Vandetanib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2, 4, 5, 6, 7, 10
Vandetanib is used for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease;1, 2 designated an orphan drug by FDA for the treatment of this cancer.19
Use vandetanib in patients with indolent, asymptomatic, or slowly progressing disease only after careful consideration of the treatment-related risks of the drug.1
The current indication for vandetanib is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study in patients with unresectable locally advanced or metastatic medullary thyroid cancer.1, 2, 4 In this study, 331 patients were randomized in a 2:1 ratio to receive either vandetanib (300 mg) or placebo once daily until disease progression occurred.1, 4, 21 Upon disease progression, patients were eligible to receive open-label vandetanib; 19 or 58% of patients initially randomized to receive vandetanib or placebo, respectively, opted to receive open-label vandetanib.1 The median duration of treatment during the randomized phase of the study was 90.1 weeks for vandetanib-treated patients and 39.9 weeks for placebo-treated patients.3, 4 At the time of the primary analysis, patients receiving vandetanib experienced prolonged median progression-free survival (30.5 [predicted via a Weibull model] versus 19.3 months) and a higher overall objective response rate (45 versus 13%) compared with patients receiving placebo.4 Overall survival data were immature at analysis cutoff.1, 4
The American Thyroid Association (ATA) published a guideline on management of medullary thyroid cancer in 2015.102 Single agent or combination cytotoxic chemotherapy regimens in patients with medullary thyroid cancer is characterized by low response rates and short durations of response; therefore, single agent or combination cytotoxic chemotherapy regimens are not recommended as first-line therapy in patients with persistent or recurrent medullary thyroid cancer.102 Systemic therapy with tyrosine kinase inhibitors targeting both rearranged during transfection (RET) proto-oncogene and vascular endothelial growth factor receptor (VEGFR) should be considered in patients with significant tumor burden and symptomatic or progressive metastatic disease.102 The ATA states that cabozantinib or vandetanib can be used as single-agent first-line therapy in patients with advanced progressive disease.102 Other experts also recommend cabozantinib and vandetanib (both strong recommendations based on high-quality evidence) as first-line systemic therapy in patients with progressive metastatic medullary thyroid cancer.101
Dispensing and Administration Precautions
Administer vandetanib orally without regard to meals.1 Swallow vandetanib tablets whole and do not crush.1 If tablets are accidentally crushed, avoid direct contact with skin.1 If such contact occurs, wash the affected area thoroughly.1
If a dose is missed, do not take the missed dose if it is ≤12 hours until the next scheduled dose.1
If vandetanib tablets cannot be swallowed whole, the manufacturer states that the tablet may be dispersed in a glass containing 60 mL (2 ounces) of noncarbonated water; no other liquids should be used.1 Stir the water, without crushing the tablet, for approximately 10 minutes until the tablet is dispersed; the tablet will not completely dissolve.1 Swallow the aqueous dispersion immediately; to ensure the full dose is administered, mix any residue in the glass with an additional 120 mL (4 ounces) of noncarbonated water and swallow.1 The aqueous dispersion also may be administered through a nasogastric or gastrostomy tube.1
Follow procedures for proper handling and disposal of antineoplastic drugs when preparing or administering vandetanib.1
The recommended adult dosage of vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease is 300 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If grade 3 or greater toxicity occurs, interrupt vandetanib therapy.1 When the toxicity resolves or improves to grade 1, vandetanib may be resumed at a reduced dosage.1 Reduce the dosage of vandetanib in decrements of 100 mg daily (i.e., from 300 to 200 mg daily, from 200 to 100 mg daily).1
Dosage Modification for Cardiovascular Toxicity
Interrupt vandetanib therapy if the QT interval (corrected for heart rate using Fridericia's formula [QTcF]) exceeds 500 msec.1 When QTcF returns to less than 450 msec, vandetanib may be resumed at a reduced dosage.1
If hypertension occurs, dosage reduction or temporary interruption of vandetanib therapy may be necessary to control blood pressure. 1 If hypertension cannot be controlled, vandetanib should not be resumed.1
If heart failure occurs, consider discontinuation of vandetanib therapy.1
Dosage Modification for Dermatologic Toxicity
If severe skin reactions occur, permanently discontinue vandetanib therapy and refer the patient for urgent medical evaluation.1 Systemic therapy (e.g., corticosteroids) may be required.1
Dosage Modification for Diarrhea
If severe diarrhea occurs, interrupt vandetanib therapy.1 When diarrhea improves, vandetanib may be resumed at a reduced dosage.1
Vandetanib should not be used in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.1
Reduce the initial dosage of vandetanib to 200 mg once daily in patients with moderate (creatinine clearance of 30-49 mL/minute) renal impairment.1 Vandetanib is not recommended for use in patients with severe (creatinine clearance less than 30 mL/minute) renal impairment.1 There is no information on use of vandetanib in patients with end-stage renal disease requiring dialysis.1
The manufacturer makes no specific dosage recommendations in patients ≥65 years of age.1
Prolongation of QT Interval and Torsades de Pointes
The prescribing information of vandetanib contains a boxed warning regarding the risk of QT prolongation, torsade de pointes, and sudden death.1 Vandetanib prolongs the QT interval in a concentration-dependent manner.1 Torsades de pointes, ventricular tachycardia, and sudden death have been reported in patients receiving vandetanib.1 In the phase 3 clinical study, patients randomized to receive vandetanib (300 once daily) had a mean increase in the QT interval (corrected for heart rate using Fridericia's formula [QTcF]) of 35 msec (range: 33-36 msec) from baseline; this increase in QTcF remained above 30 msec for the duration of the study (up to 2 years).1 In addition, an increase in QTcF of more than 60 msec from baseline occurred in 36% of patients receiving vandetanib, and QTcF exceeded 450 msec or 500 msec in 69 or 7% of patients, respectively.1
Vandetanib should not be initiated in patients with QTcF exceeding 450 msec.1 The drug should not be used in patients who have a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure, or in patients with electrolyte disturbances; hypocalcemia, hypokalemia, and/or hypomagnesemia must be corrected prior to administration of vandetanib.1 Vandetanib has not been evaluated in patients with ventricular arrhythmias or recent myocardial infarction (MI).1
Measure ECG, serum electrolytes (i.e., calcium, magnesium, potassium), and thyroid-stimulating hormone (TSH) concentrations at baseline, at 2-4 weeks and 8-12 weeks after initiating vandetanib, and then every 3 months thereafter.1 Following dosage reduction for QT prolongation or therapy interruption lasting longer than 2 weeks, monitor ECG as described above.1 Serum potassium concentrations should be at least 4 mEq/L (within normal range), and serum magnesium and calcium concentrations should be maintained within normal ranges, to reduce the risk of QT interval prolongation.1 Monitor electrolytes and ECG more frequently in patients who experience diarrhea.1 Concomitant use of vandetanib with drugs known to prolong the QT interval should be avoided .1 If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended.1
Vandetanib exposure is increased in patients with impaired renal function.1 Reduce the initial dose of vandetanib to 200 mg in patients with moderate renal impairment and monitor the QT interval frequently.1
Interrupt vandetanib therapy if QTcF exceeds 500 msec.1 When QTcF returns to less than 450 msec, vandetanib may be resumed at a reduced dosage.1
Other Warnings and Precautions
Severe skin reactions (including toxic epidermal necrolysis [TEN] and Stevens-Johnson syndrome), some resulting in death, have been reported in patients receiving vandetanib.1 If severe skin reactions occur, permanently discontinue vandetanib therapy and refer the patient for urgent medical evaluation.1 Systemic therapy (e.g., corticosteroids) may be required.1
Photosensitivity reactions, occurring during therapy and up to 4 months after treatment discontinuation, may also occur.1
Interstitial lung disease or pneumonitis, sometimes fatal, has been reported in patients receiving vandetanib.1 The mechanism of action of this adverse effect is unknown; however, review of available data (including data in patients receiving vandetanib for non-small cell lung cancer†) suggested that Japanese ethnicity, history of smoking, coincidence of interstitial pneumonia, preexisting pulmonary fibrosis, male gender, and previous radiation or chemotherapy may be possible risk factors for developing interstitial lung disease.3
Interstitial lung disease should be considered in patients presenting with nonspecific respiratory signs or symptoms.1 If pulmonary symptoms are acute or worsening, interrupt vandetanib therapy.1 If interstitial lung disease is confirmed, discontinue vandetanib.1
Ischemic Cerebrovascular Events
Ischemic cerebrovascular events, sometimes fatal, have been reported with vandetanib.1 In the phase 3 clinical study, ischemic cerebrovascular events were observed more frequently with vandetanib compared with placebo (1.3 versus 0%);1 all ischemic cerebrovascular events reported in this study were grade 3.3 Vandetanib should be discontinued in patients who experience a severe ischemic cerebrovascular event.1 The safety of resumption of vandetanib therapy after resolution of an ischemic cerebrovascular event has not been studied.1
Serious hemorrhagic events, sometimes fatal, have been reported with vandetanib.1 Vandetanib should not be used in patients with a recent history of hemoptysis (2.5 mL of red blood or more).1 Vandetanib should be discontinued in patients with severe hemorrhage.1
Heart failure, sometimes fatal, has been reported with vandetanib use.1 In the phase 3 clinical study, heart failure occurred in 0.9% of patients receiving vandetanib compared with 0% of those receiving placebo.1 Monitor patients for manifestations of heart failure.1 If heart failure occurs, discontinuance of vandetanib may be necessary; heart failure may not be reversible following discontinuance of vandetanib.1
Hypertension and hypertensive crisis have been reported in 33% of patients receiving vandetanib.1 Monitor blood pressure in all patients and control as appropriate.1 Dosage reduction or temporary interruption of vandetanib therapy may be necessary.1 If hypertension cannot be controlled, vandetanib should not be resumed.1
Diarrhea has been reported in patients receiving vandetanib.1 In the phase 3 clinical study, diarrhea or colitis (all grades) was reported in 57% and grade 3-4 diarrhea or colitis was reported in 11% of patients receiving vandetanib.1 Because diarrhea may cause electrolyte imbalances, and because QT interval prolongation has been reported in patients receiving vandetanib, the manufacturer recommends careful and more frequent monitoring of serum electrolytes and ECG in patients who develop diarrhea.1 If severe diarrhea occurs, interrupt vandetanib therapy.1 When symptoms improve, resume vandetanib at a reduced dosage.1
In the phase 3 clinical study in which 90% of enrolled patients had prior thyroidectomy, increases in the dosages of thyroid replacement therapy were required in 49% of patients receiving vandetanib compared with 17% of patients receiving placebo.1
Monitor TSH concentrations at baseline, at 2-4 weeks and 8-12 weeks after initiating vandetanib, and then every 3 months thereafter.1 If manifestations of hypothyroidism occur, examine thyroid hormone concentrations and adjust thyroid replacement therapy accordingly.1
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in patients receiving vandetanib.1
Consider RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.1 In clinical studies, 3 of the 4 patients who developed RPLS also had hypertension.1 Discontinue vandetanib if RPLS occurs.1
Renal failure has been reported in patients administered vandetanib.1 Withhold, reduce the dose, or permanently discontinue therapy based on severity.1
In moderate renal impairment, reduce the starting dose of vandetanib.1 In severe renal impairment, vandetanib is not recommended for use.1
Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway such as vandetanib.1
The manufacturer recommends discontinuing vandetanib at least 1 month prior to scheduled surgery.1 Do not administer vandetanib for at least 2 weeks following major surgery and until adequate wound healing has occurred.1
The safety of resuming vandetanib after resolution of wound healing complications has not been established.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and animal findings, vandetanib may cause fetal harm if administered to pregnant women; the drug has been shown to be embryotoxic, fetotoxic, and teratogenic in animals.1
Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with vandetanib and for 4 months following the last dose.1 If vandetanib is used during pregnancy or if the patient becomes pregnant while receiving the drug, apprise the patient of the potential fetal hazard.1
Osteonecrosis, including osteonecrosis of the jaw, has been reported with therapy.1 The risk of osteonecrosis of the jaw may be increased with concomitant exposure to other risk factors (e.g., bisphosphonates, denosumab, dental disease, invasive dental procedures).1 An oral examination should be performed prior to initiation of vandetanib therapy and periodically during treatment.1 Patients should be educated regarding good oral hygiene practices and counseled to avoid invasive dental procedures during therapy, particularly for those patients seen as higher risk.1 Vandetanib should be withheld for at least 1 month prior to dental procedures and permanently discontinued if osteonecrosis of the jaw develops.1
Based on its mechanism of action and animal findings, vandetanib can cause fetal harm when administered to a pregnant woman.1 In animal studies, vandetanib was embryotoxic, fetotoxic, and teratogenic at exposures equivalent to or lower than those expected at the 300-mg clinical dose; adverse effects on female fertility, embryofetal development, and postnatal development of pups also were observed.1
Advise patients of the potential hazard to a fetus.1 Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with vandetanib and for 4 months following the last dose.1
Vandetanib is distributed into milk in rats.1 It is not known whether vandetanib or its metabolites are distributed into human milk.1 The effects of vandetanib on the breast-fed child or on milk production are also unknown.1 Because of the potential for serious adverse reactions to vandetanib in nursing infants, advise females not to breast-feed during vandetanib therapy and for 4 months after the final dose.1
Females and Males of Reproductive Potential
Verify the pregnancy status of females of reproductive potential prior to initiating treatment with vandetanib.1 Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with vandetanib and for 4 months after the final dose.1
There are no data on the effects of vandetanib on human fertility.1 Based on animal studies, vandetanib may impair male and female fertility.1
Safety and efficacy of vandetanib have not been established in pediatric patients.1
The phase 3 clinical study in patients with medullary thyroid cancer did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger patients.1
In a pharmacokinetic study in which a limited number of individuals received a single 800-mg dose of vandetanib, mean area under the plasma concentration-time curve (AUC) and clearance of the drug were comparable between individuals with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment and individuals with normal hepatic function.1 There are limited data in patients with serum bilirubin concentrations exceeding 1.5 times the upper limit of normal (ULN).1
Because safety and efficacy of vandetanib have not been established, use of the drug is not recommended in patients with moderate or severe hepatic impairment.1
In a pharmacokinetic study in which a limited number of individuals received a single 800-mg dose of vandetanib, mean AUC and clearance of the drug were comparable between individuals with mild renal impairment and individuals with normal renal function; however, in individuals with moderate or severe renal impairment, mean AUC of vandetanib was increased by 39 or 41%, respectively, compared with individuals with normal renal function.1
Patients with moderate renal impairment should receive a lower initial dosage of vandetanib; closely monitor ECG in these patients.1 Vandetanib is not recommended for use in patients with severe renal impairment.1
Vandetanib has not been evaluated systematically in patients with end-stage renal disease requiring dialysis.1
Adverse effects reported in more than 20% of patients receiving vandetanib include diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infections, decreased appetite, abdominal pain, hypocalcemia, increased ALT concentrations, and hypoglycemia.1
Drugs Affecting Hepatic Microsomal Enzymes
Concomitant use of vandetanib with a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) (i.e., itraconazole) resulted in no clinically important interaction.1
Inducers of CYP3A4 can alter plasma vandetanib concentrations.1 Concomitant use of vandetanib with potent CYP3A4 inducers (e.g., rifampin) should be avoided .1 In healthy subjects receiving a single oral 300-mg dose of vandetanib on day 1 and day 10 in combination with rifampin 600 mg daily on days 1-31, a 40% decrease in mean AUC of vandetanib, with no clinically meaningful change in mean maximum peak vandetanib concentrations, was observed; in addition, mean AUC and peak plasma concentrations of N -desmethylvandetanib increased by 266% and 414%, respectively.1 St. John's wort ( Hypericum perforatum ) may unpredictably decrease vandetanib exposure, and concomitant use of vandetanib with this agent also should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
No effects on the mean peak plasma concentration and AUC of midazolam were observed when a single oral 7.5-mg dose of midazolam (a sensitive CYP3A4 substrate) was administered 8 days after a single 800-mg oral dose of vandetanib in healthy subjects.1
Drugs that Prolong the QT Interval
Concomitant use of vandetanib with drugs known to prolong the QT interval, including class Ia (e.g., disopyramide, procainamide, quinidine) and class III (e.g., amiodarone, sotalol, dofetilide) antiarrhythmic agents, some anti-infectives (e.g., clarithromycin, moxifloxacin), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, olanzapine, pimozide, quetiapine, ziprasidone), some type 3 serotonin (5-HT3) receptor antagonists used as antiemetic agents (e.g., dolasetron, granisetron, ondansetron), chloroquine, and methadone should be avoided .1, 3, 13, 15 If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended.1 If a 5-HT3 receptor antagonist is clinically necessary, some clinicians prefer granisetron because its effects on ECG intervals are less pronounced than those observed with dolasetron or ondansetron.15
Drugs Affecting Organic Cation Transporter Type 2
Vandetanib increased plasma concentrations of metformin, which is transported by organic cation transporter type 2 (OCT2).1 An increase of 74 and 50% in the mean AUC and peak plasma concentration, respectively, of metformin was observed when metformin (single 1-g dose) was administered 3 hours after vandetanib (single 800-mg dose) in healthy subjects.1 Use with caution and closely monitor for toxicities when vandetanib is used concomitantly with drugs that are transported by OCT2.1
Vandetanib increased plasma concentrations of digoxin (a P-glycoprotein [P-gp] substrate).1 Digoxin peak plasma concentrations and mean AUC increased by 29 and 23%, respectively, in healthy subjects receiving digoxin (single 0.25-mg dose) in combination with vandetanib (single 300-mg dose).1 Use with caution and closely monitor for digoxin toxicity when vandetanib is used concomitantly with digoxin.1
No clinically meaningful effects on the mean AUC and peak plasma concentration of vandetanib were observed when vandetanib (single 300-mg dose) was administered alone and in combination with omeprazole (40 mg once daily for 5 days) in healthy subjects.1
Vandetanib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2, 4, 5, 6, 7, 10 Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.7, 16 Various tyrosine kinases and pathways are abnormally activated in medullary thyroid carcinoma cells (e.g., rearranged during transfection [RET] proto-oncogene signaling is associated with development of hereditary medullary thyroid cancer).8, 16 In vitro studies have shown that vandetanib inhibits the activity of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), members of the epidermal growth factor receptor (EGFR) family, RET, protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptor kinase family, and members of the Src family of tyrosine kinases.1, 2, 7, 8, 16 The N -desmethyl metabolite of the drug, which represents 7 to 17.1% of vandetanib exposure, has similar inhibitory activity to the parent compound for VEGF receptors (KDR and Flt-1) and EGFR.1 In vivo , vandetanib has been shown to reduce tumor cell-induced angiogenesis and tumor vessel permeability; the drug also has been shown to inhibit tumor growth and metastasis in mouse models of cancer.1
Vandetanib is partially metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1 Approximately 44 or 25% of an oral dose of the drug is excreted in feces or urine, respectively, as unchanged drug or metabolites.1 The median plasma half-life of vandetanib is 19 days.1 Limited data indicate that systemic exposure to vandetanib is higher in Japanese and Chinese patients than in Caucasian patients receiving the same dose.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 100 mg | Genzyme Corporation | |
300 mg | Caprelsa® | Genzyme Corporation |
1. Genzyme Corporation. Caprelsa® (vandetanib) tablets prescribing information. Cambridge, MA; 2025 May. [Web]
2. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 022405: Summary review. 2011 Apr 1. From FDA website. [Web]
3. AstraZeneca Pharmaceuticals LP. Wilmington, DE: Personal communication.
4. Wells SA, Robinson BG, Gagel RF et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol . 2011;30:134-141..
5. Wells SA, Gosnell JE, Gagel RF et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol . 2010; 28:767-72. [PubMed 20065189]
6. Robinson BG, Paz-Ares L, Krebs A et al. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab . 2010; 95:2664-71. [PubMed 20371662]
7. Morabito A, Piccirillo MC, Falasconi F et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. Oncologist . 2009; 14:378-90. [PubMed 19349511]
8. Gómez K, Varghese J, Jiménez C. Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. J Thyroid Res . 2011; 2011:815826. [PubMed 21687607]
10. Herbst RS, Heymach JV, O'Reilly MS et al. Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs . 2007; 16:239-49. [PubMed 17243944]
13. Stollberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol . 2005;20:243-51. [PubMed 16096514]
15. Keefe DL. The cardiotoxic potential of the 5-HT(3) receptor antagonist antiemetics: is there cause for concern?. Oncologist . 2002; 7:65-72. [PubMed 11854548]
16. Morabito A, Piccirillo MC, Costanzo R et al. Vandetanib: An overview of its clinical development in NSCLC and other tumors. Drugs Today (Barc) . 2010; 46:683-98. [PubMed 20967300]
19. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site. [Web]
21. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 022405: Medical Review(s). 2011 Mar 24. From FDA website. [Web]
101. Filetti S, Durante C, Hartl D et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol . 2019; 30:1856-1883. [PubMed 31549998]
102. Wells SA Jr, Asa SL, Dralle H et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid . 2015; 25:567-610. [PubMed 25810047]