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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.

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

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 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 and severe 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)

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. 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.

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

Missed dose: Missed doses should be omitted if within 12 hours of the next scheduled dose.

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.

ESRD requiring dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the 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

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 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. 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.

Storage

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

Drug Interactions

Bilastine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

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

Buprenorphine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

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

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

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

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

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

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

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

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

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

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

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

Teneligliptin: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

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

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. 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%), fatigue (24%)

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

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

Gastrointestinal: Colitis (≤57%; grades 3/4: ≤11%), diarrhea (≤57%; grades 3/4: ≤11%), nausea (33%), abdominal pain (21%), decreased appetite (21%), vomiting (15%), dyspepsia (11%)

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

Hepatic: Increased serum ALT (51%)

Ophthalmic: Corneal changes (13%)

Renal: Increased serum creatinine (16%)

Respiratory: Upper respiratory tract infection (23%)

1% to 10%:

Cardiovascular: Cerebral ischemia (1%)

Central nervous system: Depression (10%)

Dermatologic: Nail disease (9%), alopecia (8%)

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

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

Genitourinary: Proteinuria (10%)

Hematologic & oncologic: Neutropenia (10%), thrombocytopenia (9%)

Neuromuscular & skeletal: Muscle spasm (6%)

Ophthalmic: Blurred vision (9%)

Frequency not defined:

Cardiovascular: Torsades de pointes, ventricular tachycardia

Central nervous system: Reversible posterior leukoencephalopathy syndrome

Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis

Respiratory: Interstitial pulmonary disease, pneumonitis

<1% (Limited to important or life-threatening): Intestinal perforation, pancreatitis

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: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other serious skin reactions (including fatal reactions) 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. Discontinue permanently for severe dermatologic toxicity and refer patient for immediate evaluation. Systemic 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). 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.

• Gastrointestinal toxicity: Diarrhea may commonly occur. May cause electrolyte imbalance (closely monitor electrolytes and ECGs 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; 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.

• Hypothyroidism: Increased doses of thyroid replacement therapy have been required in patients 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]: 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 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.

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.

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: [US 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 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, 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

Adverse events have been observed in animal reproduction studies. 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.

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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