Vandetanib (Vandetanib) - Side Effects and Adverse Reactions

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 1	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 2	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 3	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.

REPORTS OF SUSPECTED VANDETANIB SIDE EFFECTS / ADVERSE REACTIONS

Possible Vandetanib side effects / adverse reactions in 45 year old male

Reported by a individual with unspecified qualification from United States on 2011-10-03

Patient: 45 year old male

Reactions: Bone Neoplasm Malignant, Small Cell Lung Cancer Metastatic, Muscle Spasms

Adverse event resulted in: death

Suspect drug(s):
Vandetanib

Other drugs received by patient: Morphine Sulfate; Pink Magic; Prednisone; Lactulose; Oxycontin; Senna LAX

Possible Vandetanib side effects / adverse reactions in male

Reported by a physician from Canada on 2011-10-13

Patient: male weighing 103.8 kg (228.4 pounds)

Reactions: Photosensitivity Reaction, Skin Exfoliation, Oedema Peripheral

Suspect drug(s):
Celebrex
    Administration route: Oral
    Indication: Osteoarthritis
    Start date: 2006-01-01

Vandetanib
    Administration route: Oral
    Indication: Prostate Cancer
    Start date: 2011-03-25
    End date: 2011-04-21

Other drugs received by patient: Entrophen; Levocarbidopa; Atorvastatin; Lenoltec NO3; Temazepam; Tamsulosin HCL; Glucozamine; Atenolol; Lupron; Ectosone

Possible Vandetanib side effects / adverse reactions in female

Reported by a physician from Belgium on 2011-10-17

Patient: female

Reactions: Intestinal Perforation, Intestinal Obstruction

Adverse event resulted in: life threatening event, hospitalization

Suspect drug(s):
Vandetanib
    Administration route: Oral
    Start date: 2011-06-16
    End date: 2011-06-16

Vandetanib
    Administration route: Oral
    Indication: Thyroid Cancer
    Start date: 2011-05-21
    End date: 2011-05-27

Vandetanib
    Dosage: dose reduced
    Administration route: Oral
    Start date: 2011-06-17
    End date: 2011-07-01

Other drugs received by patient: Targinact; Laxoberon; Litican; Oxycodone HCL; Lorazepam; Closan; Polyethylene Glycol; Zometa; Imodium; Calcium Carbonate; Elthyrone; Loramet; Alpha LEO; Voltaren; Pantoprazole; Medrol; Redomex; MS Contin