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Vandetanib

Pronunciation: van-DET-a-nib
Class: Tyrosine kinase inhibitors

Trade Names

Caprelsa
- Tablets, oral 100 mg
- Tablets, oral 300 mg

Pharmacology

Inhibits the activity of tyrosine kinases, including members of the epidermal growth factor receptor (EGFR) family, vascular endothelial growth factor (VEGF) receptors, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the SRC family.

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Pharmacokinetics

Absorption

Absorption is slow. T max is approximately 6 h (range, 4 to 10 h).

Distribution

Human serum albumin and alpha-1 acid glycoprotein protein binding is approximately 90%; Vd is approximately 7,450 L.

Metabolism

Metabolites N-desmethyl-vandetanib and vandetanib-N-oxide are primarily produced by CYP3A4 and flavin-containing monooxygenase enzymes FMO1 and FMO3, respectively.

Elimination

Plasma half-life is 19 d and Cl is approximately 13.2 L/h. Eliminated primarily in the feces (44%) and the urine (25%).

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.

Hepatic Function Impairment

Not recommended for use in patients with moderate and severe hepatic impairment because safety and efficacy have not been established.

Elderly

No relationship was apparent between oral Cl and age.

Children

The pharmacokinetics have not been evaluated in children.

Gender

No relationship was apparent between oral Cl and gender.

Race

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

Indications and Usage

For the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Contraindications

Congenital long QT syndrome.

Dosage and Administration

Medullary Thyroid Cancer
Adults

PO 300 mg daily.

Dosage adjustment

In the event of QTcF greater than 500 msec, interrupt dosing until QTcF returns to less than 450 msec, then resume at a reduced dose. For adverse reactions grade 3 or greater toxicity, interrupt dosing until toxicity resolves or improves to grade 1, and then resume at a reduced dose. The 300 mg daily dose can be reduced to 200 mg and then to 100 mg for grade 3 or greater toxicities.

Renal Function Impairment

The starting dose should be reduced to 200 mg in patients with moderate (CrCl at least 30 to less than 50 mL/min) and severe (CrCl less than 30 mL/min) renal impairment.

General Advice

  • Administer without regard to meals.
  • Tablets should not be crushed.
  • Direct contact of crushed tablets with the skin or mucous membranes should be avoided; if such contact occurs, wash thoroughly.
  • Tablets may be dispersed in a glass containing 60 mL of noncarbonated water, stirred for approximately 10 minutes until dispersed (will not completely dissolve), and swallowed immediately. To ensure the full dose is received, any residue in the glass should be mixed again with an additional 120 mL of noncarbonated water and swallowed.
  • The dispersion can also be administered through nasogastric or gastrostomy tubes.
  • If a patient misses a dose, the missed dose should not be taken if it is less than 12 h before the next dose.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

CYP3A4 strong inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine)

Vandetanib plasma concentrations may be reduced, decreasing the pharmacologic effect. Avoid coadministration.

QT-prolonging drugs (eg, antiarrhythmic agents [eg, amiodarone, disopyramide, dofetilide, procainamide, sotalol], chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, pimozide)

The risk of life-threatening arrhythmia, including torsades de pointes, may be increased. Avoid coadministration. If coadministration cannot be avoided, more frequent ECG monitoring is recommended.

St. John's wort

Vandetanib plasma concentrations may be decreased unpredictably. Avoid coadministration.

Adverse Reactions

Cardiovascular

Hypertension/hypertensive crisis/accelerated hypertension (33%); ECG QT prolonged (14%); cardiac failure with arrhythmia.

CNS

Headache (26%); fatigue (24%); asthenia (15%); insomnia (13%); depression (10%).

Dermatologic

Rash (53%); dermatitis acneiform/acne (35%); dry skin (15%); photosensitivity reaction (13%); pruritus (11%).

GI

Diarrhea/colitis (57%); nausea (33%); abdominal pain, decreased appetite (21%); vomiting (15%); dyspepsia (11%); GI hemorrhage, gastroenteritis (1%); pancreatitis.

Hematologic-Lymphatic

Hemorrhagic events (grade 1 or 2) (14%).

Lab Tests

Calcium decreased (57%); ALT increased (51%); glucose decreased (24%); WBC decreased (19%); creatinine increased (16%); bilirubin increased, Hgb decreased (13%); neutrophils decreased (10%); platelets decreased (9%); calcium increased, magnesium decreased (7%); potassium decreased/increased (6%); glucose increased (5%); magnesium increased (3%).

Metabolic-Nutritional

Hypocalcemia (11%); proteinuria, weight decreased (10%).

Respiratory

Cough, nasopharyngitis (11%); pneumonia (more than 2%); aspiration pneumonia, respiratory arrest, respiratory failure.

Miscellaneous

Blurred vision (9%); sepsis.

Precautions

Warnings

QT prolongation, torsades de pointes, and sudden death

Vandetanib can prolong the QT interval. Torsades de pointes and sudden death have been reported. Vandetanib should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Hypocalcemia, hypokalemia, and/or hypomagnesemia must be corrected prior to vandetanib administration and should be periodically monitored. Drugs known to prolong the QT interval should be avoided. If a drug known to prolong the QT interval must be administered, more frequent ECG monitoring is recommended.

Because of the 19-day half-life, adverse reactions, including a prolonged QT interval, may not resolve quickly. Monitor appropriately. Only health care providers and pharmacies certified with the restricted distribution program are able to prescribe and dispense vandetanib.


Monitor

An ECG and levels of serum potassium, calcium, magnesium, and TSH should be obtained at baseline, at 2 to 4 wk, at 8 to 12 wk after starting treatment, and every 3 mo thereafter. Following any dose reduction for QT prolongation or any dose interruptions more than 2 wk, QT assessment should be conducted. Electrolytes and ECGs may require more frequent monitoring in case of diarrhea. Monitor for hypertension and for signs and symptoms of heart failure. Ophthalmologic examination, including slit lamp, is recommended in patients who report visual changes.


Pregnancy

Category D . Can cause fetal harm.

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Renal Function

The starting dose should be reduced in patients with moderate to severe renal impairment and QT interval should be monitored closely.

Hepatic Function

Not recommended for use in patients with moderate and severe hepatic impairment.

Photosensitivity

Photosensitivity reactions are increased.

Dermatological effects

Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have been reported. If grade 3 or greater skin reactions occur, treatment should be stopped until improved.

Diarrhea

Has been observed and may cause electrolyte imbalances. Routine antidiarrheal agents are recommended. If severe diarrhea develops, treatment should be stopped until diarrhea improves.

Heart failure

Has been observed and some cases have been fatal. Heart failure may not be reversible upon stopping treatment.

Hemorrhage

Serious hemorrhagic events have been observed and some cases have been fatal. Do not administer to patients with a recent history of hemoptysis of 25 mL or more of red blood.

Hypertension

Hypertension, including hypertensive crisis, has been observed. Dose reduction or interruption may be necessary.

Hypothyroidism

In patients with prior thyroidectomy, increases in the dose of the thyroid replacement therapy may be required during therapy.

Interstitial lung disease

Interstitial lung disease or pneumonitis has been observed and deaths have been reported. Consider a diagnosis of interstitial lung disease in patients presenting with nonspecific respiratory signs and symptoms.

Ischemic cerebrovascular events

Has been observed with vandetanib, and some cases have been fatal.

Reversible posterior leukoencephalopathy syndrome

A syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain has been observed. Discontinue therapy; the use of corticosteroids and antibiotics may be indicated until clinical symptoms resolve.

Risk evaluation and mitigation strategy (REMS) program

Vandetanib is only available through a restricted distribution program, called vandetanib REMS program.

Overdosage

Symptoms

Diarrhea, hypertension, QTc prolongation, rash, torsades de pointes.

Patient Information

  • Advise patient or caregiver to read the Medication Guide carefully before starting therapy, and to read and check for new information each time the medication is refilled.
  • Inform patients that vandetanib can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia, and sudden death have been reported. Patients should be advised that their electrolytes and the electrical activity of their heartbeat (via an ECG) should be monitored regularly during treatment.
  • Inform patients that they may be more susceptible to sunburn and to use appropriate sun protection (eg, sunscreen and/or clothing) while taking this medication and for at least 4 mo after drug discontinuation. Patients should consult their health care provider promptly if they develop a skin rash.
  • Advise patients to contact their health care provider promptly if they develop sudden onset or worsening of breathlessness, persistent cough, or fever.
  • Inform patients that they may experience diarrhea while taking this medication. Patients should also be advised to use standard antidiarrheal medications and to seek medical attention if their diarrhea becomes persistent or severe.
  • Instruct patients to contact their health care provider promptly if they experience seizures, headaches, visual disturbances, confusion, or difficulty thinking.
  • Advise women of childbearing potential to use effective contraception during therapy and for at least 4 mo following their last dose of vandetanib.
  • Advise breast-feeding women to discontinue breast-feeding while receiving vandetanib therapy.
  • Inform patients that the tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided.

Copyright © 2009 Wolters Kluwer Health.

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