Pivikto Tablets

Pivikto is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA- mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen (see section 5.1).

Treatment with Pivikto should be initiated by a medical practitioner experienced in the use of anticancer therapies. Patients with HR-positive, HER2-negative advanced breast cancer should be selected for treatment with Pivikto based on the presence of a PIK3CA mutation in tumour or plasma specimens, using a validated test. If a mutation is not detected in a plasma specimen, tumour tissue should be tested if available.

Posology

The recommended dose of Pivikto is 300 mg (2 x 150 mg film-coated tablets) taken once daily on a continuous basis. Pivikto should be taken immediately after food, at approximately the same time each day (see section 5.2).

Swallow Pivikto tablets whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

If a dose of Pivikto is missed, it can be taken immediately following food and within 9 hours after the time it is usually taken. After more than 9 hours, the dose should be skipped for that day. On the next day, Pivikto should be taken at the usual time. If the patient vomits after taking the Pivikto dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time.

When given with Pivikto, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29, and once monthly thereafter. Please refer to the full prescribing information for fulvestrant.

Dose modifications

The recommended dose modifications for adverse reactions (ARs) are listed in Table 1.

Table 1 Pivikto dose reduction guidelines for adverse reactions (ARs)

1 Pivikto dose level Dose and schedule Number and strength of tablets

Starting dose 300 mg once daily Two 150 mg tablets

First dose reduction 250 mg once daily One 200 mg tablet and one 50 mg tablet

Second dose reduction 200 mg once daily 2 One 200 mg tablet

1 Only one dose reduction is permitted for pancreatitis.

2 If further dose reduction below 200 mg once daily is required, discontinue Pivikto.

Tables 2 - 5 summarise the recommendations for dose interruption, reduction or discontinuation of Pivikto in the management of specific ARs.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy and lactation (see section 4.6).

Hypersensitivity (including anaphylactic reaction)

Serious hypersensitivity reactions (including anaphylactic reaction and anaphylactic shock), manifested by symptoms including, but not limited to, dyspnoea, flushing, rash, fever or tachycardia, were reported in patients treated with Pivikto in clinical studies. Angioedoema has been reported in the post-marketing setting in patients treated with Pivikto (see section 4.8). Pivikto should be permanently discontinued in patients with serious hypersensitivity reactions. Appropriate treatment should be promptly initiated.

Severe cutaneous reactions

Severe cutaneous reactions have been reported with Pivikto. In the Phase III clinical study, Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in 0.4 % and 1.1 % of patients, respectively. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in the post-marketing setting (see section 4.8). Pivikto treatment should not be initiated in patients with a history of severe cutaneous reactions. Patients should be advised of the signs and symptoms of severe cutaneous reactions (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash). If signs or symptoms of severe cutaneous reactions are present, Pivikto should be interrupted until the aetiology of the reaction has been determined. A consultation with a dermatologist is recommended. If a severe cutaneous reaction is confirmed, Pivikto should be permanently discontinued. Pivikto should not be re-introduced in patients who have experienced previous severe cutaneous reactions. If a severe cutaneous reaction is not confirmed, Pivikto may require treatment interruption, dose reduction or treatment discontinuation as described in Table 3 (see section 4.2).

Hyperglycaemia

Severe hyperglycaemia, in some cases associated with hyperglycemic hyperosmolar nonketotic syndrome (HHNKS) or ketoacidosis, has been reported in patients treated with Pivikto. Some cases of ketoacidosis with fatal outcome have been reported in the post marketing setting. Hyperglycaemia was reported in 65 % of patients treated with Pivikto in the Phase III clinical study. Grade 2 (FPG 160 u2013 250 mg/dl), 3 (FPG >250 u2013 500 mg/dl) or 4 (FPG > 500 mg/dl) hyperglycaemia were reported in 15,8 %, 33,1 % and 3,9 % of patients, respectively, in the Phase III clinical study. Patients should be advised of the signs and symptoms of hyperglycaemia (e.g. excessive thirst, urinating more often than usual or higher amount of urine than usual, increased appetite with weight loss). In the phase III clinical study, patients with a history of diabetes mellitus intensified anti-diabetic medication(s) while on treatment with Pivikto; therefore, these patients require monitoring and possibly intensified anti-diabetic treatment. Patients with poor glycemic control may be at a higher risk of developing severe hyperglycemia and associated complications. Patients with risk factors for hyperglycemia such as obesity (BMI u226530), elevated FG or HbA1c at or above the upper limit of normal, or age u226575 are at a higher risk of developing severe hyperglycemia. Schedule for monitoring fasting glucose is presented in Table 6-1.

Medicinal products that may increase alpelisib plasma concentrations

BCRP inhibitors

Coadministration of Pivikto with a BCRP (breast cancer resistance protein) inhibitor may increase alpelisib concentration, which may increase the risk of toxicities. Avoid the use of BCRP inhibitors in patients treated with Pivikto. If unable to use alternative drugs, when Pivikto is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions.

Medicinal products whose plasma concentrations may be altered by alpelisib

CYP3A4 Inducers

Coadministration of Pivikto with a strong CYP3A4 inducer may decrease alpelisib concentration, which may decrease alpelisib activity. Avoid coadministration of Pivikto with strong CYP3A4 inducers.

Contraception in males and females

Females of reproductive potential should be advised that animal studies and the mechanism of action have shown that alpelisib can be harmful to the developing foetus. Females of reproductive potential should use effective contraception during treatment with Pivikto and for 1 week after the last dose. It is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives.

Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms and effective contraception during Pivikto treatment and for 1 week after the last dose. Please refer to the full prescribing information of fulvestrant for pregnancy information.

Pregnancy

Pivikto should not be used during pregnancy (see section 4.3). Based on animal data and its mechanism of action, Pivikto can cause foetal harm when administered to a pregnant woman. Embryo-fetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryo-toxicity, foeto-toxicity, and teratogenicity.

Breastfeeding

It is not known if alpelisib is excreted in human or animal milk. Because of the potential for serious adverse reactions in the breastfed infant, it is recommended that women should not breastfeed during treatment and for at least 1 week after the last dose of Pivikto.

Fertility

There are no data on the effects of alpelisib on fertility. Based on repeated dose toxicity studies in animals, alpelisib may impair fertility in males and females of reproductive potential (see section 5.3).

Patients should be advised to be cautious when driving or using machines in case they experience fatigue or blurred vision during treatment(see section 4.8).

Summary of the safety profile

The safety profile is based on data from 284 patients in the Pivikto plus fulvestrant arm of the double-blind, placebo-controlled phase III study. The most common adverse drug reactions (ADRs) (all grades, incidence u2265 20 %) were glucose increased, creatinine increased, diarrhoea, gamma-glutamyltransferase increased, rash, lymphocyte count decreased, nausea, alanine aminotransferase increased, fatigue, haemoglobin increased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, hypocalcaemia, glucose decreased, activated partial thromboplastin time (aPTT) prolonged and alopecia.

Tabulated list of adverse reactions

ADRs from the phase III clinical study are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1,000 to < 1/100); rare (u2265 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Symptoms

The adverse reactions associated with overdose have been consistent with the safety profile of Pivikto and included hyperglycaemia, nausea, asthenia and rash.

Management

General symptomatic and supportive measures should be initiated in all cases of overdose where necessary. There is no known antidote for Pivikto.