6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

New Primary Cutaneous Malignancies [see Warnings and Precautions (5.1)]
Hemorrhage [see Warnings and Precautions (5.2)]
Cardiomyopathy [see Warnings and Precautions (5.3)]
Serious Dermatologic Reactions [see Warnings and Precautions (5.4)]
Serous Retinopathy and Retinal Vein Occlusion [see Warnings and Precautions (5.5)]
Hepatotoxicity [see Warnings and Precautions (5.6)]
Rhabdomyolysis [see Warnings and Precautions (5.7)]
Severe Photosensitivity [see Warnings and Precautions (5.8)]

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.

Unresectable or Metastatic Melanoma

The safety of COTELLIC was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma [see Clinical Studies (14)]. All patients received vemurafenib 960 mg twice daily on Days 1–28 and received either COTELLIC 60 mg once daily (n=247) or placebo (n=246) on Days 1–21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the COTELLIC plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year. Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies [see Clinical Studies (14)].

In Trial 1, 15% of patients receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving COTELLIC, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of COTELLIC were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). The most common (≥20%) adverse reactions with COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.

Table 3. Incidence of Adverse Drug Reactions Occurring in ≥10% (All Grades) of Unresectable or Metastatic Melanoma Patients Receiving COTELLIC with Vemurafenib and at a Higher Incidence* than Patients Receiving Vemurafenib in Trial 1
Adverse reactions	COTELLIC + Vemurafenib (n=247)		Placebo + Vemurafenib (n=246)
Adverse reactions	All Grades† (%)	Grades 3–4 (%)	All Grades (%)	Grades 3–4 (%)
* ≥5% for All Grades or ≥2% for Grades 3–4 incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib as a single agent † NCI CTCAE, v4.0. ‡ Includes stomatitis, aphthous stomatitis, mouth ulceration, and mucosal inflammation § Includes solar dermatitis, sunburn, photosensitivity reaction ¶ Includes hemorrhage, rectal hemorrhage, melena, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, hematochezia, gingival bleeding, metrorrhagia, uterine hemorrhage, hemorrhagic ovarian cyst, menometrorrhagia, menorrhagia, vaginal hemorrhage, hemoptysis, pulmonary, cerebral, subarachnoid hemorrhage, subgaleal hematoma, hematuria, epistaxis, contusion, traumatic hematoma, ecchymosis, purpura, nail bed bleeding, ocular, eye, conjunctival, and retinal hemorrhage # Includes vision blurred, visual acuity reduced, visual impairment Þ Includes retinal detachment, detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium
GASTROINTESTINAL DISORDERS
Diarrhea	60	6	31	1
Nausea	41	1	25	1
Vomiting	24	1	13	1
Stomatitis‡	14	1	8	0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Photosensitivity reaction§	46	4	35	0
Acneiform dermatitis	16	2	11	1
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Pyrexia	28	2	23	0
Chills	10	0	5	0
VASCULAR DISORDERS
Hypertension	15	4	8	2
Hemorrhage¶	13	1	7	<1
EYE DISORDERS
Vision impaired#	15	<1	4	0
Chorioretinopathy	13	<1	<1	0
Retinal detachmentÞ	12	2	<1	0

The following clinically relevant adverse reactions (all grades) of COTELLIC were reported with <10% incidence in Trial 1:

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Table 4. Incidence of Laboratory Abnormalities Occurring in ≥10% (All Grades) or ≥2% (Grades 3–4) of Patients with Unresectable or Metastatic Melanoma in Trial 1*
Laboratory	COTELLIC + Vemurafenib		Placebo + Vemurafenib
	All Grades†	Grades 3–4†	All Grades†	Grades 3–4†
	%	%	%	%
AST - aspartate aminotransferase, ALT - alanine aminotransferase, GGT - gamma-glutamyltransferase
* All the percentages are based on the number of patients who had a baseline result and at least one on-study laboratory test. The laboratory results are available for a total of 233~244 patients for COTELLIC, and 232~243 for vemurafenib, except where indicated. † NCI CTCAE v4.0. ‡ Increase creatine phosphokinase, n=213 for COTELLIC and 217 for vemurafenib. § Lymphopenia, n=185 for COTELLIC, and 181 for vemurafenib.
Chemistry
Increased creatinine	100	3.3	100	0.4
Increased AST	73	8	44	2.1
Increased ALT	68	11	55	5
Increased alkaline phosphatase	71	7	56	3.3
Increased creatine phosphokinase‡	79	14	16	0.5
Hypophosphatemia	68	12	38	6
Increased GGT	65	21	61	17
Hyponatremia	38	6	33	2.1
Hypoalbuminemia	42	0.8	20	0.4
Hypokalemia	25	4.5	17	3.3
Hyperkalemia	26	2.9	15	0.4
Hypocalcemia	24	0.4	10	1.7
Hematology
Anemia	69	2.5	57	3.3
Lymphopenia§	73	10	55	8
Thrombocytopenia	18	0	10	0

Histiocytic Neoplasms

The safety of COTELLIC was evaluated in Trial 2, a single-center single-arm trial in patients with histiocytic neoplasms [see Clinical Studies (14)]. In Trial 2, 26 patients with histiocytic neoplasms received COTELLIC 60 mg once daily for 21 days on, then 7 days off, in a 28-day treatment cycle. The median treatment duration was 10.7 months. Table 5 presents adverse reactions in at least 15% of patients reported with histiocytic neoplasms treated with COTELLIC. Table 6 presents laboratory abnormalities of grades ≥3 reported in patients with histiocytic neoplasms treated COTELLIC.

In Trial 2, 4 patients (15%) receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. One patient discontinued due to worsening of underlying dyspnea and hypoxia; one patient discontinued due to retinal vascular disorder; one patient discontinued due to hyponatremia; and the other patient discontinued due to pneumonia.

Table 5 Incidence of Adverse Reactions Reported Occurring in ≥15% (All Grades) or Any Percentage (Grade ≥3) in Patients with Histiocytic Neoplasms Treated with COTELLIC in Trial 2
Body Systems Adverse reactions	All Grades* (%) (n=26)	Grades ≥3* (%) (n=26)
* NCI CTCAE v4.0. † Gastritis, and gastroesophageal reflux disease. ‡ Oral dysesthesia and oropharyngeal pain. § Malaise ¶ Facial edema, edema genital, edema peripheral, periorbital edema, and lymphoedema. # Influenza like illness, mucosal infection, paronychia, pharyngitis, pneumonia, bronchitis, sepsis, sinusitis, skin infection, tooth infection, upper respiratory tract infection., and urinary tract infection. Þ Pneumonia and bronchitis. ß Epistaxis, contusion, purpura, hematoma, and rectal hemorrhage.
GASTROINTESTINAL DISORDERS
Diarrhea	62	8
Nausea	46	0
Dyspepsia†	27	0
Vomiting	27	0
Dry Mouth	15	0
Oral pain‡	15	0
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue§	42	0
Edema¶	42	4
Pain	15	0
INFECTIONS AND INFESTATIONS
Infections#	62	23
Urinary tract infection	23	8
Pulmonary infectionsÞ	19	12
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Fall	15	4
INVESTIGATIONS
Decreased Ejection Fraction	19	12
RENAL AND URINARY
Acute kidney injury	15	12
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Dyspnea	27	15
Cough	15	0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Acneiform dermatitis	65	0
Dry skin	31	0
Maculo-papular rash	31	0
Pruritus	31	4
VASCULAR DISORDERS
Hemorrhageß	19	0
Hypertension	15	4

The following clinically relevant adverse reactions (all grades) of COTELLIC were reported with <15% incidence in Trial 2:

Eye disorders: Vision blurred (12%), retinal vascular disorder (4%) and retinopathy (4%).

Gastrointestinal disorders: Stomatitis (12%)

Nervous system disorders: Headache (12%)

Respiratory, thoracic, and mediastinal disorders: Hypoxia (12%), pulmonary edema (4%), and respiratory failure (8%).

Table 6. Incidence of Grade ≥3 Laboratory Abnormalities Occurring in Patients with Histiocytic Neoplasms Treated with COTELLIC in Trial 2*
	Grades 3–4† %
AST - aspartate aminotransferase, ALT - alanine aminotransferase
* All the percentages are based on the number of patients who had a baseline result and at least one on-study laboratory test. † NCI CTCAE v4.0
Chemistry
Increased blood creatine phosphokinase	27
Hyponatremia	18
Hypokalemia	12
Increased blood creatinine	9
Increased AST	9
Hypocalcemia	9
Increased ALT	5
Hematology
Lymphopenia	27
Leukopenia	9
Anemia	8
Neutropenia	5