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Vandetanib

Medically reviewed by Drugs.com. Last updated on Aug 1, 2020.

Pronunciation

(van DET a nib)

Index Terms

  • AZD6474
  • Zactima
  • ZD6474
  • Zictifa

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Caprelsa: 100 mg, 300 mg

Brand Names: U.S.

  • Caprelsa

Pharmacologic Category

  • Antineoplastic Agent, Epidermal Growth Factor Receptor (EGFR) Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Vandetanib is a multikinase inhibitor; it inhibits tyrosine kinases including epidermal growth factor reception (EGFR), vascular endothelial growth factor (VEGF), rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, EPH kinase receptors and SRC kinase receptors, selectively blocking intracellular signaling, angiogenesis and cellular proliferation

Absorption

Slow

Distribution

Vd: ~7450 L

Metabolism

Hepatic, via CYP3A4 to N-desmethyl vandetanib and via flavin-containing monooxygenase enzymes to vandetanib-N-oxide

Excretion

Feces (~44%); urine (~25%)

Time to Peak

6 hours (range: 4 to 10 hours)

Half-Life Elimination

19 days

Protein Binding

~90%; to albumin and alpha 1-acid-glycoprotein

Special Populations: Renal Function Impairment

In subjects with moderate (CrCl 30 to <50 mL/minute) and severe (CrCl <30 mL/minute) renal impairment, the average AUC of vandetanib increased by 39% and 41%, respectively.

Special Populations: Race

Japanese and Chinese patients had, on average, exposures that were higher than in white patients receiving the same dose.

Use: Labeled Indications

Thyroid cancer, medullary (locally advanced or metastatic): Treatment of metastatic or unresectable locally-advanced medullary thyroid cancer (symptomatic or progressive).

Limitation of use: Use in indolent, asymptomatic, or slowly progressing disease only after careful considerations of vandetanib treatment-related risks.

Contraindications

Congenital long QT syndrome

Canadian labeling: Additional contraindications (not in the US labeling): Known hypersensitivity to vandetanib or any component of the formulation; persistent Fridericia-corrected QT interval (QTcF) ≥500 msec; uncorrected hypokalemia, hypomagnesemia, or hypocalcemia; uncontrolled hypertension

Dosing: Adult

Note: Do not initiate treatment unless QTcF ≤450 msec. To reduce the risk of QT prolongation, maintain serum calcium and magnesium within normal limits and maintain serum potassium ≥4 mEq/L. Temporarily withhold vandetanib for at least 1 month prior to elective surgery; do not administer vandetanib for at least 2 weeks following major surgery and until adequate wound healing.

Thyroid cancer, medullary (locally advanced or metastatic): Oral: 300 mg once daily, continue until disease progression or unacceptable toxicity (Wells 2012).

Missed dose: Do not administer a missed dose within 12 hours of the next dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Toxicity ≥ grade 3: Interrupt dose until resolves or improves to grade 1, then resume at a reduced dose

Dosage reduction: Reduce from 300 mg once daily to 200 mg once daily, further reduce if needed to 100 mg once daily. For recurrent toxicities, withhold vandetanib until symptom improvement to ≤ grade 1 toxicity, then if continued treatment is warranted, reduce dose to 100 mg once daily. Due to the long half-life, adverse reactions (including prolonged QT interval) may not resolve quickly; monitor closely.

Management of specific toxicities:

Cardiac: QTcF >500 msec: Withhold dose until QTcF returns to <450 msec, then resume at a reduced dose

Dermatologic toxicity: Withhold treatment for dermatologic toxicity of grade 3 or higher. Consider a reduced dose or permanent discontinuation upon improvement in symptoms. Permanently discontinue for severe dermatologic toxicity; may require systemic corticosteroid therapy.

Diarrhea (severe): Withhold treatment until resolution. Dose reduction is recommended when treatment is resumed. Closely monitor electrolytes and ECGs to detect QT prolongation resulting from dehydration.

Heart failure: May require discontinuation.

Hemorrhage (severe): Discontinue.

Hypertension: Initiate or adjust antihypertensive therapy as needed; may require vandetanib dosage adjustment or treatment interruption; discontinue permanently if blood pressure cannot be adequately controlled.

Interstitial lung disease (ILD)/pneumonitis: Interrupt therapy for acute or worsening pulmonary symptoms. Discontinue if ILD diagnosis is confirmed.

Ischemic cerebrovascular events (severe): Discontinue treatment (safety of resuming treatment after an ischemic event has not been studied).

Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue treatment.

Extemporaneously Prepared

An oral solution may be prepared using the tablet. Disperse tablet(s) in 2 ounces of water (noncarbonated only) and stir for ∼10 minutes to disperse (will not dissolve completely) and administer immediately. Rinse residue in glass with additional 4 ounces of water (noncarbonated only) and administer.

Administration

May administer with or without food. Do not crush tablet. If unable to swallow tablet whole or if NG or gastrostomy tube administration is necessary, disperse tablet(s) in 2 ounces of water (noncarbonated only) and stir for 10 minutes to disperse (will not dissolve completely) and administer immediately. Rinse residue in glass with additional 4 ounces of water (noncarbonated only) and administer.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Amiodarone: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Amiodarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Amisulpride (Oral): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride (Oral). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even greater risk. Consider therapy modification

Artesunate: Vandetanib may increase serum concentrations of the active metabolite(s) of Artesunate. Monitor therapy

Azithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Chloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Citalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram. Avoid combination

Clarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin. Avoid combination

Clofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

CloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Vandetanib. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Digoxin: Vandetanib may increase the serum concentration of Digoxin. Monitor therapy

Domperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone. Avoid combination

Doxepin-Containing Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Doxepin-Containing Products. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Dronedarone: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Dronedarone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Droperidol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Droperidol. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Escitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Avoid combination

Fingolimod: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Flecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Flupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol. Avoid combination

Gadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Gemifloxacin: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Gemifloxacin. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Gilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Consider therapy modification

Halofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Haloperidol: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Inotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Levofloxacin-Containing Products (Systemic): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Lofexidine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Lofexidine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

MetFORMIN: Vandetanib may increase the serum concentration of MetFORMIN. Monitor therapy

Methadone: QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Midostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Moxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic). Avoid combination

Nilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib. Avoid combination

OLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Ondansetron: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Osimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Pentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Pilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Pimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Avoid combination

Piperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine. Avoid combination

Probucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol. Avoid combination

Propafenone: May enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Class IA Antiarrhythmics (Highest Risk): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Class III Antiarrhythmics (Highest Risk): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Dronedarone. Consider therapy modification

QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of other QT-prolonging Kinase Inhibitors (Highest Risk). Avoid combination

QT-prolonging Miscellaneous Agents (Highest Risk): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Nilotinib; Ribociclib. Consider therapy modification

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Kinase Inhibitors (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine. Avoid combination

Ribociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib. Avoid combination

RisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Sodium Stibogluconate: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sodium Stibogluconate. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Monitor therapy

Sparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin. Avoid combination

St John's Wort: May decrease the serum concentration of Vandetanib. Avoid combination

Thioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Vemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Hypertension (≤33%), hypertensive crisis (≤33%), prolonged QT interval on ECG (14%)

Dermatologic: Acneiform eruption (≤35%), acne vulgaris (≤35%), pruritus (11%), skin photosensitivity (13%), skin rash (53%), xeroderma (15%)

Endocrine & metabolic: Hypocalcemia (11% to 57%), hypoglycemia (24%)

Gastrointestinal: Abdominal pain (21%), colitis (≤57%), decreased appetite (21%), diarrhea (≤57%), dyspepsia (11%), nausea (33%), vomiting (15%)

Hematologic & oncologic: Hemorrhage (grades ≤2: 14%)

Hepatic: Increased serum alanine aminotransferase (51%)

Nervous system: Fatigue (24%), headache (26%)

Ophthalmic: Corneal changes (13%)

Renal: Increased serum creatinine (16%)

Respiratory: Upper respiratory tract infection (23%)

1% to 10%:

Cardiovascular: Cerebral ischemia (1%)

Dermatologic: Alopecia (8%), nail disease (9%)

Endocrine & metabolic: Hypomagnesemia (7%), hypothyroidism (6%)

Gastrointestinal: Dysgeusia (8%), xerostomia (9%)

Genitourinary: Proteinuria (10%)

Hematologic & oncologic: Neutropenia (10%; grades 3/4: <1%), thrombocytopenia (9%)

Nervous system: Depression (10%)

Neuromuscular & skeletal: Muscle spasm (6%)

Ophthalmic: Blurred vision (9%)

Frequency not defined:

Cardiovascular: Torsades de pointes, ventricular tachycardia

Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis

Nervous system: Reversible posterior leukoencephalopathy syndrome

Neuromuscular & skeletal: Asthenia

Respiratory: Interstitial pulmonary disease, pneumonitis

Miscellaneous: Fever

<1%:

Cardiovascular: Cardiac failure

Gastrointestinal: Intestinal perforation, pancreatitis

Postmarketing: Cardiovascular: Vascular disease (arterial aneurysms [including aortic aneurysm], arterial dissections [including aortic dissection], and arterial rupture [including aortic rupture])

ALERT: U.S. Boxed Warning

QT prolongation, torsades de pointes, and sudden death:

Vandetanib can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving vandetanib. Do not use vandetanib in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia, and/or hypomagnesemia prior to vandetanib administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval. Only health care providers and pharmacies certified with the restricted distribution program are able to prescribe and dispense vandetanib.

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic toxicity: Serious and sometimes fatal skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with vandetanib. Permanently discontinue vandetanib for severe dermatologic adverse reactions and refer patient for immediate medical evaluation. Systemic therapies, including corticosteroids, may be required. Grade 1 acneiform rash may be managed with topical corticosteroids and topical antibiotics; grade 2 may be managed with topical corticosteroids and systemic (oral) antibiotics; grade 3 or intolerable grade 2 acneiform rash may be managed with treatment interruption, topical corticosteroids and systemic (oral) antibiotics and systemic corticosteroids (Lacouture 2014). Photosensitivity reactions may occur during vandetanib treatment and for up to 4 months after discontinuation; effective sunscreen and protective clothing are recommended.

• GI toxicity: Diarrhea may commonly occur; may be grade 3 or higher. Diarrhea may cause electrolyte imbalance (monitor electrolytes and ECGs closely and more frequently to detect QT prolongation resulting from dehydration). Withhold treatment until resolution for severe diarrhea; dose reduction is recommended when treatment is resumed. Antidiarrheal medication and/or other routine diarrhea management may be indicated.

• Heart failure: Heart failure (HF) has been reported (sometimes fatal); monitor for signs and symptoms of HF. Consider discontinuing vandetanib in patients with HF. HF may not be reversible upon discontinuation.

• Hemorrhage: Serious and sometimes fatal hemorrhagic events have been reported with vandetanib. Discontinue in patients with severe hemorrhage. Do not administer in patients with a recent history of hemoptysis with ≥2.5 mL of red blood.

• Hypertension: Hypertension and hypertensive crisis have been observed with vandetanib. Monitor blood pressure and initiate or adjust antihypertensive therapy as needed. May require vandetanib dosage adjustment or treatment interruption; discontinue vandetanib (permanently) if blood pressure cannot be adequately controlled.

• Hypothyroidism: Increased doses of thyroid replacement therapy have been required in patients receiving vandetanib with prior thyroidectomy. Obtain TSH at baseline, at 2 to 4 weeks, 8 to 12 weeks and every 3 months after vandetanib initiation. If signs and symptoms of hypothyroidism occur during treatment, evaluate thyroid hormone levels and adjust replacement therapy if needed.

• Ischemic events: Ischemic cerebrovascular events (some fatal) have been observed with vandetanib. Discontinue treatment in patients with severe ischemic events. The safety of resuming treatment after an ischemic event has not been studied.

• Pulmonary toxicity: Interstitial lung disease (ILD) or pneumonitis (including fatalities) has been reported with vandetanib. Patients should be advised to report any new or worsening respiratory symptoms; ILD should be suspected with nonspecific respiratory symptoms such as hypoxia, pleural effusion, cough or dyspnea. Interrupt therapy for acute or worsening pulmonary symptoms; discontinue if ILD diagnosis is confirmed.

• QT prolongation/sudden death: [US Boxed Warning]: Vandetanib may prolong the QT interval; torsade de pointes and sudden death have been reported. Do not use in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct electrolyte imbalance (hypocalcemia, hypokalemia, and/or hypomagnesemia) prior to initiating therapy. Monitor electrolytes periodically. Avoid the use of QT-prolonging agents. If concomitant use with QT-prolonging agents cannot be avoided, monitor ECG more frequently. Monitor electrolytes, TSH, and ECG at baseline, 2 to 4 weeks, and 8 to 12 weeks after therapy initiation, and then every 3 months or as clinically necessary (more frequently if clinically indicated). Vandetanib has a long half-life (19 days), therefore, adverse reactions (including QT prolongation) may resolve slowly; monitor appropriately. Ventricular tachycardia has also been reported. The potential for QT prolongation is dose dependent. Do not initiate in patients with QTcF >450 msec. During treatment, if QTcF >500 msec, withhold vandetanib and resume at a reduced dose when QTcF is <450 msec. Following any dose reduction for QT prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Do not use in patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure. Vandetanib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. To reduce the risk of QT prolongation, maintain serum calcium and magnesium within normal limits and maintain serum potassium ≥4 mEq/L.

• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema (diagnosed by MRI), has been observed with vandetanib. Symptoms of RPLS include altered mental function, confusion, headache, seizure, or visual disturbances; generally associated with hypertension. Discontinue vandetanib if RPLS occurs.

• Wound healing complications: Vascular endothelial growth factor receptor inhibitors are associated with impaired wound healing; therefore, vandetanib may affect wound healing. Withhold vandetanib treatment for at least 1 month prior to elective surgery; do not administer vandetanib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming vandetanib treatment after resolution of wound healing complications has not been established.

Disease-related concerns:

• Renal impairment: Dosage reduction is recommended in patients with moderate-to-severe renal impairment. Vandetanib exposure is increased in patients with impaired renal function; closely monitor QT interval.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• REMS program: [US Boxed Warning]: Vandetanib is available only through a restricted distribution program (Caprelsa REMS); prescribers and pharmacies must be certified with the restricted distribution program to prescribe and dispense vandetanib.

Monitoring Parameters

Monitor electrolytes (calcium, magnesium, potassium), TSH, and ECG (QT interval) at baseline, at 2 to 4 weeks, at 8 to 12 weeks, and every 3 months thereafter; also monitor QT interval at same frequency for dose reduction due to QT interval or treatment delays >2 weeks (monitor electrolytes and ECG more frequently if diarrhea occurs). Monitor renal function, hepatic function, and BP. Evaluate pregnancy status prior to therapy (in females of reproductive potential). Monitor for signs and symptoms of heart failure, reversible posterior leukoencephalopathy syndrome (RPLS), pulmonary and skin toxicities. Monitor adherence.

Reproductive Considerations

Pregnancy status should be evaluated prior to vandetanib therapy. Females of childbearing potential should be advised to avoid pregnancy and use effective contraception during and for at least 4 months after the last vandetanib dose.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to vandetanib may cause fetal harm.

Information related to the use of vandetanib in pregnant females is limited (Thomas 2018).

Patient Education

What is this drug used for?

• It is used to treat thyroid cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Diarrhea

• Upset stomach

• Throwing up

• Feeling tired or weak

• Not hungry

• Stomach pain

• Common cold symptoms

• Dry mouth

• Nail changes

• Hair loss

• Headache

• Change in taste

• Muscle spasms

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache

• Heart problems like shortness of breath, a big weight gain, a heartbeat that is not normal, or swelling in the arms or legs that is new or worse

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up

• Low thyroid level like constipation; not able to handle cold; memory problems; mood changes; or a burning, numbness, or tingling feeling that is not normal

• High blood pressure like very bad headache or dizziness, passing out, or change in eyesight

• Infection like fever, chills, or sore throat

• Bleeding problems like bruising; black, tarry, or bloody stools; bleeding gums; blood in the urine; coughing up blood; cuts that take a long time to stop bleeding; feel dizzy; feeling very tired or weak; nosebleeds; pain or swelling; throwing up blood or throw up that looks like coffee grounds; or very bad headache

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Lung problems like shortness of breath or other trouble breathing, cough that is new or worse, or fever

• Chest pain

• Fast or abnormal heartbeat

• Change in eyesight

• Behavioral changes

• Low mood (depression)

• Muscle or joint pain

• Pimples (acne)

• Dry skin

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.