Piqray Adverse Reactions

Summary of the safety profile: The overall safety evaluation of PIQRAY is based on data from the phase III clinical study of 572 patients (571 post-menopausal women and 1 male) who were randomized in a 1:1 ratio to receive PIQRAY plus fulvestrant or placebo plus fulvestrant; 284 of whom received PIQRAY at the recommended starting dose of 300 mg dose in combination with fulvestrant, using the proposed treatment regimen.
The median duration of exposure to PIQRAY plus fulvestrant was 8.2 months with 59.2% patients exposed for >6 months.
PIQRAY dose reductions due to adverse events (AEs), regardless of causality occurred in 57.7% of patients receiving PIQRAY plus fulvestrant and in 4.5% of patients receiving placebo plus fulvestrant. Permanent discontinuations of PIQRAY and/or fulvestrant due to adverse events were reported in 25% of patients compared to and 4.5% with placebo and/or fulvestrant. The most common AEs leading to treatment discontinuation of both PIQRAY and/or fulvestrant were hyperglycaemia (6.3%), rash (3.2%), diarrhoea (2.8%), and fatigue (2.1%).
On-treatment deaths, regardless of causality, were reported in 7 patients (2.5%) treated with PIQRAY plus fulvestrant vs. 12 patients (4.2%) treated with placebo plus fulvestrant. In PIQRAY plus fulvestrant treated patients, disease progression (5 patients, 1.8%) was the most frequent cause of death; the others were one each for cardio-respiratory arrest and second primary malignancy, neither of which were considered related to treatment with PIQRAY.
The most common adverse drug reactions (ADRs) in PIQRAY plus fulvestrant treated patients (reported at a frequency >20% and for which the frequency for PIQRAY plus fulvestrant exceeds the frequency for placebo plus fulvestrant) were hyperglycaemia, diarrhoea, rash, nausea, fatigue and asthenia, decreased appetite, stomatitis, vomiting and weight decreased.
The most common Grade 3/4 ADRs (reported at a frequency >2% in PIQRAY plus fulvestrant arm and for which the frequency for PIQRAY plus fulvestrant exceeds the frequency for placebo plus fulvestrant) were hyperglycaemia, rash and rash maculo-papular, fatigue, diarrhoea, lipase increased, hypertension, hypokalaemia, anaemia, weight decreased, gamma-glutamyltransferase increased, lymphopenia, nausea, stomatitis, alanine aminotransferase increased and mucosal inflammation.
Tabulated summary of adverse drug reactions from clinical studies: ADRs from the phase III clinical study (Tables 8a and 8b) 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 ADR is based on the following convention (CIOMS III): 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. (See Tables 8a, 8b and 9.)

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Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with PIQRAY via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. (See Table 10.)

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Description of selected ADRs and treatment recommendations, where applicable: Hyperglycaemia: In the phase III clinical study, hyperglycaemia (FPG >160 mg/dL) was reported in 184 (64.8%) of patients. An event of hyperglycaemia resolved to ≤ Grade 1 ((FPG <160 mg/dL)) in 166 (88.8%) of the 187 patients. Dose interruptions and adjustments due to hyperglycaemic events were reported in 26.8% and 28.9% of patients, respectively, in the PIQRAY plus fulvestrant arm. Hyperglycaemic events leading to discontinuation of PIQRAY and/or fulvestrant were reported in 19 (6.7%) patients.
Rash: In the phase III clinical study, rash events (including rash maculo-papular, rash macular, rash generalized, rash papular, rash pruritic, dermatitis and dermatitis acneiform) were reported in 153 (53.9%) patients. Rash may be accompanied by pruritus and dry skin in some cases. Rash was predominantly mild or moderate (Graded 1 or 2) and responsive to therapy. Maximum Grade 2 and 3 rash events were reported in 13.7% and 20.1% of patients, respectively. There were no Grade 4 cases of rash reported. Among the patients with Grade 2 or 3 rash, the median time to first onset of Grade 2 or 3 rash was 12 days (range: 2 days to 220 days). Dose interruptions and dose adjustments due to rash were reported in 21.8% and 9.2% of patients, respectively, in the PIQRAY plus fulvestrant arm.
Topical corticosteroid treatment should be initiated at the first signs of rash and systemic corticosteroids should be considered for moderate to severe rashes. Additionally, antihistamines are recommended to manage symptoms of rash. In the Phase III study, among the patients who developed a rash, 73.9% (113/153) reported use of at least one topical corticosteroid and 67.3% (103/153) of at least one oral antihistamine. Systemic corticosteroid were administered for rash events in 23% (66/284) of patients. Of the patients who received systemic corticosteroids, 55% (36/66) received oral corticosteroids for rash. At least one event of rash resolved in the majority of the patients, 141 out of 153 patients (92%). Discontinuation of PIQRAY and/or fulvestrant treatment due to rash events occurred in 12 patients (4.2%).
A subgroup of 86 patients received anti rash treatment, including anti-histamines, prior to onset of rash. In these patients, rash was reported less frequently than in the overall population, for all Grades rash (26.7% vs 53.9%), Grade 3 rash (11.6% vs 20.1%) and rash leading to permanent discontinuation of PIQRAY (3.5% vs 4.2%). Accordingly, antihistamines may be initiated prophylactically, at the time of initiation of treatment with PIQRAY. Based on the severity of rash, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table 5 (see Dosage & Administration).
GI toxicity (nausea, diarrhoea, vomiting): In the phase III study, diarrhoea, nausea and vomiting were reported in 57.7%, 44.7% and 27.1% of the patients, respectively, and led to discontinuation of PIQRAY and/or fulvestrant in 8 (2.8%), 5 (1.8%) and 3 (1.1%) of the patients, respectively (see Tables 8a and 8b).
Maximum Grade 2 and 3 diarrhoea events were reported in 18.3% and 6.7% of patients, respectively. There were no reported cases of Grade 4 diarrhoea in the Phase III clinical study. Among patients with Grade ≥2 diarrhoea, median time to onset of Grade ≥2 diarrhoea was 46 days (range: 1 to 442 days).
Severe diarrhoea and clinical consequences, such as dehydration and acute kidney injury have been reported during treatment with PIQRAY and resolved with appropriate intervention (see Table 7). Patients should be managed according to local standard of care medical management, including electrolyte monitoring, administration of anti-emetics and antidiarrhoeal medications and/or fluid replacement and electrolyte supplements, as clinically indicated. In the phase III clinical study, anti-emetics (e.g. ondansetron) and anti-diarrhoeal medications (e.g. loperamide) were used in 27/149 (18.1%) and 104/164 (63.4%) of patients to manage symptoms.
Osteonecrosis of the jaw (ONJ): In the phase III clinical study, ONJ was reported in 4.2% patients (12/284) in the PIQRAY plus fulvestrant arm compared to 1.4% patients (4/287) in the placebo plus fulvestrant arm. All patients experiencing ONJ were also exposed to prior or concomitant bisphosphonates (e.g. zoledronic acid) or RANK-ligand inhibitors (e.g. denosumab). Therefore, in patients receiving PIQRAY and bisphosphonates or RANK-ligand inhibitors, an increased risk of development of ONJ cannot be excluded.
Reporting suspected adverse effects: Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.