Vandetanib is an inhibitor of multiple tyrosine kinase families, including VEGFR-2 (vascular endothelial growth factor receptor-2), EGFR (epidermal growth factor receptor), and the RET (rearranged during transfection) proto-oncogene, which affects angiogenesis and cell survival. Approval in unresectable thyroid cancer is based on a significant improvement in progression-free survival at 2 years versus placebo. No significant difference in overall survival has been observed. Vandetanib is only available through a restricted distribution program.
Metabolized by CYP3A4 to N-desmethyl vandetanib and by monooxygenase enzymes FMO1 and FMO3 to vandetanib-N-oxide. Glucuronide conjugate is a minor metabolite.
|Active metabolites||N-desmethyl vandetanib|
|Inactive metabolites||vandetanib-N-oxide and others|
Within 21 days, about 69% of a dose is recovered in feces (44%) and in urine (25%). Due to the long half-life of the drug, elimination may continue beyond 21 days. Vandetanib may inhibit its renal excretion via hOCT2. No clear difference in clearance with respect to age and gender.
- indicated for the treatment of symptomatic or progressive medullary thyroid cancer in adult patients with unresectable locally advanced or metastatic disease
(Note: Approval was based on improvement in progression free survival; overall survival benefit has not been demonstrated.)
Extravasation Potential: Not applicable
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Cardiovascular||Arterial thromboembolism (1%)||E|
|Artery aneurysm (rare)||E D L|
|Artery dissection (rare)||E D L|
|Cardiotoxicity (heart failure < 1%)||D|
|Hypertension (32%) (2% severe)||E|
|QT interval prolonged (14%) (± arrhythmia)||E|
|Venous thromboembolism (rare)||E|
|Nail disorder (<10%)||E|
|Rash (45%) (may be severe - SJS, TEN)||E|
|Gastrointestinal||Abdominal pain (14%)||E|
|Anorexia, weight loss (21%)||E|
|Diarrhea (56%) (11% severe)||E|
|GI perforation (rare)||E|
|Nausea, vomiting (33%)||I|
|General||Delayed wound healing||E|
|Myelosuppression ± infection, bleeding (10%)||E|
|Hepatobiliary||↑ LFTs (51%)||E|
|Metabolic / Endocrine||Abnormal electrolyte(s) (57%) (↑/↓ Ca, ↓K, ↓Na, Mg)||E|
|Nervous System||Depression (1%)||E|
|RPLS / PRES (<1%)||E|
|Ophthalmic||Other - corneal opacity (5%)||E|
|Renal||Nephrotoxicity (17%) (may be severe)||E|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for vandetanib include abnormal electrolyte(s), diarrhea, ↑ LFTs, abdominal pain, rash, nausea/vomiting, hypertension, headache and fatigue.
QT prolongation appears to be dose-dependent. The average change from baseline was 35ms and 7% of patients had QTcF > 500 ms. Due to the 19 day half-life, QT prolongation may not resolve quickly. Serum potassium should be maintained at 4 mEq/L or higher; magnesium and calcium levels should be kept within normal range. Hypertensive crisis has been observed. Cardiotoxicity has been reported and may not be reversible after vandetanib discontinuation.
Severe cases of artery dissection (with or without hypertension) and artery aneurysm (including rupture) have been reported in patients using VEGFR TKIs.
LFTs usually resolve while continuing treatment with vandetanib, while others usually recover after withholding treatment for 1-2 weeks.
Vandetanib slows but does not prevent wound healing. The appropriate time period between discontinuing vandetanib and subsequent surgery is not known.
Patients taking vandetanib have a potential for photosensitivity upon sun exposure. Patients should wear protective clothing and/or sunblock during vandetanib treatment and for 4 months after the last dose.
Fatal cases of hemorrhage, hepatic failure, skin reactions or ILD have been reported.
Refer to protocol by which patient is being treated. Potassium, calcium and magnesium levels should be corrected before starting treatment, Patients should be provided with loperamide and instructions on how to manage diarrhea.
Action for Vandetanib
Grade 1 or 2 skin reactions
Treat symptomatically or by ↓ dose
Grade 3 or 4 skin toxicity
Treat symptomatically and hold until ≤ grade 1, then ↓ 1 dose level
|Toxicity (Continued)||Action for Vandetanib|
Grade 3 or 4 hypertension
Hold; control blood pressure medically. Consider ↓ dose
Grade 1 or 2 diarrhea
Treat symptomatically with loperamide and hydration.
Grade 3 or 4 diarrhea
Hold until grade 1, then ↓ 1 dose level.
Hemoptysis (≥ 2.5mL)
Hold until resolved. Consider discontinuing
QTcF ≥ 500 ms
Hold until QTcF <450 ms then ↓ 1 dose level; consider cardiology consult
Radiological changes suggestive of pneumonitis
Investigate. If mild may continue treatment ± corticosteroids / antibiotics during investigation; otherwise hold. If pneumonitis confirmed, discontinue.
Signs of symptoms of hypothyroidism
Adjust thyroid replacement therapy. Monitor TSH.
Grade 3 or 4 LFTs
Hold until grade 1. Consider ↓ dose.
Other grade 3 or 4 related organ toxicity
Hold until grade 1, then ↓ 1 dose level.
Not recommended for use in patients with moderate and severe hepatic impairment (Child Pugh B and C). Limited data exist in patients with bilirubin >1.5 x ULN.
Exposure is increased in patients with renal impairment. The patient and QTcF must be closely monitored.
|Creatinine Clearance (mL/min)||Starting Daily Dose|
|≥ 50||300 mg|
No adjustment in starting dose is required. Limited data in patients over 75 years of age.
No pediatric indications. Safety and efficacy have not been established.
- Vandetanib may be taken with or without meals
- Avoid products and juices containing grapefruit, star fruit, pomegranate, Seville oranges or other similar fruits that can inhibit CYP3A4.
- Take the dose at about the same time each day. Swallow whole; do not crush or chew.
- If the patient has difficulty swallowing the tablet(s), may mix it with water as follows:
- a) Put the whole tablet into half a glass (50mL) of non-carbonated water. Do not use other liquids.
- b) Stir the water until the tablet disintegrates. This may take about 10 minutes.
- c) Drink the mixture immediately.
- d) Rinse the empty glass well with another half a glass of water and drink it.
- e) (This liquid mixture can also be given through nasogastric or gastrostomy tubes.)
- If a dose is missed, give it if it is within 12 hours from the missed dose, otherwise skip and give the next dose as scheduled.
- Store vandetanib at room temperature.
- Congenital long QT syndrome or with a persistent QTcF of ≥500ms.
- Uncorrected hypokalemia, hypomagnesemia or hypocalcemia
- Uncontrolled hypertension or heart failure
- Patients with a recent history of hemoptysis of ≥ half teaspoon of red blood, or patients with moderate or severe hepatic impairment
- Patients who have a hypersensitivity to this drug or any of its components
- Do not give vandetanib to patients with a history of Torsade de Pointes (unless all risk factors have been corrected), bradyarrhythmias or uncompensated heart failure.
- Patients must avoid sun exposure for 4 months after the last dose of vandetanib
- Vandetanib can only be prescribed or dispensed by physicians and pharmacies who have been certified under the Caprelsa® restricted distribution program. Patients must enrol and comply with the requirements of this program before receiving vandetanib.
Other Drug Properties:
Documented in animals
Documented in animals
Documented in animals
Vandetanib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 3 months (for women) and 2 months (for men) after the last vandetanib dose.
Excretion into breast milk:
Breastfeeding is not recommended.
|Drugs that may prolong QT (i.e. Amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc)||↑ risk of QT prolongation||Additive||Avoid; if no alternative treatment exists, close QT monitoring should be performed|
|CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc)||↓ vandetanib concentration and exposure||↑ metabolism of vandetanib||Avoid; consider alternative drugs|
|CYP3A4 inhibitors (i.e. ketoconazole, voriconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges, starfruit or pomegranate )||↑ vandetanib exposure and ↓ clearance (theoretical)||↓ metabolism of vandetanib||Avoid; consider alternative drugs|
|Cisplatin||↑ cisplatin exposure||Possible accumulation of total platinum||Caution|
|P-glycoprotein substrates (i.e. verapamil, digoxin, morphine, ondansetron)||Potential to ↑ exposure of Pgp substrates (up to 23% for digoxin)||Vandetanib inhibits Pgp||Caution; monitor closely; substrate dose adjustment may be required|
|OCT2 substrates (e.g. metformin)||Potential to ↓ elimination or ↑ exposure (up to 74%) of drugs excreted by OCT2||Vandetanib inhibits OCT2||Caution; monitor closely; substrate dose adjustment may be required|
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
|Monitor Type||Monitor Frequency|
QTcF and blood pressure
|at baseline, 2-4 weeks and 8-12 weeks during treatment, and q3 months thereafter, also after dose adjustments|
|Electrolytes (including calcium, potassium, magnesium) and TSH||at baseline, 2-4 weeks and 8-12 weeks during treatment, then q3 months thereafter, also after dose adjustments|
|Liver function tests||Baseline and regular|
Clinical toxicity assessment for rash, hypertension, wound healing, diarrhea, arterial/venous thromboembolism, bleeding, neurologic, cardiovascular, ophthalmic and respiratory side effects
|At each visit|
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
|Monitor Type||Monitor Frequency|
|Renal function tests||Baseline and regular|
Exceptional Access Program (EAP Website)
- vanDETanib - Monotherapy for symptomatic and/or progressive medullary thyroid cancer (MTC), with specific criteria
Product Monograph: Caprelsa® (vandetanib). AstraZeneca Canada, December 8, 2016.
Product Monograph: Caprelsa® (vandetanib). AstraZeneca US, June 2011.
Product Monograph Update: Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs). Health Canada InfoWatch, June 2020.
Commander H, Whiteside G, Perry C. Vandetanib: first global approval. Drugs 2011;71(10):1355-68.
Martin P, Oliver S, Robertson J, et al. Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole. Drugs R D 2011;11(1):37-51.
September 2020 Updated adverse effects (artery aneurysm / dissection) based on Health Canada InfoWatch
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