Vandetanib; Uses,Dosage, Side Effects, Interactions, Pregnancy

Mechanism of Action of Vandetanib

Vandetanib is 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 signaling 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.

or

Oncogenic conversion of the RET /rearranged during transfection/ tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). Vandetanib is an ATP-competitive inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptors kinases. In this study, vandetanib mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying cysteine 634 to tryptophan (C634W) and methionine 918 to threonine (M918T) RET mutation respectively /were studied/. Vandetanib blunted MTC cell proliferation and RET, Shc and p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation. Single receptor knockdown by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the vandetanib-resistant V804M RET mutant rescued the proliferation of TT cells under vandetanib treatment, showing that RET is a key vandetanib target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell-cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by vandetanib may overcome the risk of MTC cells to escape from RET blockade through compensatory over-activation of EGFR.
Source – PubMed

Indications of Vandetanib

• Thyroid Cancer
• Acne
• Acne Vulgaris
• Actinomycosis
• Anthrax
• Intestinal Amebiasis
• Listeria infection
• Meningococcal Infections
• Meningococcal Meningitis
• Metastatic Medullary Thyroid Cancer
• Locally advanced Medullary thyroid cancer
• Vandetanib is indicated for the treatment of aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease.
• Vandetanib is indicated in adults, children, and adolescents aged 5 years and older
• For patients in whom Rearranged during Transfection (RET) mutation is not known or is negative, a possible lower benefit should be taken into account before an individual treatment decision

Contra-Indications of Vandetanib

• Hypothyroidism
• Low amount of magnesium in the blood
• Low amount of calcium in the blood
• low amount of potassium in the blood
• High blood pressure
• Very rapid heartbeat
• Prolonged QT interval on EKG
• Heart failure
• Abnormal EKG with QT changes from Birth
• Lack of Blood Supply to the brain
• Severe Diarrhea
• Pregnancy
• A Mother who is Producing Milk and Breastfeeding
• Moderate to Severe Kidney Impairment
• Lung Tissue Problems
• Brain-Capillary Leak Syndrome

Dosage of Vandetanib

• Strengths: 100 mg; 300 mg

Thyroid Cancer

• Initial dose: 300 mg orally once daily.Duration of therapy: Continue drug until disease progression or unacceptable toxicity occurs.

Side Effects of Vandetanib

The most common

• chest pain
• certainly hair loss
• a headache
• joint painPain
• dizziness
• nausea and vomiting
• Severe stomach ache
• epigastric pain,
• diarrhea,
• anorexia,
• flatulence,
• a headache,
• dizziness,
•  fainting, fast or pounding heartbeats.

More common

• Fast or irregular heartbeat
• appetite loss
• changes in nails
• constipation
• fatigue
• fever
• Back pain
• dizziness
• a headache
• increased cough
• Acid or sour stomach
• decreased appetite
• Agitation
• chest congestion
• chest pain
• cold sweats
• confusion
• decreased sexual ability or desire
• stomach or abdominal cramps, gas, or pain
• trouble sleeping

Less common

• bleeding gums
• blood in the urine or stools
• chest pain
• diarrhea
• Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
• difficulty in moving
• muscle stiffness
• redness of the face, neck, arms and occasionally, upper chest
• lack or loss of strength
• muscle spasm
• difficult or labored breathing
• dry mouth
• headache
• irritability
• lack or loss of strength
• loose stools
• loss of interest or pleasure
• muscle stiffness
• night sweats
• passing gas
• stomach discomfort, upset, or pain
• swollen joints
• trouble concentrating
• increased blood pressure

Drug Interactions of Vandetanib

Vandetanib may interact with following drugs ,suppliments & may decrease the efficacy of drug

• alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
• anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
• “azole” antifungal medications (e.g.,  fluconazole, itraconazole, ketoconazole)
• beta-blockers (e.g., atenolol, propranolol, metoprolol)
• barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
• benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
• calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine, felodipine)
• carbamazepine
• chloroquine
• corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
• cyclosporine
• dantrolene
• “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
• losartan
• macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
• metronidazole
• mirtazapine
• montelukast
• norfloxacin
• ondansetron
• carbamazepine
• phenytoin
• progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
• proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
• selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
• sildenafil
• “statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
• tacrolimus
• tadalafil
• tetracycline
• theophylline
• tocilizumab
• tolterodine
• tramadol
• other selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline)
• 5-HT3 antagonists (e.g., granisetron, ondansetron)
• tamsulosin
• tapentadol
• thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
• tramadol
• tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine, 
• trimethoprim
• other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
• tetracycline
• tocilizumab
• vandetanib
• vemurafenib
• vitamin C

Pregnancy & Lactation of Vandetanib

 FDA Pregnancy Category D

Pregnancy

This medication may cause harm to an unborn fetus and should not be used during pregnancy. If you become pregnant while taking this medication, contact your doctor immediately. Women of childbearing age who are taking vandetanib should use an effective method of birth control (e.g., birth control pill, condoms) during treatment and for at least 3 months after the last dose of vandetanib.Men receiving this medication must use an effective method of contraception during treatment and for two months following the last dose.

Lactation

It is not known if vandetanib passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.

References