vandetanib (Rx)

>10%

Diarrhea (57%)

Rash (53%)

Dermatitis acneiform/acne (35%)

Nausea (33%)

Hypertension/Hypertensive Crisis/Accelerated Hypertension (33%)

Headache (26%)

Fatigue (24%)

Upper respiratory tract infection (23%)

Decreased appetite (21%)

Abdominal pain (21%)

Dry skin (15%)

Vomiting (15%)

QT prolongation (14%)

Photosensitivity reaction (13%)

Corneal abnormalities (13%)

Dyspepsia (11%)

Hypocalcemia (11%)

Pruritus (11%)

1-10%

Proteinuria (10%)

Depression (10%)

Dry mouth (9%)

Nail abnormalities (9%)

Blurred vision (9%)

Alopecia (8%)

Dysgeusia (8%)

Hypothyroidism (6%)

Muscle spasms (6%)

<1%

Intestinal perforation (0.4%)

Postmarketing Reports

Skin Reactions and Stevens-Johnson Syndrome

Contraindications

Hypersensitivity

Congenital long QT syndrome

Cautions

Use in patients with indolent, asymptomatic, or slowly progressing disease should be carefully considered because of the treatment related risks

Prolonged QT Interval, Torsades de pointes, and sudden death have been reported

Obtain ECG, serum potassium, calcium, magnesium, and TSH at baseline, then 2-4 and 8-12 weeks after treatment initiation, then q3months for at least a year thereafter; reduce dose as appropriate

Potent CYP3A4 inducers reduce exposure to vandetanib by up to 40%; however, no clinically significant effect on exposure to vandetanib was observed in the presence of the potent CYP3A4 inhibitors

Fatal skin reactions, including Stevens-Johnson syndrome and severe toxic epidermal necrolysis reported; systemic therapies such as corticosteroids may be required; permanently discontinue therapy for severe skin reactions

Interstitial lung disease (ILD), resulting in death has been reported; interrupt vandetanib and investigate unexplained dyspnea, cough, and fever; appropriate measures should be taken for ILD

Ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypothyroidism, hypertension, and reversible posterior leukoencephalopathy syndrome, have been observed

Can cause fetal harm when administered to pregnant women; avoid pregnancy while receiving vandetanib and for 4 months following treatment

Serious hemorrhagic events, some fatal, have been observed; do not administer with recent history of hemoptysis and discontinue if severe hemorrhage occurs

Heart failure observed, including some fatal cases; may be necessary to discontinue vandetanib; heart failure may not be reversible

Diarrhea is common and routine antidiarrheal agents are recommended to avoid electrolyte disturbances that may exacerbate risk of QT prolongation

Hypothyroidism: 90% of patients enrolled in clinical trials had prior thyroidectomy, 49% of patients randomized to vandetanib required increased thyroid doses compared with 17% of patients in the placebo arm

Hypertension, including hypertensive crisis may occur

The most common laboratory abnormalities (>20%) were decreased calcium, increased ALT, and decreased glucose

Hypersensitivity including anaphylaxis has been reported

Wound healing

• Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway
• Therapy has potential to adversely affect wound healing; withhold therapy for at least 1 month prior to elective surgery
• Do not administer therapy for at least 2 weeks following major surgery and until adequate wound healing
• Safety of resumption of treatment after resolution of wound healing complications not established

Reversible posterior leukoencephalopathy syndrome (RPLS)

• Syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has been observed
• This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function
• In clinical studies, 3 or 4 patients who developed RPLS while taking vandetanib, including one pediatric patient, also had hypertension
• Consider discontinuation of vandetanib treatment in patients with RPLS

Pregnancy

Based on mechanism of action, therapy can cause fetal harm when administered to a pregnant woman; drug is embryotoxic and fetotoxic

Animal data

• Drug induced fetal malformations in rats, at exposures less than or equal to those expected at recommended human dose of 300 mg/day; advise pregnant women of potential risk to fetus

Reproductive potential

• Therapy can cause fetal harm when administered to a pregnant woman; advise females of reproductive potential to use effective contraception during treatment and for 4 months after final dose
• There are no data on effect on human fertility; results from animal studies indicate that therapy can impair male and female fertility

Lactation

There are no data on presence of drug or its metabolites in human milk or effects on breastfed child or on milk production; drug was present in milk of lactating rats; because of potential for serious adverse reactions from drug in breastfed children, advise women not to breastfeed during therapy and for 4 months after final dose

Animal data

• In nonclinical studies, drug was excreted in rat milk and found in plasma of pups following dosing to lactating rats; drug transfer in breast milk resulted in relatively constant exposure in pups due to long half-life of drug

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Tyrosine kinase inhibitor (TKI) with selective activity against RET, VEGFR-2, and EGFR; TKI inhibition blocks angiogenesis and cellular proliferation

Absorption

Peak Plasma Time: 6 hr (range 4-10 hr)

Steady State: ~3 months; accumulates ~8-fold with multiple dosing

Distribution

Protein Bound: 90%

Vd: 7450 L

Metabolism

Metabolized by CYP3A4

Elimination

Half-Life: 19 days

Clearance: 13.2 L/hr

Excretion: feces (44%), urine (25%); 21 day collection period after single dose

Pharmacogenomics

There is no evidence of a relationship between RET mutations and efficacy of vandetanib

20% of medullary thyroid carcinomas are associated with 1 of 3 inherited endocrine syndromes caused by germline mutations of the RET gene RET encodes a receptor tyrosine kinase for the glial cell line-derived neurotrophic factor family of extracellular signaling molecules

A gain of function mutations are associated with cancer (eg. medullary thyroid carcinoma, multiple endocrine neoplasias)

Vandetanib has activity against RET as well as vascular endothelial growth factor (VEGF)