Drug information of vandetanib

vandetanib

Drug group:

Vandetanib is an oral once-daily kinase inhibitor of tumor angiogenesis and tumor cell proliferation with the potential for use in a broad range of tumor types.

Mechanism of effect

A potent and selective inhibitor of VEGFR (vascular endothelial growth factor receptor), EGFR (epidermal growth factor receptor) and RET (REarranged during Transfection) tyrosine kinases.

VEGFR- and EGFR-dependent signalling are both clinically validated pathways in cancer, including non-small-cell lung cancer (NSCLC). RET activity is important in some types of thyroid cancer, and early data with vandetanib in medullary thyroid cancer has led to orphan-drug designation by the regulatory authorities in the USA and EU.

Pharmacodynamic

Mean IC50 of approximately 2.1 μg/mL.

Pharmacokinetics

Peak Plasma Time: 6 hr (range 4-10 hr)

Steady State: ~3 months; accumulates ~8-fold with multiple dosing

Protein Bound: 90%

Vd: 7450 L

Metabolism: Metabolized by CYP3A4

Half-Life: 19 days

Clearance: 13.2 L/hr

Excretion: feces (44%), urine (25%); 21 day collection period after single dose

Pharmacogenomics

There is no evidence of a relationship between RET mutations and efficacy of vandetanib

20% of medullary thyroid carcinomas are associated with 1 of 3 inherited endocrine syndromes caused by germline mutations of the RET gene encodes a receptor tyrosine kinase for the glial cell line-derived neurotrophic factor family of extracellular signaling molecules

A gain of function mutations are associated with cancer (eg. medullary thyroid carcinoma, multiple endocrine neoplasias)

Vandetanib has activity against RET as well as vascular endothelial growth factor (VEGF)

 

Drug indications

cancer

Dosage

Adult

Medullary Thyroid Cancer

300 mg PO qDay with or without food

Continued until patients are no longer benefiting from treatment or an unacceptable toxicity occurs

 

Pediatric

Safety and efficacy not established

Drug contraindications

long QT syndrome , Hypersensitivity

Interactions

Promethazine , Palonosetron , Atomoxetine , Amitriptyline , Amiodarone , Epirubicin , Adenosine , Erythromycin , lofexidine , Venetoclax , bosutinib , Bepridil , Pasireotide , bedaquiline , levomethadyl acetate , vemurafenib , glasdegib , Ceritinib , Nilutamide , norfloxacin , rilpivirine , Romidepsin , Crizotinib , Telavancin , Deutetrabenazine , Cabozantinib , Lomefloxacin , gilteritinib , Degarelix , Foscarnet , encorafenib , midostaurin , Triclabendazole , ivosidenib , Paliperidone , Pazopanib , ezogabine , Iloperidone , Perflutren , Pimavanserin , Lumefantrine / artemether , Gatifloxacin , Triflupromazine , Abarelix , Asenapine , Alfuzosin , Eribulin , Inotuzumab‎ , Idarubicin , Anagrelide , probucol , Abiraterone , Procainamide , Mefloquine , Panobinostat , Ribociclib , Dofetilide , Ibutilide , Halothane , Osimertinib , Quinine , Chloroquine , sparfloxacin , Mesoridazine , Apomorphine , valbenazine , Ivabradine , Mifepristone , Dolasetron , Telithromycin , propoxyphene , protriptyline , ISOPROTERENOL , saquinavir , Mirtazapine , primaquine , Metaproterenol , Prochlorperazine , Quinidine , Amoxapine , Ziprasidone , Histrelin , Pentamidine , Quetiapine , lithium , Buprenorphine , Toremifene , Tamoxifen , ritodrine , Leuprolide acetate , escitalopram , Clofazimine , Ranolazine , astemizole , Clozapine , Clomipramine , Solifenacin , Enzalutamide , Flecainide , Bicalutamide , Hydroxychloroquine , Vardenafil , Venlafaxine , Voriconazole , Ketoconazole , Clarithromycin , Maprotiline , Methadone , Moxifloxacin , Nortriptyline , Nilotinib , Haloperidol , Fluoxetine , Fluconazole , Fingolimod , Granisetron , Lapatinib , Levofloxacin , Sevoflurane , Ciprofloxacin , Citalopram , Cisapride , Flutamide , Fluphenazine , Disopyramide , Risperidone , Sunitinib , Sertraline , Sotalol , Sorafenib , Thioridazine , Gemifloxacin , Daunorubicin , Desipramine , Doxepin , Doxorubicin , Tramadol , Terbutaline , Trifluoperazine , Triptorelin , Trimipramine , Tizanidine , Propafenone , Posaconazole , Pimozide , Tacrolimus , Tetrabenazine , Trazodone , Ofloxacin , Oxaliplatin , Ondansetron , Imipramine , Papaverine , perphenazine , Droperidol , Goserelin , Promazine , Vasopressin , Arsenic trioxide , Efavirenz , Etravirine , Halofantrine , Grepafloxacin , Terfenadine , Apalutamide , Edoxaban , Entrectinib , riociguat , Dasatinib , Gemtuzumab , nafcillin , talazoparib , Artesunate

Alerts

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

Obtain ECG, serum potassium, calcium, magnesium, and TSH at baseline, then 2-4 and 8-12 weeks after treatment initiation, then q3months for at least a year thereafter; reduce dose as appropriate

Potent CYP3A4 inducers reduce exposure to vandetanib by up to 40%; however, no clinically significant effect on exposure to vandetanib was observed in the presence of the potent CYP3A4 inhibitors

Fatal skin reactions, including Stevens-Johnson syndrome and severe toxic epidermal necrolysis reported; systemic therapies such as corticosteroids may be required; permanently discontinue therapy for severe skin reactions

Interstitial lung disease (ILD), resulting in death has been reported; interrupt vandetanib and investigate unexplained dyspnea, cough, and fever; appropriate measures should be taken for ILD

Ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypothyroidism, hypertension, and reversible posterior leukoencephalopathy syndrome, have been observed

Can cause fetal harm when administered to pregnant women; avoid pregnancy while receiving vandetanib and for 4 months following treatment

Serious hemorrhagic events, some fatal, have been observed; do not administer with recent history of hemoptysis and discontinue if severe hemorrhage occurs

Heart failure observed, including some fatal cases; may be necessary to discontinue vandetanib; heart failure may not be reversible

Diarrhea is common and routine antidiarrheal agents are recommended to avoid electrolyte disturbances that may exacerbate risk of QT prolongation

Hypothyroidism: 90% of patients enrolled in clinical trials had prior thyroidectomy, 49% of patients randomized to vandetanib required increased thyroid doses compared with 17% of patients in the placebo arm

Hypertension, including hypertensive crisis may occur

The most common laboratory abnormalities (>20%) were decreased calcium, increased ALT, and decreased glucose

Hypersensitivity including anaphylaxis has been reported

Reversible posterior leukoencephalopathy syndrome (RPLS)

  • Syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has been observed
  • This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function
  • In clinical studies, 3 or 4 patients who developed RPLS while taking vandetanib, including one pediatric patient, also had hypertension
  • Consider discontinuation of vandetanib treatment in patients with RPLS

 

Black Box Warnings

Can prolong the QT interval

Torsades de pointes and sudden death have been reported

Should not be used in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome

Hypocalcemia, hypokalemia, and/or hypomagnesemia must be corrected prior to administration and should be periodically monitored

Drugs known to prolong 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

Points of recommendation

  • Tell all of your health care providers that you take vandetanib. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how vandetanib affects you.
  • A very bad and sometimes deadly brain problem called posterior reversible encephalopathy syndrome (PRES) has happened with vandetanib. Call your doctor right away if you have signs like feeling confused, lowered alertness, change in eyesight, loss of eyesight, seizures, or very bad headache.
  • Heart failure has happened with vandetanib, as well as heart failure that has gotten worse in people who already have it. Sometimes, this has been deadly. Tell your doctor if you have heart disease. Call your doctor right away if you have shortness of breath, a big weight gain, a heartbeat that is not normal, or swelling in the arms or legs that is new or worse.
  • Low white blood cell counts have happened with vandetanib. This may lead to a higher chance of getting an infection. Call your doctor right away if you have signs of infection like fever, chills, or sore throat.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor. Rarely, some bleeding problems have been deadly.
  • Call your doctor right away if you have any signs of bleeding problems, like bruising; black, tarry, or bloody stools; bleeding gums; blood in the urine; coughing up blood; cuts that take a long time to stop bleeding; feel dizzy; feeling very tired or weak; nosebleeds; pain or swelling; throwing up blood or throw up that looks like coffee grounds; or very bad headache.
  • If you get diarrhea, you will need to make sure to avoid getting dehydrated. Drink plenty of fluids and watch for weight loss. Talk with your doctor.
  • High blood pressure has happened with vandetanib. Have your blood pressure checked as you have been told by your doctor.
  • You may get sunburned more easily while taking vandetanib and for 4 months after your last dose. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
  • If you are taking digoxin, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with vandetanib.
  • This medicine may affect fertility. Fertility problems may lead to not being able to get pregnant or father a child. Talk with the doctor.
  • This medicine may cause harm to the unborn baby if you take it while you are pregnant.
  • If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting vandetanib. Talk with your doctor.
  • Use birth control that you can trust to prevent pregnancy while taking vandetanib and for 4 months after your last dose.
  • If you get pregnant while taking vandetanib or within 4 months after your last dose, call your doctor right away.
  • To gain the most benefit, do not miss doses.
  • Keep taking vandetanib as you have been told by your doctor or other health care provider, even if you feel well.
  • Take with or without food.
  • Swallow whole. Do not chew, break, or crush.
  • If needed, you may put your dose in 2 ounces (60 mL) of water. Mix for 10 minutes or until the drug is in very small pieces and drink. This drug will not dissolve all the way. Rinse the cup with 4 ounces (120 mL) of water and drink.
  • If the tablet is crushed or broken, do not touch the contents. If you do touch the contents or get it in your eyes, wash hands or eyes right away.
  • If you have upset stomach, throwing up, diarrhea, or are not hungry, talk with your doctor. There may be ways to lower these side effects.
  • Those who have feeding tubes may use vandetanib. Use as you have been told. Flush the feeding tube after vandetanib is given.
  • Take a missed dose as soon as you think about it.
  • If it is less than 12 hours until the next dose, skip the missed dose and go back to your normal time.
Do not take 2 doses at the same time or extra doses.


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