular coagulation icon

Vascular complications, including disseminated intravascular coagulation

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Pain

Bone abnormalities icon

Bone abnormalities, including leg asymmetry and scoliosis

Hypertrophy icon

Hypertrophy

Fatigue icon

Fatigue

  • The effects of overgrowth can add to the already severe burden on quality of life from PROS signs and symptoms6-9
  • To manage the effects of PROS, patients may require repeat surgeries, interventional procedures, and additional care10,11

 

How VIJOICE Works

VIJOICE® (alpelisib) tablets targets the underlying cause of PROS12


PIK3CA mutations lead to hyperactivation of PI3Kα, a key upstream component of the PI3K pathway.

  • The PIK3CA gene codes for the catalytic α-subunit of the PI3K protein (PI3Kα). Mutations to this gene lead to activation of PI3Kα and Akt-signaling, cellular transformation, and the generation of tumors in in vitro and in vivo models

VIJOICE inhibits the effects caused by PIK3CA mutations in PROS.

In an inducible mouse model of CLOVES syndrome, inhibition of the PI3K pathway with alpelisib resulted in the prevention or improvement of organ abnormalities associated with the disease, depending on when treatment with alpelisib was started. These findings were reversed after withdrawal of alpelisib.

Based on in vitro/in vivo studies. Preclinical activity does not necessarily correlate with clinical outcomes.

 

Diagnosis

A PROS diagnosis is the first step to targeted treatment with VIJOICE

PROS is a spectrum of diverse overgrowth disorders caused by PIK3CA mutations. Understanding the diagnosis of PROS can help you identify which patients may benefit from VIJOICE, the first and only FDA-approved treatment for patients with PROS. A National Institutes of Health (NIH) workshop* proposed the following diagnostic criteria for PROS1:

 

NIH Workshop Diagnostic Criteria1*

 

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Congenital or early childhood onset

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Sporadic and mosaic overgrowth

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2 or more spectrum features OR any 1 isolated feature

Spectrum features (2 or more)

  • Overgrowth: adipose, muscle, nerve, skeletal
  • Epidermal nevus
  • Vascular malformations: capillary, venous, arteriovenous, lymphatic

 

Isolated features (any 1)

  • Large, isolated lymphatic malformation
  • Truncal adipose overgrowth
  • Benign lichenoid keratoses
  • Seborrheic keratoses
  • HME (bilateral)/DMEG/focal cortical dysplasia type ll
  • Isolated macrodactyly or overgrown, splayed feet/hands, overgrown limbs
  • Epidermal nevus
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Presence of a somatic PIK3CA mutation

  • Due to the mosaic nature of PIK3CA mutations in PROS, genomic testing may not always reveal the presence of a PIK3CA mutation1
  • Detection of a PIK3CA mutation depends on the degree of overgrowth, as well as the distribution and amount of detectable mutation in the tissue1
  • Technical limitations, sample availability, and difficulties with interpreting the results may impact the decision to test1,15,16

 

A presumptive PROS diagnosis can be considered based on features if a PIK3CA mutation is not identified

*Clinical diagnostic criteria were determined after a 2-day workshop that included several researchers who have been studying this group of disorders and 3 parent representatives of patient-family support and advocacy organizations for individuals with these conditions. These criteria may change as research develops.1

 

Find a multidisciplinary team

The International Society for the Study of Vascular Anomalies (ISSVA) has compiled a list of multidisciplinary teams that treat vascular anomalies, which may be signs and symptoms of PROS. ISSVA believes that a team environment is the optimal setting for managing the complex problems that arise when treating vascular anomalies.

To view the list of multidisciplinary care teams, click here.

 

References:

  1. Keppler-Noreuil KM, Rios JJ, Parker VER, et al. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A. 2015;167A(2):287-295.
  2. Rodriguez-Laguna L, Ibañez K, Gordo G, et al. CLAPO syndrome: identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype. Genet Med. 2018;20(8):882-889.
  3. Alomari AI, Spencer SA, Arnold RW, et al. Fibro-adipose vascular anomaly: clinical-radiologic-pathologic features of a newly delineated disorder of the extremity. J Pediatr Orthop. 2014;34(1):109-117.
  4. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014;164A(7):1713-1733.
  5. Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P. Klippel-Trénaunay syndrome: spectrum and management. Mayo Clin Proc. 1998;73(1):28-36.
  6. van der Ploeg HM, van der Ploeg MN, van der Ploeg-Stapert JD. Psychological aspects of the Klippel-Trenaunay syndrome. J Psychosom Res. 1995;39(2):183-191.
  7. Zhang J, Wang K, Mei J. Late puerperal hemorrhage of a patient with Klippel-Trenaunay syndrome: a case report. Medicine (Baltimore). 2019;98(50):e18378.
  8. Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A. 2014;164A(suppl):1-47.
  9. Alomari AI, Chaudry G, Rodesch G, et al. Complex spinal-paraspinal fast-flow lesions in CLOVES Syndrome: analysis of clinical and imaging findings in 6 patients. Am J Neuroradiol. 2011;32(10):1812-1817.
  10. Bertino F, Braithwaite KA, Hawkins CM, et al. Congenital limb overgrowth syndromes associated with vascular anomalies. Radiographics. 2019;39(2):491-515.
  11. Bessis D, Vernhet H, Bigorre M, Quéré I, Rössler J. Life-threatening cutaneous bleeding in childhood Klippel-Trenaunay syndrome treated with oral sirolimus. JAMA Dermatol. 2016;152(9):1058-1059.
  12. Vijoice [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2022.
  13. Data on file. CBYL719F12002 clinical study report. Novartis Pharmaceuticals Corp; 2021.
  14. Venot Q, Blanc T, Rabia SH, et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature. 2018;558(7711):540-546.
  15. Kang HC, Baek ST, Song S, Gleeson JG. Clinical and genetic aspects of the segmental overgrowth spectrum due to somatic mutations in PIK3CA. J Pediatr. 2015;167(5):957-962.
  16. Kuentz P, St-Onge J, Duffourd Y, et al. Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing. Genet Med. 2017;19(9):989-997.

INDICATION

VIJOICE® (alpelisib) tablets 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 confirmatory trials.

IMPORTANT SAFETY INFORMATION

VIJOICE is contraindicated in patients with severe hypersensitivity to alpelisib or any of its ingredients.

Severe Hypersensitivity. 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.

Severe Cutaneous Adverse Reactions (SCARs). 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. 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.

Hyperglycemia. Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar nonketotic 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.

In the EPIK-P1 study, grade 1 or 2 hyperglycemia was reported in 12% of patients treated with VIJOICE.

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 (body mass index ≥30), elevated FPG, HbA1c at the upper limit of normal or above, use of concomitant systemic corticosteroids, or age ≥75.

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 antihyperglycemic 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 health care provider 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 of, or permanently discontinue VIJOICE based on severity.

Pneumonitis. 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.

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 noninfectious pneumonitis in patients presenting with nonspecific respiratory signs and symptoms, such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic examinations 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.

Diarrhea. 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. In the EPIK-P1 study, 16% of patients experienced grade 1 diarrhea during treatment with VIJOICE. Interrupt, reduce the dose of, or permanently discontinue VIJOICE based on severity.

Embryo-Fetal Toxicity. Based on findings in animals and its mechanism of action, VIJOICE can cause fetal harm when administered to a pregnant woman. 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.

The most common adverse reactions (all grades, incidence ≥10%) were diarrhea (16%), stomatitis (16%), and hyperglycemia (12%).

The most common laboratory abnormalities (all grades, incidence ≥20%) were decreased calcium (corrected) (60%), decreased phosphate (59%), increased glucose (56%), increased HbA1c (38%), increased creatinine (31%), increased bilirubin (29%), decreased magnesium (26%), increased potassium (24%), decreased leukocyte (22%), decreased lymphocyte (20%), and decreased hemoglobin (20%).

Please see full Prescribing Information for VIJOICE® (alpelisib) tablets.