The following serious adverse reactions are discussed elsewhere in the label:
- Perforations and Fistula [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Hemorrhage [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Thromboembolic Events [see WARNINGS AND PRECAUTIONS]
- Wound Complications [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Osteonecrosis of the Jaw [see WARNINGS AND PRECAUTIONS]
- Palmar-plantar erythrodysesthesia syndrome [see WARNINGS AND PRECAUTIONS]
- Proteinuria [see WARNINGS AND PRECAUTIONS]
- Reversible Posterior Leukoencephalopathy Syndrome [see WARNINGS AND PRECAUTIONS]
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. [See Clinical Studies] 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.
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 syndrome (PPES), 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 (see Table 1, Table 2).
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 dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, 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.
Table 1 : Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1or ≥ 2% (Grades 3-4)]
|MedDRA System Organ Class/ Preferred Terms||Cabozantinib
|All Grades||Grades 3-4||All Grades||Grades 3-4|
|GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS|
|METABOLISM AND NUTRITION DISORDERS|
|MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS|
|Musculoskeletal chest pain||9||1||4||0|
|NERVOUS SYSTEM DISORDERS|
|Peripheral sensory neuropathy||7||0||0||0|
|RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS|
|SKIN AND SUBCUTANEOUS TISSUE DISORDERS|
|Hair color changes/ depigmentation, graying||34||0||1||0|
|1 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0
2 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation
3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia
4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain
5 Palmar-plantar erythrodysesthesia syndrome
Table 2: Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)]
|All Grades||Grade 3-4||All Grades||Grade 3-4|
|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 Hypertensio n in Protocol XL184-301
|Hypertension, JNC1 Stage||COMETRIQ
N = 2113(%)
N = 1073 (%)
|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|
|1Joint 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.
2Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.
3Subjects with at least two blood pressure measurements after the first dose