Alpelisib

Alpelisib is an α-specific inhibitor of class I phosphatidylinositol-3-kinase (PI3K). The PI3K/AKT pathway relays growth-factor signals that control cell proliferation, and it also regulates glucose handling. A gain-of-function mutation in PIK3CA, the gene for the catalytic α-subunit, makes PI3Kα overactive in some cancers and in PROS. Alpelisib counters this by inhibiting the enzyme, with its highest specificity for the α isoform.

Mechanism of Action

• PI3Kα inhibition: alpelisib is an α-specific class I PI3K inhibitor. Gain-of-function mutations in PIK3CA lead to activation of PI3Kα and AKT signalling, cellular transformation and tumour formation in laboratory models.
• Antitumour effect: in breast cancer cell lines, alpelisib inhibited phosphorylation of PI3K downstream targets, including AKT, and was active in cell lines with a PIK3CA mutation. In xenograft models it inhibited PI3K/AKT signalling and reduced tumour growth.
• Combination with fulvestrant: PI3K inhibition increases oestrogen receptor transcription in breast cancer cells. In xenograft models from oestrogen receptor-positive, PIK3CA-mutated cell lines, alpelisib with fulvestrant had more antitumour activity than either alone.
• Glucose homeostasis: the PI3K/AKT pathway also governs glucose homeostasis, so hyperglycaemia is an expected, on-target effect of PI3K inhibition.

Pharmacokinetics

• Absorption: median time to peak concentration is 2 to 4 hours, independent of dose, time or regimen. Bioavailability is estimated at over 99% with food and lower when fasted (about 68.7% at 300 mg). Steady state is reached by day 3 in most patients.
• Food effect: compared with fasting, a high-fat, high-calorie meal raised AUC by 73% and Cmax by 84%, and a low-fat, low-calorie meal raised AUC by 77% and Cmax by 145%. The two meals did not differ significantly, so fat content and calories matter little; what matters is taking the tablets immediately after food.
• Distribution: moderately bound to plasma proteins, with a free fraction of 10.8% regardless of concentration; shared equally between red blood cells and plasma (blood-to-plasma ratio 1.03). Volume of distribution at steady state about 114 L. Because alpelisib is a substrate of efflux transporters, penetration of the blood–brain barrier is not expected in humans.
• Metabolism: the main route is chemical and enzymatic amide hydrolysis to the metabolite BZG791, carried out throughout the body by high-capacity enzymes (esterases, amidases, choline esterase) and not limited to the liver. CYP3A4-mediated hydroxylation follows, and alpelisib can also be glucuronidated.
• Elimination: mean half-life about 8 to 9 hours. About 81% of an oral dose is recovered in faeces (36% as unchanged drug, 32% as BZG791) and about 14% in urine.
• Special populations: for Piqray, no dose adjustment is needed on pharmacokinetic grounds for age 65 or over, mild or moderate renal impairment, or mild, moderate or severe hepatic impairment.

Alpelisib is authorised in the EU as two products with different indications.

• Breast cancer (Piqray): in combination with fulvestrant, for postmenopausal women and men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation, after disease progression following an endocrine-based regimen. A PIK3CA mutation must be confirmed in a tumour or plasma sample before treatment.
• PIK3CA-related overgrowth spectrum (Vijoice): adults and paediatric patients aged 2 years and older with severe or life-threatening manifestations of PROS who require systemic therapy.

• Hypersensitivity to alpelisib or to any of the excipients (both Piqray and Vijoice).

The two products have separate safety data. With Piqray, hyperglycaemia, rash and diarrhoea are among the reactions that most often lead to stopping treatment (see Special Instructions).

Piqray with fulvestrant. The safety profile rests on 376 patients given Piqray plus fulvestrant in two double-blind, placebo-controlled phase 3 studies. The most common reactions (above 40% of patients) were raised plasma glucose (77.4%), raised creatinine (68.9%), diarrhoea (57.7%), decreased lymphocyte count (56.4%), raised gamma-glutamyltransferase (54.5%), rash (50.0%), raised alanine aminotransferase (47.6%), nausea (46.3%), anaemia (45.7%), fatigue (43.4%) and raised lipase (40.2%). The most common grade 3 or 4 reactions were raised plasma glucose (35.6%), rash (20.2%) and raised gamma-glutamyltransferase (13.3%). The reactions that most often led to stopping treatment were hyperglycaemia (5.6%), rash (5.1%), diarrhoea (2.7%) and fatigue (1.9%).

Very common (≥1/10): anaemia, decreased lymphocyte count, decreased platelet count, raised plasma glucose, decreased plasma glucose, decreased appetite, hypokalaemia, hypocalcaemia, decreased magnesium, headache, dysgeusia, diarrhoea, nausea, stomatitis, vomiting, abdominal pain, dyspepsia, rash, alopecia, pruritus, dry skin, fatigue, mucosal inflammation, peripheral oedema, pyrexia, mucosal dryness, weight loss, raised blood creatinine, raised gamma-glutamyltransferase, raised alanine aminotransferase, raised lipase, prolonged activated partial thromboplastin time, decreased albumin.

Common (≥1/100 to <1/10): urinary tract infection, hypersensitivity, dehydration, insomnia, blurred vision, dry eye, hypertension, lymphoedema, pneumonitis (including interstitial lung disease), toothache, gingivitis, gingival pain, cheilitis, erythema, dermatitis, palmar-plantar erythrodysaesthesia syndrome, muscle spasms, myalgia, osteonecrosis of the jaw, acute kidney injury, oedema (including face and eyelid oedema), raised glycosylated haemoglobin.

Uncommon (≥1/1,000 to <1/100): ketoacidosis (including diabetic ketoacidosis), pancreatitis, erythema multiforme, Stevens–Johnson syndrome.

Not known: hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS), uveitis, colitis, drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema. These come from post-marketing reports, for which a frequency cannot be reliably estimated.

Grade 3 or 4 hyperglycaemia was more frequent in patients aged 65 or over (44.6%) than in younger patients (32.4%), and in those aged 75 or over (47.8%) than in those under 75 (36.1%).

Vijoice. The safety data come from retrospective chart reviews of 18 adults and 39 children treated in a compassionate use programme (median exposure 42 months), and from a phase 2 study in 89 children (median exposure about 30 months). The SmPC of Vijoice gives the frequency category of each reaction.

• Adults (chart reviews): the most common reactions were hyperglycaemia (27.8%), diarrhoea (27.8%), headache (22.2%), stomatitis (16.7%), alopecia (16.7%), dermatitis (16.7%), dry skin (16.7%) and nausea (11.1%). Grade 3 or 4 reactions were decreased blood phosphate (11.1%), dehydration (5.6%), raised blood creatinine (5.6%) and raised glucose (5.6%). Serious reactions were dehydration and hyperglycaemia (5.6% each).
• Children (chart reviews): the most common reactions were stomatitis (23.1%) and diarrhoea (12.8%). No grade 3 or 4 reactions were reported. Serious reactions were vomiting and dehydration (2.6% each).
• Children (phase 2 study): the most common reactions were abdominal pain (33.7%), headache (30.3%), diarrhoea (28.1%) and vomiting (24.7%). Grade 3 or 4 reactions were raised lipase (3.4%), decreased appetite (1.1%) and diarrhoea (1.1%). Serious reactions were diarrhoea, headache and rash (1.1% each). Doses were interrupted for a reaction in 9.0% of patients, and alopecia (2.2%) and decreased appetite (1.1%) led to permanent discontinuation.

Important serious reactions with Piqray include hypersensitivity (anaphylactic reaction, anaphylactic shock, angioedema), severe cutaneous reactions (Stevens–Johnson syndrome, erythema multiforme, DRESS), severe hyperglycaemia with HHNKS or ketoacidosis (some post-marketing cases fatal), pneumonitis, severe diarrhoea with dehydration and acute kidney injury, and osteonecrosis of the jaw, which in the studies occurred only in patients with prior or concurrent bisphosphonate or RANK-ligand inhibitor treatment.

• BCRP inhibitors (for example eltrombopag, lapatinib, pantoprazole): alpelisib is a BCRP substrate in vitro, and BCRP is involved in its removal through the liver and gut. Inhibiting BCRP may raise alpelisib exposure, so caution and monitoring for toxicity are advised.
• Acid-reducing agents: the H2-receptor antagonist ranitidine slightly lowered alpelisib exposure. With a low-fat, low-calorie meal, AUC fell by 21% and Cmax by 36%; without food the effect was larger (AUC down 30%, Cmax down 51%). A population analysis found no significant effect of acid-reducing agents, including proton pump inhibitors, H2-receptor antagonists and antacids. They can be taken with alpelisib, provided alpelisib is taken immediately after food.
• Strong CYP3A4 inducers: rifampicin (600 mg daily for 7 days, then a single 300 mg alpelisib dose) lowered alpelisib Cmax by 38% and AUC by 57% in healthy adults. St John’s wort also induces CYP3A and may lower alpelisib levels. Patients should tell the prescriber about any such medicine or herbal product; the SmPC (section 4.5) gives the full advice.
• Other medicines: alpelisib may also change the exposure of some other medicinal products. The prescriber checks the full list in section 4.5 of the SmPC.
• Bisphosphonates and RANK-ligand inhibitors (for example zoledronic acid, denosumab): osteonecrosis of the jaw occurred in patients who took them. Use caution when they are given at the same time or one after the other with alpelisib.
• Antidiabetic medicines: patients with diabetes may need intensified antidiabetic treatment while taking alpelisib.
• Fulvestrant: the combination partner for Piqray (see Administration and Dosage).
• Food: take the tablets immediately after food, at about the same time each day.

Piqray should be started by a physician experienced in anticancer therapies; Vijoice by a physician experienced in the management of PROS. Both are oral tablets taken once daily, immediately after food, at about the same time each day. Piqray tablets are swallowed whole and must not be chewed, crushed or split; tablets that are broken, cracked or otherwise not intact should not be taken.

Piqray: Recommended Dose

• 300 mg (two 150 mg tablets) once daily, continuously. The maximum recommended daily dose is 300 mg.
• With fulvestrant: 500 mg intramuscularly on days 1, 15 and 29, and once monthly thereafter (see the fulvestrant SmPC).
• Patient selection: a PIK3CA mutation must be found in a tumour or plasma sample, tested with a CE-marked in vitro diagnostic device with the right intended purpose (or another validated test if none is available). If no mutation is found in plasma, tumour tissue should be tested if available.
• Duration: as long as clinical benefit is seen or until unacceptable toxicity.

Piqray: Dose Adjustments for Side Effects

• Dose levels: starting dose 300 mg daily (2 × 150 mg tablets); first reduction 250 mg daily (1 × 200 mg and 1 × 50 mg tablet); second reduction 200 mg daily (1 × 200 mg tablet). A maximum of two reductions is recommended, after which treatment is stopped permanently. Reduction is based on the worst preceding toxicity, and only one reduction is permitted for pancreatitis.
• Specific reactions: the SmPC tables set out, by severity, when to interrupt, reduce or stop Piqray for hyperglycaemia, severe cutaneous reactions, diarrhoea or colitis, and other reactions. Follow the SmPC for these decisions.

Vijoice: Recommended Dose

• Adults: 250 mg once daily.
• Children and adolescents aged 2 to under 18 years: starting dose 50 mg once daily. From age 6, a rise to 125 mg once daily can be considered to optimise the response (clinical or radiological) after 24 weeks at 50 mg. For ages 2 to under 6, the dose stays at 50 mg. When a young person turns 18, a gradual increase up to 250 mg should be considered.
• Stopping: treatment is discontinued if the disease progresses, PROS-related symptoms worsen or toxicity becomes unacceptable, as judged by the treating physician.
• Dose reductions: in adults, 250 mg to 125 mg once daily, then 125 mg to 50 mg. In children, 125 mg to 50 mg once daily; there is no further reduction from 50 mg. Vijoice is stopped in adults or children who cannot tolerate 50 mg daily.

Special Populations

• Elderly (Piqray): no dose adjustment from age 65. Data are limited from age 75, and especially from age 85.
• Renal impairment (Piqray): no dose adjustment in mild or moderate impairment. Use caution in severe impairment, where there is no experience.
• Hepatic impairment (Piqray): no dose adjustment in mild, moderate or severe impairment (Child-Pugh class A, B or C), based on a study in non-cancer subjects.
• Children and adolescents: safety and efficacy of Piqray in children aged 0 to 18 years have not been established. Vijoice is used from age 2 (see above).

Missed or Vomited Dose

• A missed dose can be taken immediately after food, within 9 hours of the usual time. After more than 9 hours, skip the dose that day and take the next dose at the usual time.
• If vomiting follows a dose, do not take an extra dose that day; resume at the usual time the next day.

The warnings below are taken from the Piqray SmPC. The Vijoice SmPC (section 4.4) gives the corresponding advice for patients with PROS.

Hyperglycaemia

• Risk: severe hyperglycaemia, in some cases with hyperglycaemic hyperosmolar nonketotic syndrome (HHNKS) or ketoacidosis, has occurred, and some ketoacidosis cases were fatal after marketing. In the phase 3 studies hyperglycaemia was reported in 68.6% of patients (grade 3 in 33.5%, grade 4 in 4.0%).
• Higher risk: grade 3 or 4 hyperglycaemia occurred in 15 of 18 patients with diabetes, 47.4% of those with pre-diabetes, 51.6% of those with a BMI of 30 or more and 47.8% of those aged 75 or over.
• Before treatment: test fasting plasma glucose and HbA1c, and optimise blood glucose.
• After starting: because hyperglycaemia can begin quickly, check fasting glucose at weeks 1, 2, 4, 6 and 8 and monthly after that, and self-monitor regularly, more often in the first 4 weeks and especially in the first 2 weeks, as instructed by a healthcare professional. Patients with diabetes, pre-diabetes, a BMI of 30 or more, or age 75 or over, monitor fasting glucose daily for the first 2 weeks, then as often as needed. HbA1c is checked after 4 weeks and every 3 months.
• If hyperglycaemia develops: monitor fasting glucose regularly, at least until it is back to normal. During antidiabetic treatment, check at least once a week for 8 weeks and then every 2 weeks, guided by a professional with expertise in treating hyperglycaemia.
• Patient advice: explain lifestyle measures that may lower blood glucose (dietary restrictions, physical activity) and the symptoms to watch for: excessive thirst, passing urine more often or in larger amounts, and increased appetite with weight loss.
• Management: in the studies, 86% of patients with hyperglycaemia were treated with antidiabetic medicines, most often metformin alone or with other agents. Grade 2 or higher hyperglycaemia improved by at least one grade after a median of 8 days, and fasting glucose returned to baseline in 95.0% of patients who stayed on fulvestrant after stopping Piqray.
• Diabetes: the safety of Piqray in type 1 diabetes and uncontrolled type 2 diabetes has not been established (these patients were excluded from the trials). Patients with a history of diabetes may need intensified treatment and close monitoring.
• Dose changes: depending on severity, Piqray may need to be interrupted, reduced or stopped, as set out in the SmPC.

Hypersensitivity

Serious hypersensitivity reactions (anaphylactic reaction, anaphylactic shock, angioedema) have been reported, with symptoms such as breathlessness, flushing, rash, fever or fast heartbeat. Piqray should be stopped permanently and not restarted, and appropriate treatment started promptly.

Rash and Severe Cutaneous Reactions

• Severe reactions: Stevens–Johnson syndrome and erythema multiforme were reported in 0.5% and 0.8% of patients in the phase 3 studies, and DRESS after marketing. Piqray should not be started in patients with a history of severe cutaneous reactions.
• Warning signs: a prodrome of fever, flu-like symptoms, mucosal lesions or a progressive skin rash. If these appear, Piqray is interrupted until the cause is known, and a dermatologist is consulted. If a severe reaction is confirmed, Piqray is stopped permanently and never restarted; if not confirmed, it may be interrupted, reduced or stopped according to the SmPC.
• Rash overall: rash occurred in 51.9% of patients, grade 2 in 13.0% and grade 3 in 20.7%, at a median of 12 days after starting. Among patients given preventive anti-rash treatment, including antihistamines, rash was less frequent (28.9% against 51.9%), so antihistamines may be started at the beginning of treatment.

Pneumonitis

Pneumonitis, including serious cases of acute interstitial lung disease, has been reported. Patients should report any new or worsening respiratory symptoms promptly. If pneumonitis is suspected, Piqray is interrupted immediately and the patient evaluated; non-infectious pneumonitis is considered in patients with hypoxia, cough, breathlessness or interstitial infiltrates on imaging once other causes are excluded. Piqray is stopped permanently if pneumonitis is confirmed.

Diarrhoea or Colitis

• Monitoring: patients are monitored for diarrhoea and other signs of colitis, such as abdominal pain and mucus or blood in the stool.
• Frequency: diarrhoea occurred in 57.7% of patients (grade 3 in 6.1%); for grade 2 or 3 the median time to onset was 49.5 days. Severe diarrhoea with dehydration and acute kidney injury has been reported and resolved with appropriate treatment. Antidiarrhoeal medicines such as loperamide were needed by 62.2% of those affected.
• Advice: patients should start antidiarrhoeal treatment, drink more fluids and tell their doctor if diarrhoea or other symptoms of colitis occur. In colitis, additional treatment such as steroids may be considered. Piqray may need to be interrupted, reduced or stopped according to severity.

Osteonecrosis of the Jaw

Use caution when Piqray is given with bisphosphonates or RANK-ligand inhibitors (for example denosumab), at the same time or one after the other. Do not start Piqray in patients with ongoing osteonecrosis of the jaw from previous or current bisphosphonate or denosumab treatment. Patients should report new or worsening mouth symptoms promptly (loose teeth, pain or swelling, mouth sores that do not heal, discharge). Standard medical management is started if osteonecrosis of the jaw develops. In the studies it occurred in 5.1% of patients, all of whom had prior or concurrent bisphosphonate or RANK-ligand inhibitor treatment.

Prior Fulvestrant and Visceral Disease

Efficacy is not considered established in patients who have already had fulvestrant (limited data, 39 patients). Efficacy and safety have not been studied in patients with symptomatic visceral disease.

Pregnancy, Breastfeeding and Fertility

• Who it is for: Piqray is indicated in men and postmenopausal women and must not be used in women who are or may be pregnant or breastfeeding.
• Risk to the foetus: animal studies and the mechanism of action show that alpelisib can harm the developing foetus. Embryo-foetal studies in rats and rabbits showed embryotoxicity, foetotoxicity and teratogenicity. There are no data from use in pregnant women, and Piqray is not recommended in pregnancy or in women of childbearing potential who do not use contraception.
• Contraception and pregnancy testing: females of reproductive potential who take Piqray should use effective contraception (for example a double-barrier method) during treatment and for at least 1 week afterwards, and their pregnancy status should be checked before starting.
• Men: male patients with partners who are pregnant, possibly pregnant or could become pregnant should use condoms during intercourse while taking Piqray and for at least 1 week afterwards.
• Breastfeeding: it is not known whether alpelisib passes into human or animal milk. Piqray must not be used by women who are breastfeeding.
• Vijoice: see section 4.6 of the Vijoice SmPC for the advice that applies to patients with PROS.

Sodium

Piqray contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is, it is essentially sodium-free.

Effect on Driving

Piqray has a minor influence on the ability to drive and use machines. Patients who feel tired or have blurred vision should take care.

Piqray and Vijoice tablets do not require any special storage conditions. Piqray is supplied in PVC/PCTFE/aluminium blisters, with 14 tablets per blister card. Keep out of the sight and reach of children.

Piqray: 4 years. Vijoice: 3 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Piqray is subject to restricted medical prescription: treatment is started by a physician experienced in anticancer therapies, after a PIK3CA mutation has been confirmed. Vijoice is started by a physician experienced in the management of PROS. Both are taken at home as tablets, so they are supplied to the patient or to the treating clinic on prescription.