al to use condoms and effective contraception
during treatment with PIQRAY and for 1 week after the last dose.
Infertility
Based on findings from animal studies, PIQRAY may impair fertility in males and females of reproductive
potential [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and efficacy of PIQRAY in pediatric patients have not been established.
8.5 Geriatric Use
Of 284 patients who received PIQRAY in the SOLAR-1 trial, 117 patients were ≥ 65 years of age and 34
patients were ≥ 75 years of age. In patients treated with PIQRAY plus fulvestrant, there was a higher incidence
of Grade 3-4 hyperglycemia in patients ≥ 65 years of age (44%) compared to patients < 65 years of age (32%).
No overall differences in effectiveness of PIQRAY were observed between patients ≥ 65 years of age compared
to younger patients. There are an insufficient number of patients ≥ 75 years of age to assess whether there are
differences in safety or effectiveness.
8.6 Renal Impairment
The effect of severe renal impairment (CLcr < 30 mL/min) on alpelisib pharmacokinetics is unknown[see Clinical Pharmacology (12.3)].
No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90mL/min).
10 OVERDOSAGE
There is limited experience of overdose with PIQRAY in clinical trials. In the clinical studies, PIQRAY wasadministered at doses up to 450 mg once daily.
In cases where accidental overdosage of PIQRAY was reported in the clinical studies, the adverse reactionsassociated with the overdose were consistent with the known safety profile of PIQRAY and includedhyperglycemia, nausea, asthenia, and rash.
Initiate general symptomatic and supportive measures in all cases of overdosage where necessary. There is noknown antidote for PIQRAY.
11 DESCRIPTION
PIQRAY (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 toalmost 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:PIQRAY film-coated tablets are supplied for oral administration with three strengths that contain 50 mg, 150mg 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 oxideblack, iron oxide red, macrogol/polyethylene glycol (PEG) 4000, talc, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly againstPI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead toactivation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors in in vitro and invivo models.
In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets, including Aktand showed activity in cell lines harboring a PIK3CA mutation. In vivo, alpelisib inhibited the PI3K/Aktsignaling pathway and reduced tumor growth in xenograft models, including models of breast cancer.
PI3K inhibition by alpelisib treatment has been shown t |
