Vandetanib - Dosages, Indications, Contraindications, and Adverse Effects

Overview

Vandetanib is an anticancer medicine. It is used to treat advanced medullary thyroid carcinoma. It is an anti-neoplastic kinase inhibitor and works against several cell receptors like the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and RET-tyrosine kinase. It is used in cases where cancer cannot be removed by surgery or if it has spread to other parts.

The US FDA approved Vandetanib (United States Food and Drug Administration) on 6th April 2011 to treat locally advanced, unresectable, or metastatic medullary thyroid cancer. AstraZeneca developed the drug, and the rights were sold to Sanofi in 2015.

How Does Vandetanib Work?

Vandetanib is a tyrosine kinase inhibitor that stops cancer cell multiplication by binding to the enzyme receptors. It also prevents the development of new blood vessels in the tumor, thereby stopping the blood supply to the cancer cells.

Indications and Usage:

Vandetanib is indicated in treating progressive or symptomatic medullary thyroid carcinoma in patients with unresectable carcinomas that have advanced locally and are metastatic. Usage of Vandetanib in patients with slow-progressing, asymptomatic carcinoma must be considered before use due to treatment-related risks.

Dosage and Administration:

• The recommended dose of Vandetanib is 300 mg orally once daily.

• Vandetanib can be continued until the patient no longer benefits from treatment or if unacceptable toxicity occurs.

• The medicine can be taken with or without food.

• In case of a missed dose, the dose must not be taken if it is less than 12 hours before the next dose.

Administration in Patients Who Have Difficulty Swallowing Solids:

Vandetanib tablets must not be crushed and used if the patient has difficulty swallowing solids. Instead, the tablet must be dispersed in a glass containing two ounces of non-carbonated water. It must be then stirred for about ten minutes until the tablet is completely dispersed and consumed. The medicine does dissolve completely in water. No other liquids can be used for preparing the dispersion. To ensure that the complete dose is received, the glass must be filled with four ounces of non-carbonated water and consumed.

The dispersed medicine can also be administered through nasogastric or gastrostomy tubes. Exposure to crushed tablets must be avoided. The area must be washed thoroughly if there is skin or mucous membrane contact.

Dosage Adjustment:

• In case of a corrected QT interval, if QTcF is greater than 500 ms, the dosing must be interrupted till QTcF reaches 450 ms, and then the medicine must be resumed at a lower dose.

• For CTCAE (Common Terminology Criteria for Adverse Effects) grade 3 or greater toxicity levels, the dose must be interrupted and resumed once the level reaches grade 1. The daily dose of 300 mg can be reduced to 200 mg (two 100 mg doses) and later to 100 mg if CTCAE remains at grade 3.

• Vandetanib has a 19-day half-life which can cause adverse reactions like prolonged QT intervals that do not resolve quickly. In such cases, the dosing must be monitored cautiously.

In Elderly:

In patients above 65 years, no starting dose adjustment is required. However, there is limited data available for patients above 75 years.

With Concomitant Strong CYP3A4 Inducers:

Concomitant use of strong CYP3A4 inducers like phenytoin, Dexamethasone, Rifampicin, Rifabutin, Rifapentine, Carbamazepine, and Phenobarbital must be avoided. Patients must also avoid taking St. John's Wort.

Patients With Renal Impairment:

The starting dose must be reduced to 200 mg in patients with moderate to severe renal impairment.

Patients With Hepatic Impairment:

Vandetanib must not be used in patients with moderate to severe hepatic impairment as there is no data regarding its safety and efficacy. There is limited data available about the safe use of the drug in hepatic impairment patients.

Dosage Forms and Strengths:

• Vandetanib, 300 mg tablets, are white, oval, biconvex, and film-coated. They are embossed with "Z 300" on one side and plain on the other.

• Vandetanib, 100 mg tablets, are white, round, biconvex, and film-coated. They are embossed with "Z 100" on one side and plain on the other.

Contraindications:

Vandetanib is contraindicated in patients with congenital long QT syndrome.

Warnings and Precautions:

QT Prolongation and Torsades de Pointes:

Vandetanib can cause prolongation of the QT interval in a concentration-dependent manner. Ventricular tachycardia, torsades de pointes, and sudden death have been reported with Vandetanib.

1. The drug should not be started in patients with QTcF greater than 450 ms.

2. It must not be used in patients with a history of torsades de pointes, bradyarrhythmias, congenital long QT syndrome, or uncompensated heart failure.

3. Vandetanib safety has not been studied in patients with a recent myocardial infarction or ventricular arrhythmias.

4. Vandetanib exposure is elevated in patients with impaired renal function.

5. In patients with severe renal impairment, the starting dosage must be reduced to 200 mg, and the QT interval must be carefully monitored.

6. ECG and calcium, potassium, magnesium, and TSH levels must be monitored at the start of treatment, 2 to 4 weeks, 8 to 12 weeks, and every three months after that.

7. In case of diarrhea, ECG and electrolytes must be monitored more often.

8. QT assessments must be done regularly in case of dose reductions or interruptions.

9. Serum calcium, potassium, and magnesium levels must be normal to avoid the risk of ECG QT prolongation.

10. Vandetanib should not be concurrently used with drugs that prolong QT interval. If there is no alternative therapy, ECG monitoring for the QT interval must be done frequently.

11. Vandetanib must be interrupted if QTcF is greater than 500 ms and resumed when it reaches 450 ms with a reduced dosage.

Skin Reactions and Stevens-Johnsons Syndrome:

Severe skin reactions, Stevens-Johnson syndrome, and death have been reported with Vandetanib. Mild to moderate skin reactions manifest acne, rashes, dry skin, dermatitis, and pruritus, which oral antihistamines, topical and systemic corticosteroids, and topical and systemic antibiotics can manage. Severe reactions are managed with systemic corticosteroids and permanent discontinuation of Vandetanib. If CTCAE is grade 3 or has severe skin reactions, Vandetanib must be discontinued until symptoms are improved. Depending on the condition, post-improvement, continuation with reduced dosage, or permanent discontinuation must be decided.

Due to increased photosensitivity with Vandetanib use, patients are advised to wear sunscreen and protective clothing for about four months after discontinuation.

Interstitial Lung Disease:

The development of interstitial lung disease (ILD) has been reported with Vandetanib use. A diagnosis of ILD must be considered in patients with nonspecific respiratory symptoms like cough, dyspnea, hypoxia, or pleural effusion. Patients must also be informed about promptly reporting any new or worsening symptoms.

Patients with radiological changes suggestive of ILD but no symptoms can be continued with Vandetanib but with close monitoring by a physician. In case of moderate symptoms, the therapy must be interrupted, and corticosteroids and antibiotics may be started. In severe cases, permanent discontinuation of Vandetanib must be considered.

Ischemic Cerebrovascular Events:

Ischemic cerebrovascular events that have been fatal have been reported with Vandetanib use. Therefore, the drug must be discontinued in severe cases. The resumption of drug use after reversing cerebrovascular events has not been studied.

Hemorrhage:

Severe hemorrhage has been reported with Vandetanib in a few patients. Therefore, it is recommended to avoid drug use if the patient has a recent history of hemoptysis, more than half a teaspoon, or severe hemorrhage.

Heart Failure:

Cases of irreversible heart failure with Vandetinib use have been reported. Therefore, monitoring the signs and symptoms after stopping the drug is advised.

Diarrhea:

Diarrhea has been reported in patients on Vandetanib. Therefore, Vandetanib must be stopped and resumed in patients with severe diarrhea at a reduced dose upon improvement. Administering anti-diarrheal medications and monitoring the ECG and electrolytes is recommended.

Hypothyroidism:

TSH (thyroid stimulating hormone) levels should be obtained at therapy, at 2 to 3 weeks, 8 to 12 weeks, and three months after that. If symptoms of hypothyroidism occur, thyroid hormone levels must be recorded, and thyroid replacement therapy must be initiated accordingly.

Hypertension:

Hypertension and the hypertensive crisis have been reported with Vandetanib use. Therefore, dose reduction or interruption may be necessary for patients with uncontrolled hypertension. Also, it must be re-considered before starting the drug.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS):

RPLS is a syndrome of subcortical vasogenic edema. Patients on Vandetanib developed symptoms like headache, seizures, mental alterations, confusion, and visual disturbances due to RPLS. Therefore, discontinuation of the drug is recommended in severe cases.

Drug Interactions:

Concurrent use of Vandetanib with strong CYP3A4 inducers, anti-arrhythmic drugs, and drugs that prolong the QT interval must be avoided.

Renal Impairment:

In moderate to severe renal impairment patients, Vandetanib exposure is increased. Therefore, the starting dose must be reduced to 200 mg. There is no evidence regarding patients with end-stage renal disease who require dialysis.

Hepatic Impairment:

Vandetanib is not advised for use in patients with moderate to severe hepatic impairment, as its safety and efficacy have not been studied.

Use in Pregnancy:

Vandetanib can cause fetal harm when used during pregnancy. Therefore, it is advised to avoid becoming pregnant during drug use. Also, effective contraception must be followed during treatment and four months following the stop of treatment.

Vandetanib REMS (Risk Evaluation and Mitigation Strategy) Program:

As Vandetanib is associated with an increased risk of QT prolongation, Torsades de pointes, and sudden death, the medicine is available only through a restricted program called the Vandetanib REMS program. Only prescribers and pharmacies certified with the program can prescribe the drug.

Adverse Reactions:

The following adverse effects were noted with Vandetanib, which included:

• Nausea.

• Vomiting.

• Loss of appetite.

• Weight loss.

• Heartburn.

• Runny nose.

• Weakness.

• Tiredness.

• Stomach pain.

• Insomnia.

• Depression.

• Diarrhea.

• Rash.

• Dermatitis Acneiform.

• Hypertension or Hypertensive crisis.

• Asthenia.

• Prolonged QT interval.

• Photosensitivity reaction.

• Nasopharyngitis.

• Dyspepsia.

• Hypocalcemia.

• Pruritus.

• Proteinuria.

Serious adverse effects that require immediate medical attention include:

• Dry, peeling, or itchy skin.

• Sores or blisters on the skin or in the mouth.

• Fever.

• Chest pain.

• Muscle pain.

• Sudden shortness of breath.

• Persistent cough.

• Rapid breathing.

• Swelling of the hands, feet, and ankles.

• Sudden weight gain.

• Sudden confusion.

• Numbness on one side of the body.

• Difficulty seeing, speaking, walking, or balancing.

• Seizures.

• Sudden severe headache.

• Unusual bruising or bleeding.

For Patients:

What Is Medullary Thyroid Carcinoma, and How Is It Treated?

Medullary thyroid carcinoma is a rare type of thyroid cancer in the thyroid gland's medulla (inner part). It is an aggressive type that metastasizes to the lymphatic system, lungs, liver, bones, and brain. About 75 % of the cases are sporadic, which develop independently, whereas 25 % develop as a part of an inherited condition called multiple endocrine neoplasia type 2.

The main treatment aim is to remove the entire thyroid gland through a thyroidectomy procedure. In case of lymph node involvement, the surgeon may opt for the removal of the affected lymph nodes during the thyroidectomy procedure. The other treatment procedures include radiation, chemotherapy, and targeted therapies, which act on the changes in the DNA.

Vandetanib is a prescription medicine advised in cases of medullary thyroid carcinoma that cannot be removed by surgery or has spread to other structures. The drug works by stopping the growth of cancer cells and restricting the formation of new blood vessels that promote tumor growth.

For Doctors

Drug Interactions

CYP3A4 Inducers:

Concomitant use of CYP3A4 inducers must not be used along with Vandetanib as the plasma concentrations of Vandetanib may vary. St. John's wort can also decrease Vandetanib exposure due to unknown reasons.

CYP3A4 Inhibitors:

In healthy subjects, there was no significant drug interaction between Vandetanib and the potent CYP3A4 inhibitor, Itraconazole.

Drugs That Prolong the QT Interval:

Concurrent use of Vandetanib with drugs that prolong the QT interval must be avoided.

Use in Specific Populations:

Pregnancy:

Vandetanib can lead to fetal harm when administered to pregnant women. Studies conducted on rats have shown to be embryotoxic, fetotoxic, and teratogenic. Therefore, patients who become pregnant during treatment with Vandetanib must be warned about the potential harm to the fetus. Patients are advised to avoid becoming pregnant from treatment until four months after the drug discontinuation.

Nursing Mothers:

It is recommended to avoid using Vandetanib in nursing mothers due to the risk of excretion of most drugs in breast milk. Studies have shown the drug in rats' breast milk. However, depending upon the cause, a doctor must take a stand on whether to advise the patient to discontinue breastfeeding or discontinue the drug based on the importance of drug use in the nursing mother.

Pediatric Patients:

The safety and effectiveness of Vandetanib in pediatric patients are yet to be studied.

Geriatric Patients:

There is no overall difference in the safety and effectiveness of Vandetanib in patients above 65 years compared to younger patients. Therefore, there is no need for adjustment of starting dosage in patients above 65 years. However, there is limited data available on patients over 75 years.

Patients With Renal Impairment:

Patients with mild renal impairment had AUC and clearance values similar to those with normal renal function. However, in moderate to severe renal impairment patients, the average AUC was increased by 39 % and 41 %, respectively, compared with patients with normal renal function. Therefore, reducing the starting dose to 200 mg is recommended in patients with moderate to severe renal impairment.

Patients With Hepatic Impairment:

The drug is not recommended in patients with moderate to severe hepatic impairment as the safety and efficacy of the drug have not been established. Also, there needs to be more data available about the safe use of Vandetanib in patients with hepatic impairment.

Overdosage:

Adverse events due to overdosage must be treated symptomatically. Cases of diarrhea must be managed appropriately. In the event of overdosage, Vandetanib must be immediately interrupted, and measures must be taken to prevent adverse effects. For example, monitoring the ECG within 24 hours to determine QTc prolongation.

Description:

Vandetanib is available in two dosages: 100 mg and 300 mg.

Ingredients:

Tablet Core:

Calcium hydrogen phosphate dihydrate, microcrystalline cellulose, povidone, crospovidone, and magnesium stearate.

Inactive Ingredients:

Hypromellose 2910, macrogol 300, and titanium dioxide E171.

Chemical Name:

Vandetanib is chemically described as N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1­ methylpiperidin-4-yl) methoxy]quinazolin-4-amine.

Molecular Weight:

475.36.

Physical Properties:

Vandetanib has an increased solubility at lower pH. As a result, the drug is practically insoluble in water.

Clinical Pharmacology

Mechanism of Action:

Vandetanib is a kinase inhibitor. It inhibits the activity of tyrosine kinase that includes members of vascular endothelial growth factor (VEGF) receptors, epithelial growth factor receptor (EGFR), protein tyrosine kinase 6, TIE2, and rearranged during transfection (RET). Vandetanib inhibited in vitro endothelial cell migration, proliferation, and survival of new blood vessels. The drug inhibits VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells and EGF-stimulated tyrosine kinase phosphorylation in tumor and endothelial cells.

In vivo studies demonstrated reduced tumor cell-induced angiogenesis, vessel permeability, tumor growth, and metastasis with Vandetanib use.

Pharmacokinetics:

Absorption:

Following oral administration, absorption of Vandetanib is slow. Peak plasma concentrations are achieved at a median of six hours, ranging from four to ten hours. Vandetanib absorption is not affected by food.

Distribution:

In vitro protein binding was about 90 %, with Vandetanib binding significantly to human serum albumin and alpha1 acid glycoprotein. Plasma studies of colorectal cancer patients administered a 300 mg oral dose had 93.7 % protein binding.

Metabolism:

N-oxide and N-desmethyl Vandetanib are the metabolites of Vandetanib that are primarily detected in the plasma, urine, and feces. CYP3A4 and Vandetanib-N-oxide produce n-desmethyl Vandetanib by flavin-containing monooxygenase enzymes FMO1 and FMO3. A glucuronide conjugate was detected in small amounts only in the feces.

Excretion:

Vandetanib is excreted in urine and feces. Therefore, increased plasma creatinine can occur due to Vandetanib's inhibition of creatinine excretion.

Pharmacokinetics in Special Populations:

In the pharmacokinetic evaluation of populations, there was no relationship between oral clearance and the patient's age and gender.

Ethnicity:

Cross-study data suggested that the average exposure in Chinese and Japanese patients was relatively higher compared to Caucasian patients exposed to the same dose.

Pediatric Patients:

The pharmacokinetics of Vandetanib has not been studied in pediatric patients.

Nonclinical Toxicology:

Carcinogenesis, Mutagenesis, and Fertility Impairment:

• Carcinogenicity studies have not been conducted on Vandetanib use.

• In vitro studies revealed that Vandetanib did not have mutagenic properties.

• Nonclinical findings on rats suggested male and female fertility impairment in both male and female rats.

Supply and Storage:

Vandetanib is available in two dosage strengths:

1. 100 mg Tablets - In bottles containing 30 tablets each.

2. 300 mg Tablets - In bottles containing 30 tablets each.

Vandetanib should be stored at 25 degrees Celsius, with excursions permitted to 15 to 30 degrees Celsius. Procedures for the correct handling and disposal of anticancer medicines must be considered. Vandetanib tablets must not be crushed, and direct contact with the skin and mucous membranes must be avoided. In case of accidental contact, the area must be washed thoroughly. Personnel handling the medicines must avoid exposure to crushed tablets.