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Vandetanib

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. [DSC] = Discontinued product

Tablet, Oral:

Caprelsa: 100 mg, 300 mg

Generic: 100 mg [DSC], 300 mg [DSC]

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

Multikinase inhibitor; 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: 4-10 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 and severe renal impairment, the average AUC of vandetanib increased by 39% and 41%, respectively. There is no information available for patients with ESRD requiring dialysis.

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

Contraindications

Congenital long QT syndrome

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to vandetanib or any component of the formulation; persistent Fridericia-corrected QT interval (QTcF) ≥500 ms; uncorrected hypokalemia, hypomagnesemia, or hypocalcemia; uncontrolled hypertension

Dosing: Adult

Note: Do not initiate treatment unless QTcF <450 msec. Avoid concomitant use of QT-prolonging agents and strong CYP3A4 inducers. To reduce the risk of QT prolongation, maintain serum calcium and magnesium within normal limits and maintain serum potassium ≥4 mEq/L.

Medullary thyroid cancer, locally-advanced or metastatic: Oral: 300 mg once daily, continue treatment until no longer clinically benefiting or until unacceptable toxicity

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: Reduce initial dose to 200 mg once daily; closely monitor QT interval.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment provided in manufacturer's labeling.

Moderate and severe impairment (Child-Pugh class B or C): Use is not recommended.

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, reduce dose to 100 mg once daily after symptom improvement to ≤ grade 1 toxicity, if continued treatment is warranted.

Management of specific toxicities:

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

Diarrhea (severe): Withhold treatment until resolution. Dose reduction is recommended when treatment is resumed. Routine antidiarrheals are recommended. 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.

Skin reactions: Withhold treatment for dermatologic toxicity of grade 3 or higher. Consider a reduced dose or permanent discontinuation upon improvement in symptoms. Consider permanent discontinuation for severe dermatologic toxicity. Mild-to-moderate toxicity has responded to corticosteroids (systemic or topical), oral antihistamines, and antibiotics (topical or systemic).

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

An oral solution may be prepared using the tablet. Disperse one tablet 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 be administered with or without food. Missed doses should be omitted if within 12 hours of the next scheduled dose. Do not crush tablet. If unable to swallow tablet whole or if nasogastric or gastrostomy tube administration is necessary, disperse one tablet 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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Dietary Considerations

May be taken with or without food.

Storage

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

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

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

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

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

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

MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Hypertension (33%; grades 3/4: 9%), prolonged Q-T interval on ECG (14%; grades 3/4: 8%)

Central nervous system: Headache (26%; grades 3/4: 1%), fatigue (24%; grades 3/4: 6%), insomnia (13%)

Dermatologic: Skin rash (53%; grades 3/4: 5%), acne vulgaris (35%; grades 3/4: 1%), xeroderma (15%), skin photosensitivity (13%; grades 3/4: 2%), pruritus (11%; grades 3/4: 1%)

Endocrine & metabolic: Hypocalcemia (11% to 57%; grades 3/4: 2%), hypoglycemia (24%)

Gastrointestinal: Pseudomembranous colitis (57%; grades 3/4: 11%), nausea (33%; grades 3/4: 1%), abdominal pain (21%; grades 3/4: 3%), decreased appetite (21%; grades 3/4: 1% to 4%), vomiting (15%; grades 3/4: 1%), dyspepsia (11%)

Hematologic & oncologic: Leukopenia (19%), hemorrhage (13% to 14%), anemia (13%; grades 3/4: <1%)

Hepatic: Increased serum ALT (51%), increased serum bilirubin (13%)

Neuromuscular & skeletal: Weakness (15%)

Ophthalmic: Corneal changes (13%; corneal edema, corneal opacity, corneal dystrophy, iris hyperpigmentation, keratopathy, arcus lipoides, corneal deposits, acquired corneal dystrophy)

Renal: Increased serum creatinine (16%)

Respiratory: Upper respiratory tract infection (23%), cough (11%), nasopharyngitis (11%)

1% to 10%:

Cardiovascular: Cardiac failure (2%), cerebral ischemia (1%)

Central nervous system: Depression (10%; grades 3/4: 2%)

Dermatologic: Nail disease (9%; inflammation, tenderness, paronychia), alopecia (8%)

Endocrine & metabolic: Weight loss (10%), hypercalcemia (7%), hypomagnesemia (7%), hyperkalemia (6%), hypokalemia (6%), hypothyroidism (6%), hyperglycemia (5%), hypermagnesemia (3%)

Gastrointestinal: Xerostomia (9%), dysgeusia (8%)

Genitourinary: Proteinuria (10%)

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

Infection: Sepsis (2%)

Neuromuscular & skeletal: Muscle spasm (6%)

Ophthalmic: Blurred vision (9%)

Respiratory: Aspiration pneumonia (2%), respiratory arrest (2%), respiratory failure (2%)

<1% (Limited to important or life-threatening): Cardiorespiratory arrest, interstitial pulmonary disease, palmar-plantar erythrodysesthesia, pancreatitis, pneumonitis, reversible posterior leukoencephalopathy syndrome, Stevens-Johnson syndrome, torsades de pointes, ventricular tachycardia

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 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:

• Diarrhea: Diarrhea has been reported with use; may cause electrolyte imbalance (closely monitor electrolytes and ECGs to detect QT prolongation resulting from dehydration). Routine antidiarrheals are recommended. Withhold treatment until resolution for severe diarrhea; dose reduction is recommended when treatment is resumed.

• Heart failure: Heart failure (HF) has been reported; monitor for signs and symptoms of HF. May require discontinuation. HF may not be reversible upon discontinuation.

• Hemorrhage: Serious and sometimes fatal hemorrhagic events have been reported with use. 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. Canadian labeling contraindicates use in uncontrolled hypertension.

• Hypothyroidism: Increased doses of thyroid replacement therapy have been required in patients with prior thyroidectomy. Obtain TSH at baseline, at 2-4 weeks, 8-12 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: [U.S. Boxed Warning]: 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 prior to initiating therapy. Monitor electrolytes and ECG (to monitor QT interval) at baseline, at 2-4 weeks, at 8-12 weeks, and every 3 months thereafter; monitoring (at the same frequency) is required following dose reductions for QT prolongation or with dose interruptions >2 weeks. Avoid the use of QT-prolonging agents; if concomitant use with QT prolonging agents cannot be avoided, monitor ECG more frequently. 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 treatment unless Fridericia-corrected QT interval (QTcF) is <450 msec. During treatment, if QTcF >500 msec, withhold vandetanib and resume at a reduced dose when QTcF is <450 msec. Do not use in patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure. Patients with ventricular arrhythmias or recent MI were excluded from clinical trials. 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 (RPLS): RPLS been observed with vandetanib. Symptoms of RPLS include altered mental function, confusion, headache, seizure, or visual disturbances; generally associated with hypertension. Discontinue treatment if RPLS occurs.

• Skin reactions: Stevens-Johnson syndrome and other serious skin reactions (including fatal) have been reported. Mild-to-moderate skin reactions, including acne, dermatitis, dry skin, palmar-plantar erythrodysesthesia syndrome, pruritus, and rash have also been reported. Withhold treatment for dermatologic toxicity of grade 3 or higher; consider a reduced dose or permanent discontinuation upon improvement in symptoms. Consider discontinuation for severe dermatologic toxicity. Mild-to-moderate toxicity has responded to corticosteroids (systemic or topical), oral antihistamines, and antibiotics (topical or systemic). Increased risk of photosensitivity is associated with vandetanib; effective sunscreen and protective clothing are recommended during and for at least 4 months after treatment discontinuation.

Disease-related concerns:

• Hepatic impairment: Data is limited; a single-dose pharmacokinetic study demonstrated comparable mean vandetanib AUC and clearance between healthy patients and hepatically impaired (mild-severe) patients. Manufacturer labeling does not provide specific recommendations in mild impairment; not recommended for use in patients with moderate-to-severe hepatic impairment.

• Renal impairment: Dosage reduction is recommended in patients with moderate-to-severe renal impairment. Exposure is increased in patients with impaired renal function; closely monitor QT interval. Has not been studied in patients with end stage renal disease requiring dialysis.

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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Appropriate use: Due to the risk for serious treatment-related adverse events, use in patients whose disease is not progressive or symptomatic should be only be undertaken after careful consideration.

• Restricted access: [U.S. Boxed Warning]: Vandetanib is only available through a restricted access program; 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 2-4 weeks, at 8-12 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). Monitor renal function, hepatic function, blood pressure; monitor for signs and symptoms of heart failure, reversible posterior leukoencephalopathy syndrome (RPLS), pulmonary and skin toxicities

Pregnancy Risk Factor

D

Pregnancy Considerations

Animal reproduction studies have demonstrated teratogenic effects and fetal loss. Because vandetanib inhibits angiogenesis, a critical component of fetal development, adverse effects on pregnancy would be expected. Women of childbearing potential should be advised to avoid pregnancy and use effective contraception during and for 4 months following treatment with vandetanib. Canadian labeling recommends that nonsterile males employ reliable contraceptive methods (barrier method in conjunction with spermicide) during and for 2 months after vandetanib treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, headache, loss of strength and energy, acne, dry skin, itching, lack of appetite, abdominal pain, dry mouth, nail changes, hair loss, change in taste, or muscle spasms. Have patient report immediately to prescriber signs of posterior reversible encephalopathy syndrome (illogical thinking, not alert, vision changes, seizures, or severe headache), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), angina, tachycardia, severe dizziness, passing out, difficulty breathing, cough that will not go away, behavioral changes, depression, muscle pain, joint pain, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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