6 ADVERSE REACTIONS

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

Perforations and Fistula [see Warnings and Precautions (5.1)]
Hemorrhage [see Warnings and Precautions (5.2)]
Thromboembolic Events [see Warnings and Precautions (5.3)]
Impaired Wound Healing [see Warnings and Precautions (5.4)]
Hypertension and Hypertensive Crisis [see Warnings and Precautions (5.5)]
Osteonecrosis of the Jaw [see Warnings and Precautions (5.6)]
Diarrhea [see Warnings and Precautions (5.7)]
Palmar-Plantar Erythrodysesthesia [see Warnings and Precautions (5.8)]
Proteinuria [see Warnings and Precautions (5.9)]
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions(5.10)]
Hypocalcemia [see Warnings and Precautions (5.12)]

6.1 Clinical Trial 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 safety of COMETRIQ was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, doubleblind, controlled trial (Study 1) [see Clinical Studies (14)]. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years.

Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration.

The COMETRIQ dose was reduced in 79% of patients receiving COMETRIQ and in 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ and in no patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ. The most frequent adverse reactions leading to permanent discontinuation of COMETRIQ were: hypocalcemia, increased lipase, PPE, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting.

Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia (PPE), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (Table 1 and Table 2 summarize the adverse reactions and laboratory abnormalities reported in Study 1).

Table 1. Selected Adverse Reactions Occurring at a Higher Incidence in COMETRIQ-Treated Patients (Study 1) [Between Arm Difference of ≥ 5% (All Grades)* or ≥ 2% (Grades 3-4)]
System Organ Class/Preferred Terms	COMETRIQ (n=214)		Placebo (n=109)
System Organ Class/Preferred Terms	All Grades (%)	Grades 3-4 (%)	All Grades (%)	Grades 3-4 (%)
* National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 † Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation ‡ Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia § Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain ¶ Palmar-plantar erythrodysesthesia
GASTROINTESTINAL DISORDERS
Diarrhea	63	16	33	2
Stomatitis†	51	5	6	0
Nausea	43	1	21	0
Oral pain‡	36	2	6	0
Constipation	27	0	6	0
Abdominal pain§	27	3	13	1
Vomiting	24	2	2	1
Dysphagia	13	4	6	1
Dyspepsia	11	0	0	0
Hemorrhoids	9	0	3	0
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
PPE¶	50	13	2	0
Hair color changes/ depigmentation, graying	34	0	1	0
Rash	19	1	10	0
Dry skin	19	0	3	0
Alopecia	16	0	2	0
Erythema	11	1	2	0
Hyperkeratosis	7	0	0	0
INVESTIGATIONS
Decreased weight	48	5	10	0
METABOLISM AND NUTRITION DISORDERS
Decreased appetite	46	5	16	1
Dehydration	7	2	2	1
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Fatigue	41	9	28	3
Asthenia	21	6	15	1
NERVOUS SYSTEM DISORDERS
Dysgeusia	34	0	6	0
Headache	18	0	8	0
Dizziness	14	0	7	0
Paresthesia	7	0	2	0
Peripheral sensory neuropathy	7	0	0	0
Peripheral neuropathy	5	0	0	0
VASCULAR DISORDERS
Hypertension	33	8	4	0
Hypotension	7	1	0	0
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Dysphonia	20	0	9	0
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia	14	1	7	0
Muscle spasms	12	0	5	0
Musculoskeletal chest pain	9	1	4	0
PSYCHIATRIC DISORDERS
Anxiety	9	0	2	0

Table 2 Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients (Study 1) [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)]
Test	COMETRIQ (n=214)		Placebo (N=109)
	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
Chemistries
Increased AST	86	3	35	2
Increased ALT	86	6	41	2
Increased ALP	52	3	35	3
Hypocalcemia	52	12	27	3
Hypoalbuminemia	43	2	16	0
Hypophosphatemia	28	3	10	1
Hyperbilirubinemia	25	2	14	5
Hypomagnesemia	19	1	4	0
Hypokalemia	18	4	9	3
Hyponatremia	10	2	5	0
Hematologic
Lymphopenia	53	16	51	11
Neutropenia	35	3	15	2
Thrombocytopenia	35	0	4	3

ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Table 3 Per-Patient Incidence of Hypertension (Study 1)
* Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. † Patients classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. ‡ Patients with at least two blood pressure measurements after the first dose
Hypertension, JNC* Stage†	COMETRIQ N=211‡(%)	Placebo N=107‡(%)
Normal: Grade 0: Systolic < 120 mmHg and Diastolic < 80 mmHg	4	15
Pre-hypertension: Systolic ≥ 120 mmHg or Diastolic ≥ 80 mmHg	34	54
Stage 1: Systolic ≥ 140 mmHg or Diastolic ≥ 90 mmHg	46	25
Stage 2: Systolic ≥ 160 mmHg or Diastolic ≥ 100 mmHg	15	5
Malignant: Diastolic ≥ 120 mmHg	0	0

Other clinically important adverse reactions (all grades) that were reported in clinical trials include: hepatitis cholestatic (<1%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of COMETRIQ. Because these reactions 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.

Hematology: A case of supratherapeutic international normalized ratio (INR) and epistaxis during concomitant use of warfarin

Musculoskeletal and Connective Tissue Disorders: Extremity pain

Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture