The following serious adverse reactions are discussed elsewhere in the label:
- QT Prolongation and Torsades de Pointes [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Skin Reactions and Stevens-Johnson Syndrome [see WARNINGS AND PRECAUTIONS]
- Interstitial Lung Disease [see WARNINGS AND PRECAUTIONS]
- Ischemic Cerebrovascular Events [see WARNINGS AND PRECAUTIONS]
- Hemorrhage [see WARNINGS AND PRECAUTIONS]
- Heart Failure [see WARNINGS AND PRECAUTIONS]
- Diarrhea [see WARNINGS AND PRECAUTIONS]
- Hypothyroidism [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Reversible Posterior Leukoencephalopathy Syndrome [see WARNINGS AND PRECAUTIONS]
- Embryofetal Toxicity [see WARNINGS AND PRECAUTIONS]
Clinical Studies 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.
Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58% male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to CAPRELSA for 607 days.
The most commonly reported adverse drug reactions which occurred in > 20% of CAPRELSA-treated patients and with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection, decreased appetite, and abdominal pain.
Among CAPRELSA-treated patients, dose interruption occurred in 109 (47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of 231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions leading to permanent discontinuation in 2 or more ( ≥ 0.9%) patients treated with CAPRELSA were: asthenia (1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation (0.9%), and hypertension (0.9%).
Table 1 : Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in CAPRELSA-Treated Patients During Randomized Treatment [Between-Arm Difference of ≥ 5% (All Grades)1]
|System Organ Class Preferred Term||CAPRELSA 300 mg
|All Grades (%)||Grade 3-4 (%)||All Grades (%)||Grade 3-4 (%)|
|Skin and Cutaneous Disorders|
|Hypertension/Hypertensive Crisis/Accelerated Hypertension||33||9||5||1|
|Nervous System Disorders|
|Upper Respiratory Tract Infections6||23||0||16||0|
|Metabolic and Nutritional Disorders|
|ECG QT Prolonged7||14||8||1||1|
|1CTCAE version 3 was used to grade adverse events.
2Includes abdominal pain, abdominal pain upper, lower abdominal pain and abdominal discomfort.
3Includes rash, rash (erythematous, generalized, macular, maculo-papular, papular, pruritic, and exfoliative), dermatitis, dermatitis bullous, generalized erythema, and eczema.
4Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection.
5Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group.
6Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and tracheitis.
769% had QT prolongation > 450ms and 7% had QT prolongation > 500ms by ECG using Fridericia correction.
8Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits, acquired corneal dystrophy.
Clinically important uncommon adverse drug reactions in patients who received CAPRELSA versus patients who received placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%).
Blurred vision was more common in patients who received CAPRELSA versus patients who received placebo for medullary thyroid cancer (9% vs. 1%, respectively). Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination, including slit lamp examination, in patients who report visual changes.
CAPRELSA is an inhibitor of vascular endothelial growth factor receptor (VEGFR) signaling. Inhibition of VEGFR signaling can result in intestinal perforation. Intestinal perforation occurred in 0.4% of CAPRELSA treated patients versus 0% of placebo treated patients. The incidence of Grade 1-2 bleeding events was 14% in patients receiving CAPRELSA compared with 7% on placebo in the randomized portion of the medullary thyroid cancer (MTC) study.2
Table 2 : Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at a Higher Incidence in CAPRELSA-Treated Patients [Between-Arm Difference of ≥ 5% (All Grades)1]
|Laboratory Abnormalities||CAPRELSA 300 mg
|All Grades (%)||Grade 3–4 (%)||All Grades (%)||Grade 3–4 (%)|
|1CTCAE version 3 was used to grade laboratory abnormalities.|
No patient with a Grade 3-4 ALT elevation had a concomitant increase in bilirubin in the MTC study.