Vandetanib

Vandetanib
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Black Box Warning

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH See full prescribing information for complete Boxed Warning. * Vandetanib can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving vandetanib. 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. Given the half-life of 19 days, ECGs should be obtained to monitor the QT at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessment should be conducted as described above. Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately. Only prescribers and pharmacies certified through the vandetanib REMS education program are able to prescribe and dispense vandetanib

Overview

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Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

Medullary Thyroid Cancer (MTC)

• Vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

• Use of vandetanib in patients with indolent, asymptomatic or slowly progressing disease should be carefully considered because of the treatment related risks of vandetanib.

Dosage

• The recommended daily dose is 300 mg of vandetanib taken orally. Vandetanib treatment should be continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs.

• Vandetanib may be taken with or without food.

• If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose.

For Patients who have Difficulty Swallowing Solids

• Vandetanib tablets should not be crushed. If vandetanib tablets cannot be taken whole, the tablets can be dispersed in a glass containing 2 ounces of non-carbonated water and stirred for approximately 10 minutes until the tablet is dispersed (will not completely dissolve). No other liquids should be used. The dispersion should be swallowed immediately. To ensure the full dose is received, any residues in the glass should be mixed again with an additional 4 ounces of non-carbonated water and swallowed.

• The dispersion can also be administered through nasogastric or gastrostomy tubes.

• Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly. Avoid exposure to crushed tablets.

Dosage Adjustment

• In the event of corrected QT interval, Fridericia (QTcF) greater than 500 ms, interrupt dosing until QTcF returns to less than 450 ms, then resume at a reduced dose.

• For CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or greater toxicity, interrupt dosing until toxicity resolves or improves to CTCAE grade 1, and then resume at a reduced dose.

• Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately.

• The 300-mg daily dose can be reduced to 200 mg (two 100-mg tablets) and then to 100 mg for CTCAE grade 3 or greater toxicities.

Elderly

• No adjustment in starting dose is required for patients over 65 years of age. There are limited data for patients over the age of 75.

Concomitant Strong CYP3A4 Inducers

• Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also avoid taking St. John’s Wort.

Patients With Renal Impairment

• The starting dose should be reduced to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment.

Patients with Hepatic Impairment

• Single dose pharmacokinetic data from volunteers with hepatic impairment receiving 800 mg suggest that there were no differences in pharmacokinetics compared to patients with normal hepatic function. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). Vandetanib is not recommended for use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, as safety and efficacy have not been established.

DOSAGE FORMS & STRENGTHS

• Vandetanib 100-mg tablets are white, round, biconvex, film-coated, and intagliated with ‘Z 100‘ on one side and plain on the reverse side.

• Vandetanib 300-mg tablets are white, oval, biconvex, film-coated, and intagliated with ‘Z 300’ on one side and plain on the reverse side.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Vandetanib in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Vandetanib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Vandetanib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Vandetanib in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Vandetanib in pediatric patients.

Contraindications

• Do not use in patients with congenital long QT syndrome.

Warnings

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH See full prescribing information for complete Boxed Warning. * Vandetanib can prolong the QT interval. Torsades de pointes and sudden death have been reported in patients receiving vandetanib. 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. Given the half-life of 19 days, ECGs should be obtained to monitor the QT at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessment should be conducted as described above. Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. Monitor appropriately. Only prescribers and pharmacies certified through the vandetanib REMS education program are able to prescribe and dispense vandetanib

Prolongation and Torsades de Pointes

• Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have been reported in patients administered vandetanib.

• Vandetanib treatment should not be started in patients whose QTcF interval is greater than 450 ms. Vandetanib should not be given to patients who have a history of torsades 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. Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate to severe renal impairment and QT interval should be monitored closely.

• An ECG and levels of serum potassium, calcium, magnesium and TSH should be obtained at baseline, at 2-4 weeks and 8-12 weeks after starting treatment with vandetanib and every 3 months thereafter. Electrolytes and ECGs may require more frequent monitoring in case of diarrhea. Following any dose reduction for QT prolongation, or any dose interruptions greater than 2 weeks, QT assessments should be conducted as described above. Serum potassium levels should be maintained at 4 mEq/L or higher (within normal range) and serum magnesium and serum calcium should be kept within normal range to reduce the risk of electrocardiogram QT prolongation.

• Avoid using vandetanib with drugs known to prolong the electrocardiogram QT interval. If such drugs are given to patients already receiving vandetanib and no alternative therapy exists, ECG monitoring of the QT interval should be performed more frequently.

• Patients who develop a QTcF greater than 500 ms should stop taking vandetanib until QTcF returns to less than 450 ms. Dosing of vandetanib can be resumed at a reduced dose.

Skin Reactions and Stevens-Johnson Syndrome

• Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have been reported with vandetanib. Treatment of severe skin reactions has included systemic corticosteroids and permanent discontinuation of vandetanib. Mild to moderate skin reactions may manifest as rash, acne, dry skin, dermatitis, pruritis and other skin reactions (including photosensitivity reactions and palmar-plantar erythrodysesthesia syndrome). Mild to moderate skin reactions have been treated with topical and systemic corticosteroids, oral antihistamines, and topical and systemic antibiotics. If CTCAE grade 3 or greater skin reactions occur, vandetanib treatment should be stopped until improved. Upon improvement, consideration should be given to continuing treatment at a reduced dose or permanent discontinuation of vandetanib.

• Photosensitivity reactions are increased with vandetanib. Patients should be advised to wear sunscreen and protective clothing when exposed to the sun. Due to the long half-life of vandetanib, protective clothing and sunscreen should continue for 4 months after discontinuation of treatment.

Interstitial Lung Disease

• Interstitial Lung Disease (ILD) or pneumonitis has been observed with vandetanib and deaths have been reported. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

• Patients who develop radiological changes suggestive of ILD and have few or no symptoms may continue vandetanib therapy with close monitoring at the discretion of the treating physician.

• If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids and antibiotics may be indicated.

• For cases where symptoms of ILD are severe, discontinue vandetanib therapy and the use of corticosteroids and antibiotics may be indicated until clinical symptoms resolve. Even upon resolution of severe ILD, permanent discontinuation of vandetanib should be considered.

Ischemic Cerebrovascular Events

• Ischemic cerebrovascular events have been observed with vandetanib and some cases have been fatal. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events were observed more frequently with vandetanib compared to placebo (1.3% compared to 0%) and no deaths were reported. The safety of resumption of vandetanib therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue vandetanib in patients who experience a severe ischemic cerebrovascular event.

Hemorrhage

• Serious hemorrhagic events, which in some cases were fatal, have been observed with vandetanib. There were no fatal bleeding events in the randomized MTC study. Three patients died of fatal bleeding events while on vandetanib therapy in clinical studies. Do not administer vandetanib to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue vandetanib in patients with severe hemorrhage.

Heart Failure

• Heart failure has been observed with vandetanib and some cases have been fatal. Discontinuation of vandetanib may be necessary in patients with heart failure. Heart failure may not be reversible upon stopping vandetanib. Monitor for signs and symptoms of heart failure.

Diarrhea

• Diarrhea was observed in patients who received vandetanib. Routine anti-diarrheal agents are recommended. Diarrhea may cause electrolyte imbalances. Since QT prolongation is seen with vandetanib, serum electrolytes and ECGs should be carefully monitored in patients with diarrhea.If severe diarrhea develops, vandetanib treatment should be stopped until diarrhea improves. Upon improvement, treatment with vandetanib should be resumed at a reduced dose.

Hypothyroidism

• In the randomized MTC study where 90% of the patients enrolled had prior thyroidectomy, increases in the dose of the thyroid replacement therapy were required in 49% of the patients randomized to vandetanib compared to 17% of the patients randomized to placebo. Thyroid-stimulating hormone (TSH) should be obtained at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment with vandetanib and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, thyroid hormone levels should be examined and thyroid replacement therapy should be adjusted accordingly.

Hypertension

• Hypertension, including hypertensive crisis, has been observed with vandetanib. All patients should be monitored for hypertension and it should be controlled as appropriate. Dose reduction or interruption may be necessary. If high blood pressure cannot be controlled, vandetanib should not be restarted.

Reversible posterior leukoencephalopathy syndrome

• Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has been observed with vandetanib. This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking vandetanib, including one pediatric patient, also had hypertension. Discontinuation of vandetanib treatment in patients with RPLS should be considered.

5.11 Drug Interactions The administration of vandetanib with agents that are strong CYP3A4 inducers should be avoided [see DOSAGE AND ADMINISTRATION (2.3)and DRUG INTERACTIONS (7.1)].

The administration of vandetanib with anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to cloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided [see DRUG INTERACTIONS (7.3)].

5.12 Renal Impairment Vandetanib exposure is increased in patients with impaired renal function. The starting dose should be reduced to 200 mg in patients with moderate to severe renal impairment and QT interval should be monitored closely. There is no information available for patients with end-stage renal disease requiring dialysis. [see BOXED WARNING, DOSAGE AND ADMINISTRATION (2.4)and USE IN SPECIFIC POPULATIONS (8.6)]

5.13 Hepatic Impairment Vandetanib is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established. [see DOSAGE AND ADMINISTRATION (2.5)]

5.14 Use in PregnancyVandetanib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women using vandetanib. In nonclinical studies in rats, vandetanib was embryotoxic, fetotoxic, and teratogenic, at exposures equivalent to or lower than those expected at the recommended human dose of 300 mg/day. As expected from its pharmacological actions, vandetanib has shown significant effects on all stages of female reproduction in rats. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with vandetanib. Women should be advised that they must use effective contraception to prevent pregnancy during treatment and for at least four months following the last dose of vandetanib [see USE IN SPECIFIC POPULATIONS (8.1)].

5.15 Vandetanib REMS (Risk Evaluation and Mitigation Strategy) Program Because of the risk of QT prolongation, Torsades de pointes, and sudden death, vandetanib is available only through a restricted distribution program called Vandetanib REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense vandetanib.

An overview of the requirements for prescribers and pharmacies is included below.

To be certified, prescribers must review the educational materials, agree to comply with the REMS requirements and enroll in the program. To be certified, pharmacies that dispense vandetanib must enroll in the program, train their pharmacy staff to verify that each prescription is written by a certified prescriber before dispensing to a patient, and agree to comply with the REMS requirements.

To learn about the specific REMS requirements and to enroll in the Vandetanib REMS Program call 1-800-236-9933 or visit www.vandetanibrems.com.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Vandetanib Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Vandetanib Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Vandetanib Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Vandetanib in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vandetanib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Vandetanib during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Vandetanib in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Vandetanib in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Vandetanib in geriatric settings.

Gender

There is no FDA guidance on the use of Vandetanib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Vandetanib with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Vandetanib in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Vandetanib in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Vandetanib in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Vandetanib in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Vandetanib Administration in the drug label.

Monitoring

There is limited information regarding Vandetanib Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Vandetanib and IV administrations.

Overdosage

There is limited information regarding Vandetanib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Vandetanib Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Vandetanib Mechanism of Action in the drug label.

Structure

There is limited information regarding Vandetanib Structure in the drug label.

Pharmacodynamics

There is limited information regarding Vandetanib Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Vandetanib Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Vandetanib Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Vandetanib Clinical Studies in the drug label.

How Supplied

There is limited information regarding Vandetanib How Supplied in the drug label.

Storage

There is limited information regarding Vandetanib Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Vandetanib Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Vandetanib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Vandetanib Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Vandetanib Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.