6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Diarrhea [see Warnings and Precautions ( 5.1)]
Hepatotoxicity [see Warnings and Precautions ( 5.2)]

6.1 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 increased (0.3%), AST increased (0.3%), nausea (0.3%), fatigue (0.2%), and abdominal pain (0.2%).

Table 7summarizes the adverse reactions in ExteNET.

Table 7: Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in ExteNET
* 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
System Organ Class (Preferred Term)	NERLYNX n=1408			Placebo n=1408
System Organ Class (Preferred Term)	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

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-positive 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 NERLYNX 240 mg orally once daily Days 1–21 of a 21-day cycle in combination with capecitabine (750 mg/m 2given 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/m 2given 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 8summarizes the adverse reactions in NALA.

Table 8: Adverse Reactions Reported in ≥2% of NERLYNX-Treated Patients in Combination with Capecitabine in NALA
* Renal impairment includes acute kidney injury, blood creatinine increased, renal failure, and renal impairment.
System Organ Class (Preferred Term)	NERLYNX + Capecitabine n=303			Lapatinib + Capecitabine n=311
System Organ Class (Preferred Term)	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

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 [see Dosage and Administration ( 2.1)]. 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 [see Dosage and Administration ( 2.2)] .

Table 9summarizes the diarrhea adverse reactions for NERLYNX with loperamide prophylaxis and NERLYNX dose escalation.

Table 9: 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