Dosing & Uses
Dosage Forms & Strengths
tablet
- 100mg
- 300mg
Medullary Thyroid Cancer
Indicated for treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease
300 mg PO qDay with or without food
Continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs
Dose Reduction
- Dose reduction may be necessary with emergence of severe toxicities or QTc interval prolongation
- In event of QTc interval >500 ms, interrupt dosing until <450 ms, then resume at a reduced dose
- In the presence of CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or greater, interrupt dosing until toxicity resolves or improves to grade 1, then resume at reduced dose
- 300 mg daily dose may be reduced to 200 mg/day and then 100 mg for CTCAE grade 3 or greater
Renal and Hepatic Impairment
CrCl 50 mL/min or greater: Dose adjustment not necessary
Moderate (CrCl 30 to <50 mL/min) to severe (CrCl <30 mL/min) renal impairment: Reduce starting dose to 200 mg PO qDay
Hepatic Impairment
Mild liver impairment: Dose adjustment not described in manufacturer's label
Moderate-to-severe liver impairment (Child-Pugh B/C): Not recommended because of limited data
Administration
If a patient misses a dose, the missed dose should not be taken if it is <12 hours before the next dose
Vandetanib tablets should not be crushed
Only available via restricted access prescribing and dispensing program, to enroll in the Vandetanib REMS Program, call 1-800-817-2722 or visit www.vandetanibrems.com
Dispersing tablets in water to aid swallowing
- If patient unable to swallow tablet whole, disperse tablet in 2 ounces of noncarbonated water and stir for approximately 10 minutes until the tablet is dispersed (will not completely dissolve); no other liquids besides water should be used
- The dispersion should be swallowed immediately
- To ensure the full dose is received, any residues in the glass should be mixed again with an additional 4 ounces of noncarbonated water and swallowed
- The dispersion can also be administered via NG or GT
- Avoid direct contact of crushed tablets with the skin or mucous membranes; if contact occurs, wash thoroughly
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>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
Warnings
Black Box Warnings
Can prolong the QT interval
Torsades de pointes and sudden death have been reported
Should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome
Hypocalcemia, hypokalemia, and/or hypomagnesemia must be corrected prior to administration and should be periodically monitored
Drugs known to prolong QT interval should be avoided
If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended
Given the half-life of 19 days, ECGs should be obtained to monitor the QT at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter
Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessment should be conducted as described above
Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly
Monitor appropriately
Because of risks of QT prolongation, Torsades de pointes, and sudden death, therapy available only through restricted distribution program called the CAPRELSA REMS Program. 1-800-236-9933 or visit www.caprelsarems.com
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
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 & Lactation
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.
Pharmacology
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)
Images
Patient Handout
Formulary
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