vandetanib (Caprelsa)

Dosing and uses of Vandetanib (Caprelsa)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 100mg
• 300mg

 

Medullary Thyroid Cancer

Indicated for treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease

300 mg PO qDay with or without food

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

Dose Reduction

• Dose reduction may be necessary with emergence of severe toxicities or QTc interval prolongation
• In event of QTc interval >500 ms, interrupt dosing until <450 ms, then resume at a reduced dose
• In the presence of CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or greater, interrupt dosing until toxicity resolves or improves to grade 1, then resume at reduced dose
• 300 mg daily dose may be reduced to 200 mg/day and then 100 mg for CTCAE grade 3 or greater

 

Renal and Hepatic Impairment

CrCl 50 mL/min or greater: Dose adjustment not necessary

Moderate (CrCl 30 to <50 mL/min) to severe (CrCl <30 mL/min) renal impairment: Reduce starting dose to 200 mg PO qDay

 

Hepatic Impairment

Mild liver impairment: Dose adjustment not described in manufacturer's labeL

Moderate-to-severe liver impairment (Child-Pugh B/C): Not recommended because of limited data

 

Administration

If a patient misses a dose, the missed dose should not be taken if it is <12 hours before the next dose

Vandetanib tablets should not be crushed

Only available via restricted access prescribing and dispensing program, to enroll in the Vandetanib REMS Program, call 1-800-817-2722 or visit www.vandetanibrems.com

Dispersing tablets in water to aid swallowing

• If patient unable to swallow tablet whole, disperse tablet in 2 ounces of noncarbonated water and stir for approximately 10 minutes until the tablet is dispersed (will not completely dissolve); no other liquids besides water 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 noncarbonated water and swallowed
• The dispersion can also be administered via NG or GT
• Avoid direct contact of crushed tablets with the skin or mucous membranes; if contact occurs, wash thoroughly

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Vandetanib (Caprelsa) adverse (side) effects

>10%

Diarrhea (57%)

Rash (53%)

Dermatitis acneiform/acne (35%)

Nausea (33%)

Hypertension/Hypertensive Crisis/Accelerated Hypertension (33%)

Headache (26%)

Fatigue (24%)

Upper respiratory tract infection (23%)

Decreased appetite (21%)

Abdominal pain (21%)

Dry skin (15%)

Vomiting (15%)

QT prolongation (14%)

Photosensitivity reaction (13%)

Corneal abnormalities (13%)

Dyspepsia (11%)

Hypocalcemia (11%)

Pruritus (11%)

 

1-10%

Proteinuria (10%)

Depression (10%)

Dry mouth (9%)

Nail abnormalities (9%)

Blurred vision (9%)

Alopecia (8%)

Dysgeusia (8%)

Hypothyroidism (6%)

Muscle spasms (6%)

 

<1%

Intestinal perforation (0.4%)

 

Postmarketing Reports

Skin Reactions and Stevens-Johnson Syndrome

 

Warnings

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

Monitor appropriately

Because of risks of QT prolongation, Torsades de pointes, and sudden death, therapy available only through restricted distribution program called the CAPRELSA REMS Program. 1-800-236-9933 or visit www.caprelsarems.com

 

Contraindications

Hypersensitivity

Congenital long QT syndrome

 

Cautions

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

Prolonged QT Interval, Torsades de pointes, and sudden death have been reported

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

 

Pregnancy and lactation

Pregnancy category: d

If vandetanib 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 4 months following the last dose of vandetaniB

Lactation: Unknown whether distributed in breast milk; do not breastfeed during or for at least 4 months following last dose of vandetaniB

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Vandetanib (Caprelsa)

Mechanism of action

Tyrosine kinase inhibitor (TKI) with selective activity against RET, VEGFR-2, and EGFR; TKI inhibition blocks angiogenesis and cellular proliferation

 

Absorption

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

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

 

Distribution

Protein Bound: 90%

Vd: 7450 L

 

Metabolism

Metabolized by CYP3A4

 

Elimination

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 RET 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)