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]; Hepatotoxicity [see Hepatotoxicity 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.
The pooled safety population described in the Precautions reflects exposure to KRYXANA in 1065 patients with advanced or metastatic breast cancer (MONALEESA-2, MONALEESA-3, MONALEESA-7), of whom 76% were exposed for 6 months or longer, and 62% were exposed for greater than one year. The most common (≥20%) adverse reactions, including laboratory abnormalities, were leukocytes decreased (95%), neutrophils decreased (93%), hemoglobin decreased (68%), lymphocytes decreased (66%), aspartate aminotransferase increased (55%), gamma-glutamyl transferase increased (53%), alanine aminotransferase increased (52%), infections (47%), nausea (47%), creatinine increased (42%), fatigue (35%), platelets decreased (34%), diarrhea (33%), vomiting (29%), headache (27%), constipation (25%), alopecia (25%), cough (24%), rash (24%), back pain (24%), and glucose serum decreased (20%).
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 of KRYXANA was evaluated in MONALEESA-2, a clinical trial of 668 postmenopausal women receiving KRYXANA plus letrozole or placebo plus letrozole [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The median duration of exposure to KRYXANA plus letrozole was 13 months with 58% of patients exposed for ≥12 months.
Serious adverse reactions occurred in 21% of patients who received KRYXANA plus letrozole. Serious adverse reactions in ≥1% of patients receiving KRYXANA plus letrozole included abdominal pain (1.5%), vomiting (1.5%), constipation (1.2%), nausea (1.2%), anemia (1.2%), febrile neutropenia (1.2%), dyspnea (1.2%), and alanine aminotransferase increased (1.2%).
Fatal adverse reactions occurred in 1.8% of patients who received KRYXANA. Fatal adverse reactions in ≥0.1% of patients receiving KRYXANA included acute respiratory failure (0.6%), acute myocardial infarction, sudden death (with Grade 3 hypokalemia and Grade 2 QT prolongation), unknown cause, and pneumonia (0.3% each). Permanent discontinuation of both KRYXANA and letrozole due to an adverse reaction occurred in 7% of patients. Permanent discontinuation of KRYXANA alone occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of both KRYXANA and letrozole in ≥2% of patients were alanine aminotransferase increased (5%), aspartate aminotransferase increased (3%), and vomiting (2%).
Dosage interruptions of both KRYXANA and letrozole due to an adverse reaction occurred in 71% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included neutropenia (39%), neutrophils decreased (12%), vomiting (6%), nausea (5%), alanine aminotransferase increased (5%), and leukocytes decreased (5%).
Dose reductions of KRYXANA due to an adverse reaction occurred in 45% of patients receiving KRYXANA plus letrozole. Adverse reactions which required dose reductions in ≥2% of patients included neutropenia (24%), neutrophils decreased (8%), and alanine aminotransferase increased (3%).
Antiemetics and antidiarrheal medications were used to manage symptoms as clinically indicated.
The most common (≥20% on the KRYXANA arm and ≥2% higher than placebo) adverse reactions, including laboratory abnormalities, were neutrophils decreased, leukocytes decreased, hemoglobin decreased, nausea, lymphocytes decreased, alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhea, alopecia, vomiting, platelets decreased, constipation, headache, and back pain.
Table 12 summarizes the adverse reactions in MONALEESA-2. (See Table 12.)

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Clinically relevant adverse reactions in <10% of patients in MONALEESA-2 receiving KRYXANA plus letrozole included interstitial lung disease (0.3%), lung infiltration (0.3%), pneumonitis (0.3%), and pulmonary fibrosis (0.6%). Table 13 summarizes the laboratory abnormalities in MONALEESA-2. (See Table 13.)

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MONALEESA-7: KRYXANA in Combination with a Non-Steroidal Aromatase Inhibitor: Pre/perimenopausal Patients with HR-positive, HER2-negative Advanced or Metastatic Breast Cancer for Initial Endocrine-Based Therapy: The safety of KRYXANA was evaluated in MONALEESA-7, a clinical trial of 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. [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The median duration of exposure in the KRYXANA plus a NSAI 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.
Serious adverse reactions occurred in 17% of patients who received KRYXANA plus NSAI plus goserelin. Serious adverse reactions in ≥1% of patients receiving KRYXANA plus NSAI plus goserelin included drug-induced liver injury (1.6%), abdominal pain (1.2%), dyspnea (1.2%), febrile neutropenia (1.2%), and back pain (1.2%).
Permanent discontinuation of both KRYXANA and NSAI due to an adverse reaction occurred in 3% of patients. Permanent discontinuation of KRYXANA alone occurred in 3% of patients. Adverse reactions which resulted in permanent discontinuation of both KRYXANA and NSAI in ≥2% of patients were alanine aminotransferase increased (2%), and aspartate aminotransferase increased (2%).
Dosage interruptions of KRYXANA plus NSAI plus goserelin due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included neutropenia (41%), neutrophils decreased (26%), and leukocytes decreased (6%).
Dose reductions of KRYXANA due to an adverse reaction occurred in 33% of patients receiving KRYXANA plus NSAI plus goserelin. Adverse reactions which required dose reductions in ≥2% of patients included neutropenia (17%), neutrophils decreased (5%), and alanine aminotransferase increased (2%).
The most common (≥20% on the KRYXANA arm and ≥2% higher than placebo) adverse reactions, including laboratory abnormalities, were leukocytes decreased, neutrophils decreased, hemoglobin decreased, lymphocytes decreased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, infections, arthralgia, alanine aminotransferase increased, nausea, platelets decreased, and alopecia.
Table 14 summarizes the adverse reactions in MONALEESA-7. (See Table 14.)

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Clinically relevant adverse reactions in <10% of patients in MONALEESA-7 receiving KRYXANA plus NSAI included thrombocytopenia (9%), dry skin (9%), 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 of KRYXANA was evaluated in MONALEESA-3, a clinical trial of 724 postmenopausal women receiving KRYXANA plus fulvestrant or placebo plus fulvestrant. [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. The median duration of exposure to KRYXANA plus fulvestrant was 15.8 months with 58% of patients exposed for ≥12 months.
Serious adverse reactions occurred in 29% of patients who received KRYXANA plus fulvestrant. Serious adverse reactions in ≥1% of patients receiving KRYXANA plus fulvestrant included pneumonia (1.9%), nausea (1.4%), vomiting (1.4%), anemia (1.2%), dyspnea (1.2%), neutropenia (1.2%). One case (0.2%) of fatal adverse reaction (pneumonia) occurred in patients who received KRYXANA plus fulvestrant.
Fatal adverse reactions occurred in 1.2% of patients who received KRYXANA. Fatal adverse reactions in ≥0.1% of patients receiving KRYXANA included cardiac failure, ventricular arrhythmia, pneumonia, acute respiratory distress, pulmonary embolism, and hemorrhagic shock (0.2% each). Permanent discontinuation of both KRYXANA and fulvestrant due to an adverse reaction occurred in 8% of patients. Permanent discontinuation of KRYXANA alone occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of both KRYXANA and fulvestrant in ≥2% of patients were alanine aminotransferase increased (5%), and aspartate aminotransferase increased (3%).
Dosage interruptions of KRYXANA plus fulvestrant due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included neutropenia (40%), neutrophils decreased (13%), alanine aminotransferase increased (8%), aspartate aminotransferase increased (8%), and leukocytes decreased (5%).
Dose reductions of KRYXANA due to an adverse reaction occurred in 32% of patients receiving KRYXANA plus fulvestrant. Adverse reactions which required dose reductions in ≥2% of patients included neutropenia (15%), and neutrophils decreased (3%).
The most common (≥20% on the KRYXANA arm and ≥2% higher than placebo) adverse reactions, including laboratory abnormalities, were leukocytes decreased, neutrophils decreased, lymphocytes decreased, creatinine increased, hemoglobin decreased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, nausea, alanine aminotransferase increased, infections, platelets decreased, diarrhea, vomiting, constipation, glucose serum decreased, cough, rash, and pruritus.
Table 16 summarizes the adverse reactions in MONALEESA-3. (See Table 16.)

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Clinically relevant adverse reactions in <10% of patients in MONALEESA-3 receiving KRYXANA plus fulvestrant included 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 trial 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).