Trezilent Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling: Severe Hypersensitivity [see Severe Hypersensitivity under Precautions]; Severe Cutaneous Adverse Reactions [see Severe Cutaneous Adverse Reactions under Precautions]; Hyperglycemia [see Hyperglycemia under Precautions]; Pneumonitis [see Pneumonitis under Precautions]; Diarrhea or Colitis [see Diarrhea or Colitis under Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of TREZILENT was evaluated in a randomized, double-blind, placebo-controlled trial (SOLAR-1) in 571 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer enrolled into two cohorts, with or without a PIK3CA mutation [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
Patients received either TREZILENT 300 mg plus fulvestrant (n = 284) or placebo plus fulvestrant (n = 287). Fulvestrant 500 mg was administered intramuscularly on Cycle 1, Day 1 and 15 and then at Day 1 of each 28-day cycle during treatment phase.
Two patients (0.7%) died while on treatment with TREZILENT plus fulvestrant due to causes other than the underlying malignancy. Causes of death included one cardio-respiratory arrest and one second primary malignancy. Neither was suspected to be related to study treatment.
Serious adverse reactions occurred in 35% of patients receiving TREZILENT plus fulvestrant. Serious adverse reactions in > 2% of patients receiving TREZILENT plus fulvestrant included hyperglycemia (10%), rash (3.5%), diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%).
Osteonecrosis of the jaw (ONJ) was reported in 4.2% of patients (12/284) in the TREZILENT plus fulvestrant arm compared to 1.4% of patients (4/287) in the placebo arm. All patients experiencing ONJ had prior or concomitant bisphosphonates or RANK-ligand inhibitor administration.
Among patients receiving TREZILENT plus fulvestrant, 4.6% permanently discontinued both TREZILENT and fulvestrant and 21% permanently discontinued TREZILENT alone, due to ARs. The most frequent ARs leading to treatment discontinuation of TREZILENT in > 2% patients receiving TREZILENT plus fulvestrant were hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%).
Dose reductions due to ARs occurred in 55% of patients receiving TREZILENT plus fulvestrant. The most frequent ARs leading to dose reduction in > 2% patients receiving TREZILENT plus fulvestrant were hyperglycemia (29%), rash (9%), diarrhea (6%), stomatitis (3.5%), and mucosal inflammation (2.1%).
The most common adverse reactions, including laboratory abnormalities (all grades, incidence ≥ 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, gamma-glutamyl transferase (GGT) increased, nausea, alanine aminotransferase (ALT) increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, activated partial thromboplastin time (aPTT) prolonged, and alopecia.
Adverse reactions and laboratory abnormalities are listed in Table 7 and Table 8, respectively. (See Table 7.)

Click on icon to see table/diagram/image

Among the patients with Grade 2 or 3 rash, the median time to first onset of Grade 2 or 3 rash was 12 days. A subgroup of 86 patients received prophylaxis, including antihistamines, prior to onset of rash. In these patients, rash was reported less frequently than in the overall population, for all grades rash (27% vs 54%), Grade 3 rash (12% vs 20%) and rash leading to permanent discontinuation of TREZILENT (3.5% vs 4.2%). Of the 153 patients who experienced rash, 141 had resolution of the rash. (See Table 8.)

Click on icon to see table/diagram/image

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of TREZILENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: Colitis.
Metabolism and nutrition disorders: Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS).
Skin and subcutaneous tissue disorders: Angioedema, Drug reaction with eosinophilia and systemic symptoms (DRESS).