Vandetanib

Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine
Molecular Formula: C22H24BrFN4O2
CAS Number: 443913-73-3
Brands: Caprelsa

Warning(s)

  • Prolongation of QT Interval, Torsades de Pointes, and Sudden Death
  • Risk of QT interval prolongation, torsades de pointes, ventricular tachycardia, and sudden death.1 Do not initiate in patients with QTcF interval (QT interval corrected using Fridericia’s formula) >450 msec.1 Do not use in patients with a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure, or in patients with electrolyte disturbances.1 Correct hypocalcemia, hypokalemia, and/or hypomagnesemia before administering vandetanib.1 (See Prolongation of QT Interval and Torsades de Pointes under Cautions.)

  • Measure ECG, serum electrolytes (i.e., calcium, magnesium, potassium), and TSH concentrations at baseline, at 2–4 weeks and 8–12 weeks after initiating vandetanib, and then every 3 months thereafter.1 Following dosage reduction for QT interval prolongation or therapy interruption lasting >2 weeks, monitor ECG as described above.1

  • Because of long half-life (19 days), QT interval prolongation and other adverse effects may not resolve quickly.1 Monitor appropriately.1

  • Avoid concomitant use with drugs known to prolong QT interval.1 (See Specific Drugs under Interactions.) If concomitant use cannot be avoided, monitor ECG more frequently.1

  • Restricted Distribution Program
  • Available only through the CAPRELSA REMS Program.1 Only prescribers and pharmacies certified with the program can prescribe and dispense vandetanib.1 (See REMS and see Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for vandetanib to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of vandetanib and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). Also see Restricted Distribution Program under Dosage and Administration: Administration.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.1 2 4 5 6 7 10

Uses for Vandetanib

Medullary Thyroid Cancer

Treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease1 2 (designated an orphan drug by FDA for this use19 ). Efficacy determined based on improved progression-free survival.1

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Vandetanib Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1 18

  • Diarrhea occurs frequently;1 4 routine use of antidiarrheal agents recommended.1

  • Adverse effects may not resolve immediately because of long half-life (19 days).1 Monitor appropriately.1

Restricted Distribution Program

  • Because of risk of QT interval prolongation, torsades de pointes, and sudden death, FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for vandetanib.20

  • Available only under a restricted distribution program (CAPRELSA REMS Program).1 Only prescribers and pharmacies certified with the program are able to prescribe and dispense vandetanib.1 Contact 800-236-9933 or visit for additional information and to enroll in the program for vandetanib.1

Administration

Oral Administration

Administer tablets orally once daily without regard to meals; do not crush tablets.1

If tablets cannot be swallowed whole, prepare dispersion by placing tablet in a glass containing 60 mL of noncarbonated water (do not use other liquids).1 Without crushing the tablet, stir water for approximately 10 minutes until tablet is dispersed (tablet will not completely dissolve).1 Swallow dispersion immediately; to ensure full dose is administered, mix any residues in the glass again with an additional 120 mL of noncarbonated water and swallow.1

Avoid direct contact of crushed tablets with skin or mucous membranes.1 If such contact occurs, wash affected area thoroughly.1

NG or Gastrostomy Tube

May administer aqueous dispersion through a nasogastric or gastrostomy tube.1 (See Oral Administration under Dosage and Administration.)

Dosage

Adults

Medullary Thyroid Cancer
Oral

300 mg once daily.1 Continue therapy for as long as the patient derives clinical benefit or until unacceptable toxicity occurs.1

Dosage Modification for Toxicity
Oral

If grade 3 or greater toxicity occurs, interrupt vandetanib therapy.1 When toxicity resolves or improves to grade 1, resume at a reduced dosage.1 Adjust dosage in decrements of 100 mg daily (i.e., from 300 to 200 mg daily, from 200 to 100 mg daily).1

Dosage Modification for Cardiovascular Toxicity

If QTcF interval >500 msec, interrupt vandetanib therapy.1 When QTcF returns to <450 msec, resume vandetanib at a reduced dosage.1

If hypertension occurs, may need to reduce dosage or interrupt therapy to control BP.1 If hypertension cannot be controlled, do not resume.1

Dosage Modification for Dermatologic Toxicity

If grade 3 or greater skin reactions occur, interrupt vandetanib therapy.1 When symptoms improve, consider resuming at a reduced dosage or discontinuing permanently.1

Dosage Modification for Diarrhea

If severe diarrhea occurs, interrupt vandetanib therapy.1 When diarrhea improves, resume at a reduced dosage.1

Special Populations

Hepatic Impairment

Do not use in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Reduce initial dosage to 200 mg once daily in patients with moderate (Clcr of 30–49 mL/minute) or severe (Clcr <30 mL/minute) renal impairment.1

Geriatric Patients

No dosage adjustment necessary in patients >65 years of age.1 Manufacturer makes no specific dosage recommendations in patients >75 years of age because of limited data.1

Cautions for Vandetanib

Contraindications

  • Congenital long QT syndrome. 1

Warnings/Precautions

Warnings

Prolongation of QT Interval and Torsades de Pointes

QT interval prolongation, torsades de pointes, ventricular tachycardia, and sudden death reported.1

Do not initiate vandetanib therapy in patients with QTcF interval >450 msec.1 Do not use in patients with a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias, uncompensated heart failure, or in patients with electrolyte disturbances; correct hypocalcemia, hypokalemia, and/or hypomagnesemia before administering.1

Monitor ECG, serum electrolytes (i.e., calcium, magnesium, potassium), and TSH concentrations at baseline, at 2–4 weeks and 8–12 weeks after initiating vandetanib, and then every 3 months thereafter.1 Following dosage reduction for QT interval prolongation or therapy interruption lasting >2 weeks, monitor ECG as described above.1 Maintain serum potassium concentrations at ≥4 mEq/L (within normal range) and serum magnesium and calcium concentrations within normal range.1

Avoid concomitant use with drugs known to prolong QT interval.1 (See Specific Drugs under Interactions.) If concomitant use cannot be avoided, monitor ECG more frequently.1

If QTcF interval >500 msec, interrupt vandetanib therapy.1 When QTcF interval returns to <450 msec, resume at a reduced dosage.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Sensitivity Reactions

Photosensitivity Reactions

Risk of photosensitivity reactions.1 In patients receiving vandetanib for malignancies other than medullary thyroid cancer (i.e., non-small cell lung cancer, hepatocellular carcinoma, brain tumor), photosensitivity reactions (including hyperpigmentation and erythematous edematous lesions) occurred within 3 weeks to 2 months after initiating the drug.3 (See Advice to Patients.)

Other Warnings and Precautions

Dermatologic Effects

Mild to moderate (i.e., rash, acne, dry skin, dermatitis, pruritus, other skin reactions [including palmar-plantar erythrodysesthesia syndrome]) or severe, sometimes fatal, skin reactions (including Stevens-Johnson syndrome) reported.1

Treatment options for mild to moderate skin reactions included topical and systemic corticosteroids, oral antihistamines, and topical and systemic antibiotics.1 Treatment options for severe skin reactions included systemic corticosteroids and permanent discontinuance of vandetanib.1

If grade 3 or greater skin reactions occur, interrupt vandetanib therapy.1 When symptoms improve, consider resuming at a reduced dosage or permanently discontinuing therapy.1

Pulmonary Effects

Interstitial lung disease or pneumonitis, sometimes fatal, reported.1

Consider possible interstitial lung disease in patients presenting with nonspecific respiratory manifestations (e.g., hypoxia, pleural effusion, cough, dyspnea) and in whom infectious, neoplastic, and other causes have been excluded.1

If symptoms of interstitial lung disease are moderate, consider temporarily interrupting vandetanib therapy until symptoms improve; use of corticosteroids and antibiotics may be required.1

If symptoms of interstitial lung disease are severe, discontinue vandetanib; use of corticosteroids and antibiotics may be required until symptoms resolve.1 Upon resolution of severe interstitial lung disease, consider permanent discontinuance of vandetanib.1

In patients who develop radiologic changes suggestive of interstitial lung disease who have few or no symptoms, continue vandetanib therapy with close monitoring at the discretion of the clinician.1

Cerebrovascular Events

Ischemic cerebrovascular events reported.1 Discontinue vandetanib in patients who experience a severe ischemic cerebrovascular event.1 Safety of resuming vandetanib therapy after resolution of an ischemic cerebrovascular event not studied.1

Hemorrhage

Serious, sometimes fatal, hemorrhagic events reported.1 Do not use in patients with a recent history of hemoptysis (≥2.5 mL of red blood).1 Discontinue in patients with severe hemorrhage.1

Cardiovascular Effects

Heart failure reported;1 monitor for manifestations.1 If heart failure occurs, may need to discontinue vandetanib; heart failure may not be reversible following discontinuance.1

Hypertension and hypertensive crisis reported.1 2 Monitor and control BP in all patients as appropriate.1 May need to reduce dosage or interrupt vandetanib therapy.1 If hypertension cannot be controlled, do not resume vandetanib.1

Diarrhea

Diarrhea occurs frequently.1 4 Routine use of antidiarrheal drugs recommended.1

Monitor serum electrolytes and ECG carefully and more frequently in patients with diarrhea.1 (See Prolongation of QT Interval and Torsades de Pointes under Cautions.)

If severe diarrhea occurs, interrupt vandetanib therapy.1 When symptoms improve, resume at a reduced dosage.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Hypothyroidism

Increases in dosages of thyroid replacement therapy were required in 49% of patients in the phase 3 clinical study.1

Monitor TSH concentrations at baseline, at 2–4 weeks and 8–12 weeks after initiating vandetanib, and then every 3 months thereafter.1

If manifestations of hypothyroidism occur, determine thyroid hormone concentrations and adjust thyroid replacement therapy accordingly.1

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) reported.1

Consider possible RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function.1

If RPLS occurs, consider discontinuance of vandetanib.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryotoxic, fetotoxic, and teratogenic in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 (See Advice to Patients.)

Ocular Effects

Blurred vision and corneal opacities (which can lead to halos and decreased visual acuity) reported.1 Not known if corneal opacities will improve after discontinuance of vandetanib.1

If visual changes occur, ophthalmologic evaluation, including slit lamp examination, recommended.1 (See Advice to Patients.)

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in safety or efficacy in geriatric patients (≥65 years of age) compared with younger adults.1 Limited data in patients >75 years of age.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Safety and efficacy not established in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment; use not recommended in these patients.1

Renal Impairment

A lower initial dosage is recommended in patients with moderate (Clcr of 30–49 mL/minute) or severe (Clcr <29 mL/minute) renal impairment.1 (See Renal Impairment under Dosage and Administration.) Monitor ECG closely.1

Not evaluated systematically in patients with end-stage renal disease requiring dialysis.1

Common Adverse Effects

Diarrhea,1 4 rash,1 4 acne,1 nausea,1 4 hypertension,1 4 headache,1 4 fatigue,1 decreased appetite,1 abdominal pain,1 decreased calcium concentrations,1 increased ALT concentrations,1 decreased glucose concentrations.1

Interactions for Vandetanib

Metabolized partially by CYP3A4.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: No clinically important interaction.1

Potent inducers of CYP3A4: Potential decreased plasma vandetanib concentrations.1

Drugs that Prolong QT Interval

Potential additive effect on QT interval prolongation.1 Avoid concomitant use.1 If concomitant use cannot be avoided, monitor ECG more frequently.1 (See Prolongation of QT Interval and Torsades de Pointes under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmic agents, class Ia and III (e.g., amiodarone, disopyramide, dofetilide, procainamide, quinidine, sotalol)

Possible additive effect on QT interval prolongation1 11 12 14

Avoid concomitant use; if concomitant use cannot be avoided, monitor ECG more frequently1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decrease in plasma vandetanib concentrations1

Avoid concomitant use1

Antiemetic agents that prolong QT interval, type 3 serotonin (5-HT3) receptor antagonists (e.g., dolasetron, granisetron, ondansetron)

Possible additive effect on QT interval prolongation1 15

Avoid concomitant use; if concomitant use is necessary, granisetron preferred by some clinicians because of less pronounced effects on ECG intervals compared with dolasetron or ondansetron15

Monitor ECG more frequently during concomitant use1

Antimycobacterials (rifabutin, rifampin, rifapentine)

Possible decrease in plasma vandetanib concentrations1

Avoid concomitant use1

Antipsychotic agents that prolong QT interval (e.g., asenapine, chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone)

Possible additive effect on QT interval prolongation1 12 13 14

Avoid concomitant use; if concomitant use cannot be avoided, monitor ECG more frequently1

Chloroquine

Possible additive effect on QT interval prolongation1

Avoid concomitant use; if concomitant use cannot be avoided, monitor ECG more frequently1

Clarithromycin

Possible additive effect on QT interval prolongation1

Avoid concomitant use; if concomitant use cannot be avoided, monitor ECG more frequently1

Dexamethasone

Possible decrease in plasma vandetanib concentrations1

Avoid concomitant use1

Gatifloxacin

Possible additive effect on QT interval prolongation1 12 14

Avoid concomitant use; if concomitant use cannot be avoided, monitor ECG more frequently1

Itraconazole

Pharmacokinetic interaction unlikely 1

Methadone

Possible additive effect on QT interval prolongation1

Avoid concomitant use; if concomitant use cannot be avoided, monitor ECG more frequently1

Moxifloxacin

Possible additive effect on QT interval prolongation1

Avoid concomitant use; if concomitant use cannot be avoided, monitor ECG more frequently1

St. John’s wort (Hypericum perforatum)

Possible unpredictable decreases in plasma vandetanib concentrations1

Avoid concomitant use1

Tetrabenazine

Possible additive effect on QT interval prolongation1 11

Avoid concomitant use; if concomitant use cannot be avoided, monitor ECG more frequently1

Vandetanib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained within 4–10 hours.1

Steady-state concentrations achieved after approximately 3 months.1

Food

Food has no effect on exposure.1

Special Populations

Following administration of a single 800-mg dose, AUC was comparable between individuals with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment and individuals with normal hepatic function.1 (See Hepatic Impairment under Cautions.)

Following administration of a single 800-mg dose, mean AUC was comparable between individuals with mild renal impairment and individuals with normal renal function; however, in individuals with moderate or severe renal impairment, mean AUC of vandetanib was increased by 39 or 41%, respectively, compared with individuals with normal renal function.1

Higher systemic exposure in Japanese and Chinese patients compared with Caucasian patients receiving the same dose.1

Pharmacokinetics not evaluated in pediatric patients.1

Distribution

Extent

Not known whether vandetanib is distributed into human milk.1 (See Lactation under Cautions.)

Plasma Protein Binding

90–96% (mainly albumin and α1-acid glycoprotein).1

Elimination

Metabolism

Metabolized by CYP3A4 and by flavin-containing monooxygenase enzymes FM01 and FM03 to N-desmethyl-vandetanib and vandetanib-N-oxide, respectively.1

Elimination Route

Eliminated in feces (63%) and urine (25%) as unchanged drug or metabolites.1

Half-life

Median terminal half-life: 19 days.1

Special Populations

No relationship between clearance and age or gender.1

Following administration of a single 800-mg dose, mean clearance was comparable between individuals with mild, moderate, or severe hepatic impairment and individuals with normal hepatic function.1 (See Hepatic Impairment under Cautions.)

Following administration of a single 800-mg dose, mean clearance was comparable between individuals with mild renal impairment and individuals with normal renal function.1 (See Renal Impairment under Cautions.)

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits multiple receptor tyrosine kinases (RTKs),1 2 4 5 6 7 10 which are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis).7 16

  • Various tyrosine kinases and pathways are abnormally activated in medullary thyroid carcinoma cells (e.g., rearranged during transfection [RET] proto-oncogene signaling is associated with development of hereditary medullary thyroid cancer).8 16

  • In vitro, shown to inhibit activity of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), members of the epidermal growth factor receptor (EGFR) family, RET, protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptor kinase family, and members of the Src family of tyrosine kinases.1 2 7 8 16

  • In vivo, shown to reduce tumor cell-induced angiogenesis and tumor vessel permeability; also shown to inhibit tumor growth and metastasis in mouse models of cancer.1

  • No evidence of a relationship between RET mutations and efficacy of vandetanib.1

Advice to Patients

  • A copy of the manufacturer’s patient information (medication guide) for vandetanib must be provided to all patients with each prescription of the drug.20 (See REMS and see also Restricted Distribution Program under Dosage and Administration.) Importance of patients reading the medication guide prior to initiation of therapy and each time the prescription is refilled.1

  • Importance of not crushing vandetanib tablets.1 Importance of avoiding direct contact of crushed tablets with the skin or mucous membranes.1

  • If a dose is missed, importance of not taking the missed dose if it is <12 hours before the next dose.1

  • Risk of QT interval prolongation, torsades de pointes, ventricular tachycardia, and sudden death.1 Importance of regular monitoring of ECG and serum electrolytes.1 Importance of contacting clinician promptly if feelings of lightheadedness or faintness or an irregular heartbeat occurs.1

  • Risk of photosensitivity/phototoxicity reactions.1 Importance of using sunscreen and protective clothing and limiting sun exposure during therapy and for at least 4 months after discontinuance of the drug.1

  • Risk of severe adverse dermatologic effects.1 Importance of contacting clinician promptly if dermatologic manifestations (e.g., rash; acne; dry skin; itching; blisters on skin or in mouth; peeling; fever; muscle or joint aches; redness or swelling of face, hands, or soles of feet) occur.1

  • Risk of interstitial lung disease.1 Importance of promptly reporting new or worsening respiratory manifestations (e.g., shortness of breath, persistent cough, fever).1

  • Risk of diarrhea.1 Importance of using antidiarrheal drugs to manage symptoms; importance of contacting clinician if diarrhea becomes persistent or severe.1 Importance of contacting clinician for regular monitoring of serum electrolytes.1

  • Risk of RPLS.1 Importance of contacting clinician promptly if seizures, headache, visual disturbances, confusion, or difficult thinking occurs.1

  • Importance of women using an effective method of contraception while receiving vandetanib and for at least 4 months after discontinuance.1 Importance of discontinuing nursing while receiving vandetanib therapy.1

  • Risk of blurred vision.1 Importance of avoiding driving a vehicle or operating machinery if blurred vision occurs.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., hepatic or renal impairment, cardiovascular disease).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of vandetanib is restricted.1 (See REMS and Restricted Distribution Program under Dosage and Administration: General.)

Vandetanib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

100 mg

Caprelsa

AstraZeneca

300 mg

Caprelsa

AstraZeneca

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 27, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. AstraZeneca Pharmaceuticals LP. Caprelsa (vandetanib) tablets prescribing information. Wilmington, DE; 2011 Jun.

2. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 022405: Summary review. 2011 Apr 1. From FDA website.

3. AstraZeneca Pharmaceuticals LP. Wilmington, DE: Personal communication.

4. Wells SA, Robinson BG, Gagel RF et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA). J Clin Oncol. 2010; 28 (Suppl. 15): Abstr. No. 5503.

5. Wells SA, Gosnell JE, Gagel RF et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010; 28:767-72. [PubMed 20065189]

6. Robinson BG, Paz-Ares L, Krebs A et al. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2010; 95:2664-71. [PubMed 20371662]

7. Morabito A, Piccirillo MC, Falasconi F et al. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. Oncologist. 2009; 14:378-90. [PubMed 19349511]

8. Gómez K, Varghese J, Jiménez C. Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. J Thyroid Res. 2011; 2011:815826. [PubMed 21687607]

10. Herbst RS, Heymach JV, O’Reilly MS et al. Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs. 2007; 16:239-49. [PubMed 17243944]

11. Lundbeck inc. Xenazine (tetrabenazine) tablets prescribing information. Deerfield, IL.;2009 Sep.

12. Ortho-McNeil-Janssen Pharmaceuticals. Invega (paliperidone) extended-release tablets prescribing information. Titusville, NJ; 2011 Apr.

13. Stollberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol. 2005;20:243-51.

14. Schering Corporation, a subsidiary of Merck & Co., Inc. Saphris (asenapine maleate) sublingual tablets prescribing information. Whitehouse Station, NJ;2011 Jan.

15. Keefe DL. The cardiotoxic potential of the 5-HT(3) receptor antagonist antiemetics: is there cause for concern?. Oncologist. 2002; 7:65-72. [PubMed 11854548]

16. Morabito A, Piccirillo MC, Costanzo R et al. Vandetanib: An overview of its clinical development in NSCLC and other tumors. Drugs Today (Barc). 2010; 46:683-98. [PubMed 20967300]

18. Institute for Safe Medication Practices. ISMP’s list of high-alert medications. Horsham, PA;2008. From ISMP website. Accessed 2011 Jul 22.

19. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site.

20. AstraZeneca Pharmaceuticals LP. Caprelsa (vandetanib) NDA 22-405 proposed risk evaluation and mitigation strategy (REMS). Wilmington, DE; 2011 Apr. Available from FDA website.

21. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 022405: Medical Review(s). 2011 Mar 24. From FDA website.

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