Kryxana Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the monograph: Interstitial Lung Disease/Pneumonitis [see Interstitial Lung Disease/Pneumonitis under Precautions]; Severe Cutaneous Adverse Reactions [see Severe Cutaneous Adverse Reactions under Precautions]; QT Interval Prolongation [see QT Interval Prolongation and Increased QT Prolongation With Concomitant Use of Tamoxifen under Precautions]; Hepatobiliary Toxicity [see Hepatobiliary Toxicity under Precautions]; Neutropenia [see Neutropenia 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.
MONALEESA-2: KRYXANA in Combination with Letrozole: Postmenopausal Women with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: The safety data reported as follows are based on MONALEESA-2, a clinical study of 668 postmenopausal women receiving KRYXANA plus letrozole or placebo plus letrozole. The median duration of exposure to KRYXANA plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months.
Dose reductions due to adverse reactions (ARs) occurred in 45% of patients receiving KRYXANA plus letrozole and in 3% of patients receiving placebo plus letrozole. Among patients receiving KRYXANA plus letrozole, 7% were reported to have permanently discontinued both KRYXANA and letrozole and 7% were reported to have permanently discontinued KRYXANA alone due to ARs. Among patients receiving placebo plus letrozole, 2% were reported to have permanently discontinued both and 0.9% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of KRYXANA in patients receiving KRYXANA plus letrozole were ALT increased (4%), AST increased (3%), vomiting (2%). Antiemetics and antidiarrheal medications were used to manage symptoms as clinically indicated.
On-treatment deaths, regardless of causality, were reported in three cases (0.9%) of KRYXANA plus letrozole treated patients vs. one case (0.3%) of placebo plus letrozole treated patients. Causes of death on KRYXANA plus letrozole included one case each of the following: progressive disease, death (cause unknown), and sudden death (in the setting of Grade 3 hypokalemia and Grade 2 QT prolongation).
The most common ARs (reported at a frequency ≥ 20% on the KRYXANA arm and ≥ 2% higher than placebo) were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain.
The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, abnormal liver function tests, and lymphopenia.
In MONALEESA-2, syncope occurred in 9 patients (3%) in the KRYXANA plus letrozole arm vs. 3 (1%) in placebo plus letrozole arm.
Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-2 are listed in Table 12 and Table 13, respectively. (See Table 12.)

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Additional adverse reactions in MONALEESA-2 for patients receiving KRYXANA plus letrozole included interstitial lung disease (0.3%), lung infiltration (0.3%), pneumonitis (0.3%), and pulmonary fibrosis (0.6%). (See Table 13.)

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MONALEESA-7: KRYXANA in Combination with an Aromatase Inhibitor: Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: MONALEESA-7 was conducted in 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either KRYXANA plus a NSAI or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin. The median duration of exposure on the KRYXANA arm was 15.2 months with 66% of patients exposed for ≥ 12 months. The safety data reported as follows are based on 495 pre/perimenopausal patients receiving KRYXANA plus NSAI plus goserelin or placebo plus NSAI plus goserelin.
Dose reductions due to ARs occurred in 33% of patients receiving KRYXANA plus NSAI plus goserelin, and in 4% of patients receiving placebo plus NSAI plus goserelin. Among patients receiving KRYXANA plus NSAI, 3% were reported to have permanently discontinued both KRYXANA and NSAI and 3% were reported to have permanently discontinued KRYXANA alone due to ARs. Among patients receiving placebo plus NSAI, 2% were reported to have permanently discontinued both and 0.8% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation on KRYXANA in patients receiving KRYXANA plus NSAI (as compared to the placebo arm) were ALT increased (2% vs. 0.8%), AST increased (2% vs. 0.8%), drug-induced liver injury (1% vs. 0.4%). One patient (0.4%) died while on treatment with KRYXANA plus NSAI plus goserelin due to the underlying malignancy.
The most common ARs (reported at a frequency ≥ 20% on the KRYXANA arm and ≥ 2% higher than placebo) were neutropenia, infections, leukopenia, arthralgia, nausea, and alopecia. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, and abnormal liver function tests. See Table 14 as follows.
Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-7 are listed in Table 14 and Table 15, respectively. (See Table 14.)

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Additional adverse reactions in MONALEESA-7 for patients receiving KRYXANA plus NSAI included asthenia (12%), thrombocytopenia (9%), dry skin (8%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia (2%), blood bilirubin increased (1%), syncope (0.4%), and pneumonitis (0.4%). (See Table 15.)

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MONALEESA-3: KRYXANA in Combination with Fulvestrant: Postmenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy or After Disease Progression on Endocrine Therapy: The safety data reported as follows are based on MONALEESA-3, a clinical study of 724 postmenopausal women receiving KRYXANA plus fulvestrant or placebo plus fulvestrant. The median duration of exposure to KRYXANA plus fulvestrant was 15.8 months with 58% of patients exposed for ≥ 12 months.
Dose reductions due to ARs occurred in 32% of patients receiving KRYXANA plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Among patients receiving KRYXANA plus fulvestrant, 8% were reported to have permanently discontinued both KRYXANA and fulvestrant and 9% were reported to have discontinued KRYXANA alone due to ARs. Among patients receiving placebo plus fulvestrant, 4% were reported to have permanently discontinued both and 2% were reported to have discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of KRYXANA in patients receiving KRYXANA plus fulvestrant (as compared to the placebo arm) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).
On-treatment deaths, regardless of causality, were reported in seven patients (1.4%) due to the underlying malignancy and six patients (1.2%) due to other causes while on treatment with KRYXANA plus fulvestrant. Causes of death included one pulmonary embolism, one acute respiratory distress syndrome, one cardiac failure, one pneumonia, one hemorrhagic shock, and one ventricular arrhythmia. Seven patients (2.9%) died due to the underlying malignancy and 1 patient (0.4%) died due to pulmonary embolism while on placebo plus fulvestrant.
The most common ARs (reported at a frequency ≥ 20% on the KRYXANA arm and ≥ 2% higher than placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, infections, and abnormal liver function tests. See Table 16.
Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 16 and Table 17, respectively. (See Table 16.)

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Additional adverse reactions in MONALEESA-3 for patients receiving KRYXANA plus fulvestrant included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%), dry skin (8%), dysgeusia (7%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), syncope (1%), interstitial lung disease (0.4%), pneumonitis (0.4%), hypersensitivity pneumonitis (0.2%), and acute respiratory distress syndrome (0.2%). (See Table 17.)

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COMPLEEMENT-1: KRYXANA in Combination with Letrozole and Goserelin or Leuprolide: Men with HR-positive, HER2-negative Advanced Breast Cancer for Initial Endocrine-Based Therapy: The safety of KRYXANA in combination with letrozole was evaluated in men (n=39) in an open-label, multicenter clinical study for the treatment of adult patients with HR-positive, HER2-negative, advanced breast cancer who received no prior hormonal therapy for advanced disease (COMPLEEMENT-1) [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
The median duration of exposure to KRYXANA was 20.8 months (range: 0.5 to 30.6 months).
Other adverse reactions occurring in men treated with KRYXANA plus letrozole and goserelin or leuprolide were similar to those occurring in women treated with KRYXANA plus endocrine therapy.
Postmarketing Experience: The following adverse events have been reported during post-approval use of KRYXANA. Because these events 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.
Respiratory disorders: Interstitial lung disease/pneumonitis.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome (SJS), Toxic epidermal necrolysis (TEN), Drug-induced hypersensitivity syndrome (DiHS)/Drug reaction with eosinophilia and systemic symptoms (DRESS).