ADVERSE REACTIONS
The most commonly reported adverse drug reactions (>20%) have been diarrhea, rash, acne, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain. The most common laboratory abnormalities (>20%) were decreased calcium, increased ALT, and decreased glucose [see Dosage and Administration and Warnings and Precautions (5.2, 5.3 and 5.9)].
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.
Clinical Studies Experience
Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with vandetanib 300 mg (n=231) or Placebo (n= 99). Patients with investigator-determined progression or patients who continued treatment after the data cut-off could receive open label vandetanib. The following adverse reactions have been reported. [see Clinical Studies]
Table 1 - Adverse Reactions in > 10% of Patients on Vandetanib During Randomized Treatment
Preferred Term |
Vandetanib 300 mg N=231 |
Placebo N=99 |
|
All Grades
|
Grade 3–4
|
All Grades
|
Grade 3–4
|
Diarrhea/Colitis
|
132 (57%)
|
26 (11%)
|
27 (27%)
|
2 (2%)
|
Rash
|
123 (53%)
|
11 (5%)
|
12 (12%)
|
0
|
Dermatitis Acneiform/Acne
|
81 (35%)
|
2 (1%)
|
7 (7%)
|
0
|
Nausea
|
77 (33%)
|
2 (1%)
|
16 (16%)
|
0
|
Hypertension/Hypertensive Crisis/Accelerated Hypertension
|
76 (33%)
|
20 (9%)
|
5 (5%)
|
1 (1%)
|
Headache
|
59 (26%)
|
2 (1%)
|
9 (9%)
|
0
|
Fatigue
|
55 (24%)
|
13 (6%)
|
23 (23%)
|
1 (1%)
|
Decreased Appetite
|
49 (21%)
|
10 (4%)
|
12 (12%)
|
0
|
Abdominal Pain
|
48 (21%)
|
6 (3%)
|
11 (11%)
|
0
|
Dry Skin
|
35 (15%)
|
0 |
5 (5%) |
0 |
Vomiting
|
34 (15%)
|
2 (1%)
|
7 (7%)
|
0 |
Asthensia
|
34 (15%)
|
6 (3%)
|
11 (11%)
|
1 (1%) |
ECG QT Prolonged
|
33 (14%)
|
18 (8%)
|
1 (1%)
|
1 (1%)
|
Photosensitivity Reaction
|
31 (13%)
|
4 (2%)
|
0
|
0
|
Insomnia
|
30 (13%)
|
0
|
10 (10%)
|
0
|
Nasopharyngitis
|
26 (11%)
|
0
|
10 (10%)
|
0
|
Dyspepsia
|
25 (11%)
|
0
|
4 (4%)
|
0
|
Hypocalcemia
|
25 (11%)
|
4 (2%)
|
3 (3%) |
0 |
Cough
|
25 (11%)
|
0
|
10 (10%)
|
0
|
Pruritus
|
25 (11%)
|
3 (1%)
|
4 (4%)
|
0
|
Weight Decreased
|
24 (10%)
|
2 (1%)
|
9 (9%)
|
0
|
Proteinuria
|
23 (10%)
|
0
|
2 (2%)
|
0
|
Depression
|
22 (10%)
|
4 (2%)
|
3 (3%)
|
0
|
Adverse reactions resulting in death in patients receiving vandetanib (N=5) were respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. Adverse reactions resulting in death in patients receiving placebo were gastrointestinal hemorrhage (1%) and gastroenteritis (1%). In addition there was one sudden death and one death from cardiopulmonary arrest, in patients receiving vandetanib after data cut-off. Causes of discontinuation in vandetanib-treated patients in >1 patient included asthenia, fatigue, rash, arthralgia, diarrhea, hypertension, prolonged QT interval, increase in creatinine and pyrexia. Serious adverse events in vandetanib-treated patients in >2% of patients included diarrhea, pneumonia, and hypertension. Clinically important uncommon adverse drug reactions in patients who received vandetanib versus patients who received placebo included pancreatitis (0.4% vs. 0%) and heart failure (0.9% vs. 0%). In the integrated summary of safety database, the most common cause of death in patients who received vandetanib was pneumonia.
The incidence of Grade 1-2 bleeding events was 14% in patients receiving vandetanib compared with 7% on placebo in the randomized portion of the medullary thyroid cancer (MTC) study. The incidence was similar in the 300 mg monotherapy safety program with a 13% incidence.
Blurred vision was more common in patients who received vandetanib versus patients who received placebo for medullary thyroid cancer (9% vs. 1%, respectively). Scheduled slit lamp examinations have revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. It is unknown if this will improve after discontinuation. Ophthalmologic examination, including slit lamp, is recommended in patients who report visual changes. If a patient has blurred vision, do not drive or operate machinery.
Table 2 provides the frequency and severity of laboratory abnormalities reported for patients with medullary thyroid cancer receiving randomized treatment with vandetanib or placebo.
Table 2 - Laboratory Abnormalities in Patients with MTC
Laboratory Parameter |
Vandetanib 300 mg |
Placebo N=99 |
|
All Grades
|
Grade 3–4
|
All Grades
|
Grade 3–4
|
Chemistries
|
|
Calcium Decreased
|
132 (57%)
|
13 (6%)
|
25 (25%)
|
3 (3%)
|
ALT Increased
|
118 (51%)
|
4 (2%)
|
19 (19%)
|
0
|
Glucose Decreased
|
55 (24%)
|
0
|
7 (7%)
|
1 (1%)
|
Creatinine Increased
|
38 (16%)
|
0
|
1 (1%)
|
0
|
Bilirubin Increased
|
29 (13%)
|
0
|
17 (17%)
|
0
|
Magnesium Decreased
|
17 (17%)
|
1 (<1%)
|
2 (2%)
|
0
|
Calcium Increased
|
16 (7%)
|
2 (1%)
|
9 (9%)
|
1 (1%)
|
Potassium Decreased
|
15 (6%)
|
1 (<1%)
|
3 (3%)
|
0
|
Potassium Increased
|
13 (6%)
|
1 (<1%)
|
4 (4%)
|
2 (2%)
|
Glucose Increased
|
12 (5%)
|
4 (2%)
|
7 (7%)
|
0
|
Magnesium Increased
|
6 (3%)
|
0
|
4 (4%)
|
0
|
Hematologic
|
|
WBC Decreased
|
45 (19%)
|
0
|
25 (25%)
|
0
|
Hemoglobin Decreased
|
31 (13%)
|
1 (<1%)
|
19 (19%)
|
2 (2%)
|
Neutrophils Decreased
|
21 (10%)
|
1 (<1%)
|
5 (5%)
|
2 (2%)
|
Platelets Decreased
|
18 (9%)
|
0
|
3 (3%)
|
0
|
Alanine aminotransferase elevations occurred in 51% of patients on vandetanib in the randomized medullary thyroid cancer (MTC) study. Grade 3-4 ALT elevations were seen in 2% of patients and no patients had a concomitant increase in bilirubin. Elevations in ALT have resulted in temporary discontinuation of vandetanib. However, 16 of 22 patients with a grade 2 elevation in ALT continued 300 mg vandetanib. Seven patients who continued vandetanib had a normal ALT within 6 months. In the protocol, ALT was monitored every 3 months and more frequently as indicated.
|