NERLYNX SIDE EFFECTS
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Diarrhea
- Hepatotoxicity
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.
Extended Adjuvant Treatment Of Early-Stage Breast Cancer
ExteNET
The data described below reflect the safety data of NERLYNX as a single agent in ExteNET, a multicenter, randomized, double-blind, placebo-controlled study of NERLYNX within 2 years after completion of adjuvant treatment with trastuzumab-based therapy in women with HER2-positive early-stage breast cancer. Patients who received NERLYNX in this trial were not required to receive any prophylaxis with antidiarrheal agents to prevent the NERLYNX-related diarrhea. Patients were treated with 240 mg of NERLYNX given orally once daily with food, continuously until disease recurrence or for up to one year. The median duration of treatment was 11.6 months in the NERLYNX arm and 11.8 months in the placebo arm. The median age was 52 years (60% were ≥50 years old, 12% were ≥65 years old); 81% were Caucasian, 3% Black or African American, 14% Asian, and 3% other. A total of 1408 patients were treated with NERLYNX.
NERLYNX dose reduction due to an adverse reaction of any grade occurred in 31% of patients receiving NERLYNX compared to 2.6% of patients receiving placebo. Permanent discontinuation due to any adverse reaction was reported in 28% of NERLYNX-treated patients. The most common adverse reaction leading to discontinuation was diarrhea, accounting for 17% of NERLYNX-treated patients.
The most common adverse reactions (≥5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, vomiting, nausea, and abdominal pain.
Serious adverse reactions in the NERLYNX arm included diarrhea (1.6%), vomiting (0.9%), dehydration (0.6%), cellulitis (0.4%), renal failure (0.4%), erysipelas (0.4%), ALT (0.3%), AST increased (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%).
Table 1 summarizes the adverse reactions in ExteNET.
Table 1: Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in ExteNET
| System Organ Class (Preferred Term) | NERLYNX n=1408 |
Placebo n=1408 |
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| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Gastrointestinal Disorders | ||||||
| Diarrhea | 95 | 40 | 0.1 | 35 | 2 | 0 |
| Nausea | 43 | 2 | 0 | 22 | 0.1 | 0 |
| Abdominal pain* | 36 | 2 | 0 | 15 | 0.4 | 0 |
| Vomiting | 26 | 3 | 0 | 8 | 0.4 | 0 |
| Stomatitis† | 14 | 0.6 | 0 | 6 | 0.1 | 0 |
| Dyspepsia | 10 | 0.4 | 0 | 4 | 0 | 0 |
| Abdominal distension | 5 | 0.3 | 0 | 3 | 0 | 0 |
| Dry mouth | 3 | 0.1 | 0 | 2 | 0 | 0 |
| General Disorders and Administration Site Conditions | ||||||
| Fatigue | 27 | 2 | 0 | 20 | 0.4 | 0 |
| Hepatobiliary Disorders | ||||||
| Alanine aminotransferase increased | 9 | 1 | 0.2 | 3 | 0.2 | 0 |
| Aspartate aminotransferase increased | 7 | 0.5 | 0.2 | 3 | 0.3 | 0 |
| Infections and Infestations | ||||||
| Urinary tract infection | 5 | 0.1 | 0 | 2 | 0 | 0 |
| Investigations | ||||||
| Weight decreased | 5 | 0.1 | 0 | 0.5 | 0 | 0 |
| Metabolism and Nutrition Disorders | ||||||
| Decreased appetite | 12 | 0.2 | 0 | 3 | 0 | 0 |
| Dehydration | 4 | 0.9 | 0.1 | 0.4 | 0.1 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||||
| Muscle spasms | 11 | 0.1 | 0 | 3 | 0.1 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||||
| Epistaxis | 5 | 0 | 0 | 1 | 0.1 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||||
| Rash‡ | 18 | 0.6 | 0 | 9 | 0 | 0 |
| Dry skin | 6 | 0 | 0 | 2 | 0 | 0 |
| Nail Disorder§ | 8 | 0.3 | 0 | 2 | 0 | 0 |
| Skin fissures | 2 | 0.1 | 0 | 0.1 | 0 | 0 |
| * Includes abdominal pain, abdominal pain upper, and abdominal pain lower † Includes stomatitis, aphthous stomatitis, mouth ulceration, oral mucosal blistering, mucosal inflammation, oropharyngeal pain, oral pain, glossodynia, glossitis, and cheilitis ‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash pruritic, rash pustular, rash maculo-papular, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption § Includes nail disorder, paronychia, onychoclasis, nail discoloration, nail toxicity, nail growth abnormal, and nail dystrophy |
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Advanced Or Metastatic Breast Cancer
NALA
The data described below reflect the safety data of NERLYNX plus capecitabine in NALA, a randomized, multicenter, multinational, open-label, active-controlled study of HER2+ metastatic breast cancer in patients, with or without brain metastases, who have received two or more prior anti HER2-based regimens in the metastatic setting.
Patients were treated with NERLNX 240 mg orally once daily Days 1–21 of a 21-day cycle in combination with capecitabine (750 mg/m2 given orally twice daily) Days 1–14 of a 21-day cycle, or lapatinib 1250 mg orally once daily Days 1–21 of a 21-day cycle in combination with capecitabine (1000 mg/m2 given orally twice daily) Days 1–14 of a 21-day cycle until disease progression. The median duration of treatment was 5.7 months in the NERLYNX plus capecitabine arm and 4.4 months in the lapatinib plus capecitabine arm.
NERLYNX dose reduction due to an adverse reaction of any grade occurred in 10% of patients receiving NERLYNX plus capecitabine. Permanent discontinuation due to any adverse reaction was reported in 14% of NERLYNX plus capecitabine treated patients. The most common adverse reactions leading to discontinuation were vomiting (3.6%), diarrhea (2.6%), nausea (2.6%), and palmar-plantar erythrodysaesthesia syndrome (2.3%) of NERLYNX plus capecitabine-treated patients.
The most common adverse reactions of any grade (≥5%) in the NERLYNX plus capecitabine arm were diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms. The most frequently reported Grade 3 or 4 adverse reactions were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Serious adverse reactions ≥2% in the NERLYNX plus capecitabine arm included diarrhea (7%), vomiting (3%), nausea (2.3%), and acute kidney injury (2.3%).
Table 2 summarizes the adverse reactions in NALA.
Table 2: Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in Combination with Capecitabine in NALA
| System Organ Class (Preferred Term) |
NERLYNX + capecitabine n=303 |
Lapatinib + capecitabine n=311 |
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| All Grades (%) | Grade 3 (%) | Grade 4 (%) | All Grades (%) | Grade 3 (%) | Grade 4 (%) | |
| Gastrointestinal Disorders | ||||||
| Diarrhea | 83 | 25 | 0 | 66 | 13 | 0 |
| Nausea | 53 | 4.3 | 0 | 42 | 2.9 | 0 |
| Vomiting | 46 | 4 | 0 | 31 | 1.9 | 0 |
| Constipation | 31 | 1 | 0 | 13 | 0 | 0 |
| Abdominal distension | 8 | 0.3 | 0 | 3.2 | 0.6 | 0 |
| General Disorders and Administration Site Conditions | ||||||
| Fatigue/asthenia | 45 | 6 | 0 | 40 | 4.5 | 0 |
| Malaise | 4.3 | 0 | 0 | 2.3 | 0.3 | 0 |
| Influenza like illness | 4 | 0 | 0 | 1.3 | 0 | 0 |
| Infections and Infestations | ||||||
| Urinary tract infection | 9 | 0.7 | 0 | 4.2 | 0.6 | 0 |
| Upper respiratory tract infection | 8 | 0.3 | 0 | 4.5 | 0.3 | 0 |
| Investigations | ||||||
| Weight decreased | 20 | 0.3 | 0 | 13 | 0.6 | 0 |
| Metabolism and Nutrition Disorders | ||||||
| Decreased appetite | 35 | 2.6 | 0 | 22 | 2.3 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||||
| Back Pain | 10 | 0.3 | 0 | 8 | 0.3 | 0 |
| Arthralgia | 10 | 0 | 0 | 6 | 1 | 0 |
| Muscle spasms | 5 | 0 | 0 | 1.9 | 0 | 0 |
| Nervous System Disorder | ||||||
| Dizziness | 14 | 0.3 | 0 | 10 | 0.6 | 0 |
| Renal and urinary disorders | ||||||
| Renal impairment* | 7 | 2 | 0.3 | 1 | 0 | 0.3 |
| Dysuria | 4.6 | 0 | 0 | 1.9 | 0 | 0 |
| * Renal impairment includes acute kidney injury, blood creatinine increased, renal failure, and renal impairment | ||||||
Management Of Diarrhea
CONTROL
The CONTROL (NCT02400476) study was a multicenter, open-label, multi-cohort trial evaluating patients with early-stage HER2-positive breast cancer treated with NERLYNX 240 mg daily for up to one year receiving loperamide prophylaxis with additional anti-diarrheal treatment as needed or NERLYNX dose escalation with loperamide as needed. All patients in the prophylaxis cohort received loperamide 4 mg loading dose, followed by 4 mg three times a day from days 1-14, followed by 4 mg twice a day on days 15-56, followed by loperamide as needed through 1 year of treatment with NERLYNX. All patients in the dose escalation cohort received NERLYNX 120 mg for Week 1, followed by NERLYNX 160 mg for Week 2, followed by NERLYNX 240 mg for Week 3 and thereafter .
Table 3 summarizes the diarrhea adverse reactions for NERLYNX with loperamide prophylaxis and NERLYNX dose escalation.
Table 3: Diarrhea in Patients Treated with NERLYNX with Antidiarrheal Prophylaxis or Dose Escalation
| Loperamide Prophylaxis n=109 |
NERLYNX Dose Escalation n=60 |
|
| Duration of Treatment, months | ||
| Median | 11.8 | 12.0 |
| Range | 0.1, 12.8 | 0.2, 12.4 |
| Dose Intensity, mg per day | ||
| Median | 234 | 230 |
| Range | 46, 240 | 32, 236 |
| Incidence of Diarrhea, % | ||
| Any Grade | 78 | 98 |
| Grade 2 | 25 | 45 |
| Grade 3 | 32 | 13 |
| Action Taken, % | ||
| Discontinuation due to diarrhea | 18 | 3.3 |
SRC: NLM .