Alpelisib

In vitro evaluations indicated that alpelisib (and/or its metabolite BZG791) has a potential to inhibit the activities of OAT3 drug transporters and intestinal BCRP and P-gp. Alpelisib should be used with caution in combination with sensitive substrates of these transporters which exhibit a narrow therapeutic index because alpelisib may increase the systemic exposure of these substrates.

Alpelisib is a substrate for BCRP in vitro. BCRP is involved in the hepatobiliary export and intestinal secretion of alpelisib, therefore inhibition of BCRP in the liver and in the intestine during elimination may lead to an increase in systemic exposure of alpelisib. Therefore, caution and monitoring for toxicity are advised during concomitant treatment with inhibitors of BCRP (e.g. eltrombopag, lapatinib, pantoprazole).

Once-daily administration of 600 mg rifampin (a strong CYP3A4 inducer) for 7 days followed by co-administration with a single 300 mg oral dose of alpelisib on day 8, decreased alpelisib C_max by 38% and AUC by 57% in healthy adults (N=25). Co-administration of rifampin 600 mg once daily for 15 days with alpelisib 300 mg once daily starting from day 8 to day 15 decreased the steady-state alpelisib C_max by 59% and AUC by 74%.

Co-administration with a strong CYP3A4 inducer decreases alpelisib AUC, which may reduce alpelisib efficacy. Co-administration of alpelisib with strong CYP3A4 inducers (e.g. apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort) should be avoided and selection of an alternative concomitant medicinal product, with no or minimal potential to induce CYP3A4, should be considered.

Caution should be used in patients with severe renal impairment as there is no experience with alpelisib in this population.

The co-administration of the H₂ receptor antagonist ranitidine in combination with a single 300 mg oral dose of alpelisib slightly reduced the bioavailability of alpelisib and decreased overall exposure of alpelisib. In the presence of a low-fat low-calorie (LFLC) meal, AUC_inf was decreased on average by 21% and C_max by 36% with ranitidine. In the absence of food, the effect was more pronounced with a 30% decrease in AUC_inf and a 51% decrease in C_max with ranitidine compared to the fasted state without co-administration of ranitidine. Population pharmacokinetic analysis showed no significant effect of co-administration of acid-reducing agents, including proton pump inhibitors, H₂ receptor antagonists and antacids, on the pharmacokinetics of alpelisib. Therefore, alpelisib can be co-administered with acid-reducing agents, provided alpelisib is taken immediately after food.

The safety of alpelisib in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the phase III clinical study. Patients with a medical history of Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment and should be closely monitored.

Alpelisib is not indicated and is not to be used in women who are, or may be, pregnant.

There are no data from the use of alpelisib in pregnant women. Studies in animals have shown reproductive toxicity. Alpelisib is not recommended during pregnancy and in women of childbearing potential not using contraception.

The pregnancy status of females of reproductive potential should be verified prior to starting treatment with alpelisib.

It is not known if alpelisib is excreted in human or animal milk.

Because of the potential for serious adverse reactions in the breast-fed infant, it is recommended that women should not breast-feed during treatment and for at least 1 week after the last dose of alpelisib.

Alpelisib is indicated in men and postmenopausal women.

Women of childbearing potential / 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. Embryo-foetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity.

In case females of reproductive potential take alpelisib, they should use effective contraception (e.g. double-barrier method) when taking alpelisib and for at least 1 week after stopping treatment with alpelisib.

Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms during sexual intercourse while taking alpelisib and for at least 1 week after stopping treatment with alpelisib.

Please refer to section 4.6 of the prescribing information for fulvestrant.

Fertility

There are no clinical data available on the effects of alpelisib on fertility. Based on repeated dose toxicity and fertility studies in animals, alpelisib may impair fertility in males and females of reproductive potential.

Alpelisib has minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or blurred vision during treatment.

Summary of the safety profile

The safety profile is based on data from 284 patients in the alpelisib plus fulvestrant arm of the double-blind, placebo-controlled phase III study.

The most common ADRs (reported at a frequency >20% in the combined mutant and non-mutant study population) were plasma glucose increased (79.2%), creatinine increased (67.6%), diarrhoea (59.5%), gamma-glutamyltransferase increased (53.2%), rash (51.8%), lymphocyte count decreased (55.3%), nausea (46.8%), alanine aminotransferase increased (44.0%), anaemia (44.0%), fatigue (43.3%), lipase increased (42.6%), decreased appetite (35.9%), stomatitis (30.3%), vomiting (28.5%), weight decreased (27.8%), hypocalcaemia (27.8%), plasma glucose decreased (26.8%), activated partial thromboplastin time (aPTT) prolonged (22.2%) and alopecia (20.4%).

The most common grade 3 or 4 ADRs (reported at a frequency ≥2%) were plasma glucose increased (39.1%), rash (19.4%), gamma-glutamyltransferase increased (12.0%), lymphocyte count decreased (9.2%), diarrhoea (7.0%), lipase increased (7.0%), hypokalaemia (6.3%), fatigue (5.6%), weight decreased (5.3%), anaemia (4.9%), hypertension (4.6%), alanine aminotransferase increased (4.2%), nausea (2.8%), creatinine increased (2.8%), stomatitis (2.5%), hypocalcaemia (2.1%) and mucosal inflammation (2.1%).

The most common ADRs leading to treatment discontinuation were hyperglycaemia (6.3%), rash (4.2%), diarrhoea (2.8%) and fatigue (2.5%).

Tabulated list of adverse reactions

ADRs from the phase III clinical study and post-marketing experience (table) 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 (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data).

ADRs observed in phase III clinical study and during post-marketing experience:

^* No grade 4 ADRs were observed
^# Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product.
¹ Urinary tract infection: also includes a single case of urosepsis
² Hypersensitivity: also includes allergic dermatitis
³ Ketoacidosis: also includes diabetic ketoacidosis
⁴ Dysgeusia: also includes ageusia, hypogeusia
⁵ Pneumonitis: also includes interstitial lung disease
⁶ Stomatitis: also includes aphthous ulcer and mouth ulceration
⁷ Rash: also includes rash maculopapular, rash macular, rash generalised, rash papular, rash pruritic
⁸ Dry skin: also includes skin fissures, xerosis, xeroderma
⁹ Erythema: also includes erythema generalised
¹⁰ Dermatitis: also includes dermatitis acneiform
¹¹ Fatigue: also includes asthenia
¹² Mucosal dryness: also includes dry mouth, vulvovaginal dryness
¹³ Oedema: also includes face swelling, face oedema, eyelid oedema

Description of selected ADRs

Hyperglycaemia

Hyperglycaemia (FPG >160 mg/dl) was reported in 190 (66.9%) patients; grade 2 (FPG 160-250 mg/dl), 3 (FPG >250-500 mg/dl) and 4 (FPG >500 mg/dl) events were reported in 16.2%, 33.8% and 4.6% of patients, respectively.

Based on baseline FPG and HbA1c values, 56% of patients were considered pre-diabetic (FPG >100-126 mg/dl [5.6 to 6.9 mmol/l] and/or HbA1c 5.7-6.4%) and 4.2% of patients were considered diabetic (FPG ≥126 mg/dl [≥7.0 mmol/l] and/or HbA1c ≥6.5%). 74.8% of patients who were pre-diabetic at baseline experienced hyperglycaemia (any grade) when treated with alpelisib. Among all patients with hyperglycaemia of grade ≥2 (FPG ≥160 mg/dl), the median time to first occurrence was 15 days (range: 5 days to 900 days) (based on laboratory findings). The median duration of grade ≥2 hyperglycaemia was 10 days (95% CI: 8 to 13 days). In patients with grade ≥2 hyperglycaemia, median time to improvement (at least one grade from the first event) was 8 days (95% CI: 8 to 10 days). In all patients who continued on fulvestrant after discontinuing alpelisib, FPG levels returned to baseline (normal).

Hyperglycaemia was managed with antidiabetic medicinal products.

Rash

Rash events (including rash maculopapular, macular, generalised, papular and pruritic, dermatitis and dermatitis acneiform) were reported in 153 (53.9%) patients. Rash was predominantly mild or moderate (grade 1 or 2) and responsive to therapy, and in some cases rash was accompanied by pruritus and dry skin. Grade 2 and 3 events were reported in 13.7% and 20.1% of patients, respectively, with a median time to first onset of 12 days (range: 2 days to 220 days).

Among patients who received prophylactic antirash treatment including antihistamines, rash was reported less frequently than in the overall population; 26.1% vs 53.9% for all grades, 11.4% vs 20.1% for grade 3, and 3.4% vs 4.2% for rash leading to the permanent discontinuation of alpelisib. Accordingly, antihistamines may be initiated prophylactically, at the time of initiation of treatment with alpelisib.

Gastrointestinal toxicity (nausea, diarrhoea, vomiting)

Diarrhoea, nausea and vomiting were reported in 59.5%, 46.8% and 28.5% of the patients, respectively (see table above).

Grade 2 and 3 diarrhoea events were reported in 19.7% and 7.0% of patients, respectively, with a median time to onset of grade ≥2 diarrhoea of 50 days (range: 1 day to 954 days).

Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury, have been reported during treatment with alpelisib and resolved with appropriate intervention. Antiemetics (e.g. ondansetron) and antidiarrhoeal medicinal products (e.g. loperamide) were used in 28/153 (17.6%) and 109/169 (64.5%) patients, respectively, to manage symptoms.

Osteonecrosis of the jaw (ONJ)

ONJ was reported in 5.6% patients (16/284) in the alpelisib plus fulvestrant arm. Fifteen patients experiencing ONJ were exposed to concomitant bisphosphonates (e.g. zoledronic acid) or RANKligand inhibitors (e.g. denosumab). Therefore, in patients receiving alpelisib and bisphosphonates or RANK-ligand inhibitors, an increased risk of development of ONJ cannot be excluded.

Elderly

In patients ≥65 years of age treated with alpelisib plus fulvestrant, there was a higher incidence of grade 3-4 hyperglycaemia (45.3%) compared to patients <65 years of age (33.5%), while in patients <75 years of age, grade 3-4 hyperglycaemia was 36% compared to 55.9% in patients ≥75 years of age.