Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
vanDETanib
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.
| PPB | 94% |
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.
| Half-life | 19 days |
- Thyroid cancer
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
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 | ||||
| Dermatological | Alopecia (<10%) | E | |||
| Nail disorder (<10%) | E | ||||
| Photosensitivity (13%) | E | ||||
| Rash (45%) (may be severe - SJS, TEN) | E | ||||
| Gastrointestinal | Abdominal pain (14%) | E | |||
| Anorexia, weight loss (21%) | E | ||||
| Diarrhea (56%) (11% severe) | E | ||||
| Dyspepsia (11%) | E | ||||
| GI perforation (rare) | E | ||||
| Mucositis (<1%) | E | ||||
| Nausea, vomiting (33%) | I | ||||
| General | Delayed wound healing | E | |||
| Fatigue (24%) | E | ||||
| Hematological | Hemorrhage (<1%) | E | |||
| Myelosuppression ± infection, bleeding (10%) | E | ||||
| Hepatobiliary | ↑ LFTs (51%) | E | |||
| Pancreatitis (rare) | E | ||||
| Metabolic / Endocrine | Abnormal electrolyte(s) (57%) (↑/↓ Ca, ↓K, ↓Na, Mg) | E | |||
| Hypothyroidism (49%) | E | ||||
| Nervous System | Depression (1%) | E | |||
| Headache (26%) | E | ||||
| Insomnia (13%) | E | ||||
| Posterior reversible leukoencephalopathy syndrome (PRES) (<1%) | E | ||||
| Tremor (<10%) | E | ||||
| Ophthalmic | Other - corneal opacity (5%) | E | |||
| Renal | Nephrotoxicity (17%) (may be severe) | E | |||
| Respiratory | Cough (11%) | E | |||
| Pneumonitis (<1%) | D | ||||
* "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.
Hold vandetanib for at least 1 month before elective surgery. Do not administer vandetanib for at least 2 weeks after major surgery and until adequate wound healing.
|
Toxicity
|
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 |
|
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. |
|
Discontinue
|
|
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.
Vandetanib is not recommended for use in patients with severe renal impairment (clearance below 30 mL/min).
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 |
| 30-49 | 200 mg |
| <30 | Not recommended for use |
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:
-
Carcinogenicity:
Unknown
-
Fetotoxicity:
Documented in animals
-
Embryotoxicity:
Documented in animals
-
Teratogenicity:
Documented in animals
-
Fertility effects:
Probable
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. -
Mutagenicity:
No
-
Clastogenicity:
No
-
Genotoxicity:
No
-
Excretion into breast milk:
Yes
Breastfeeding is not recommended.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| 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 2016 and April 2022.
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.
July 2022 Modified Dose modifications and Dosage in renal impairment sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.