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Vandetanib

FDA Drug Information • Also known as: Caprelsa

Brand Names
Caprelsa
Dosage Form
POWDER
Product Type
BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval [see Warnings and Precautions (5.1) ] . WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH See full prescribing information for complete boxed warning. CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval ( 5.1 ).

Description

11 DESCRIPTION Vandetanib has the chemical name N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl) methoxy]quinazolin-4-amine. The structural and molecular formulas are: C 22 H 24 BrFN 4 O 2 Vandetanib has a molecular weight of 475.36 g/mol. Vandetanib exhibits pH-dependent solubility, with increased solubility at lower pH. Vandetanib is practically insoluble in water with a value of 0.008 mg/mL at 25°C (77°F). CAPRELSA tablets for daily oral administration are available in two dosage strengths containing either 100 mg or 300 mg of vandetanib. The tablet cores contain the following inactive ingredients: calcium hydrogen phosphate dihydrate, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone. The tablet film-coat contains the following inactive ingredients: hypromellose 2910, macrogol 300, and titanium dioxide E171. Chemical Structure

What Is Vandetanib Used For?

1 INDICATIONS AND USAGE CAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA. CAPRELSA is a kinase inhibitor indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. ( 1 ) Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION The recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable toxicity occurs. CAPRELSA may be taken with or without food. Do not take a missed dose within 12 hours of the next dose. Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immediately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow. The dispersion can also be administered through nasogastric or gastrostomy tubes. 300 mg once daily. ( 2 ) CAPRELSA may be taken with or without food. ( 2 ) Dosage reduction may be necessary in the event of severe toxicities or QTc interval prolongation. ( 2.1 ) The starting dose is 200 mg in patients with moderate renal impairment. ( 2.1 ) 2.1 Dosage Adjustment For Adverse Reactions The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or greater toxicities. Interrupt CAPRELSA for the following: Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns to less than 450 ms. CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1. For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade 1 severity, if continued treatment is warranted. Adverse events including QT interval prolongation should be monitored closely as they may not resolve fully until approximately three plasma half-lives of the drug. Monitor appropriately [see Warnings and Precautions (5.1) , (5.2) , (5.3) , (5.4) , (5.5) , (5.6) , (5.7) , and (5.9) ] . For Patients with Renal Impairment Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) renal impairment [see Warnings and Precautions (5.12) and Use in Specific Populations (8.6) ] . For Patients with Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment [see Use in Specific Populations (8.7) ] .

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the label: QT Prolongation and Torsades de Pointes [see Boxed Warning , Warnings and Precautions (5.1) ] Severe Skin Reactions [see Warnings and Precautions (5.2) ] Interstitial Lung Disease [see Warnings and Precautions (5.3) ] Ischemic Cerebrovascular Events [see Warnings and Precautions (5.4) ] Hemorrhage [see Warnings and Precautions (5.5) ] Heart Failure [see Warnings and Precautions (5.6) ] Diarrhea [see Warnings and Precautions (5.7) ] Hypothyroidism [see Warnings and Precautions (5.8) ] Hypertension [see Warnings and Precautions (5.9) ] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10) ] Renal Failure [see Warnings and Precautions (5.12) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.15) ] Osteonecrosis [see Warnings and Precautions (5.16) ] The most common adverse drug reactions (>20%) seen with CAPRELSA and with a between-arm difference of ≥5 % have been diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infections, decreased appetite and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, Contact Sanofi Genzyme at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58% male, 94% white, and had a median age of 50 years. The data described below reflect a median exposure to CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection, decreased appetite, and abdominal pain. Among CAPRELSA-treated patients, dose interruption occurred in 109 (47%) and dose reduction occurred in 83 (36%). Adverse reactions led to study treatment discontinuation in 28 of 231 patients (12%) receiving CAPRELSA and in 3 of 99 patients (3.0%) receiving placebo. Adverse reactions leading to permanent discontinuation in 2 or more (≥0.9%) patients treated with CAPRELSA were: asthenia (1.7%), rash (1.7%), diarrhea (0.9%), fatigue (0.9%), pyrexia (0.9%), elevated creatinine (0.9%), QT prolongation (0.9%), and hypertension (0.9%). Table 1: Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in CAPRELSA-Treated Patients During Randomized Treatment (Between-Arm Difference of ≥5% [All Grades] CTCAE version 3 was used to grade adverse events. ) System Organ Class CAPRELSA 300 mg Placebo Preferred Term N=231 N=99 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Diarrhea/Colitis 57 11 27 2 Nausea 33 1 16 0 Abdominal Pain Includes abdominal pain, abdominal pain upper, lower abdominal pain, and abdominal discomfort. 21 3 11 0 Vomiting 15 1 7 0 Dyspepsia 11 0 4 0 Dry Mouth 9 0 3 0 Skin and Cutaneous Disorders Rash Includes rash, rash (erythematous, generalized, macular, maculopapular, papular, pruritic, and exfoliative), dermatitis, dermatitis bullous, generalized erythema, and eczema. 53 5 12 0 Dermatitis Acneiform/Acne 35 1 7 0 Dry Skin 15 0 5 0 Photosensitivity Reaction 13 2 0 0 Pruritus 11 1 4 0 Nail abnormalities Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection. 9 0 0 0 Alopecia 8 N/A 0 N/A Vascular Disorders Hypertension/Hypertensive Crisis/Accelerated Hypertension 33 9 5 1 Nervous...

Drug Interactions

7 DRUG INTERACTIONS Avoid the use of strong CYP3A4 inducers because they may decrease CAPRELSA exposure. ( 7.1 ) Avoid the use of agents that prolong the QT interval. ( 5.11 ) 7.1 Effect of CYP3A4 Inducers on CAPRELSA Rifampicin, a strong CYP3A4 inducer, decreased vandetanib plasma concentrations. Avoid concomitant use of known strong CYP3A4 inducers during CAPRELSA therapy. Avoid concomitant use of St. John's wort because it can decrease vandetanib exposure unpredictably [see Clinical Pharmacology (12.3) ] . 7.2 Effect of CAPRELSA on OCT2 Transporter CAPRELSA increased plasma concentrations of metformin that is transported by the organic cation transporter type 2 (OCT2). Use caution and closely monitor for toxicities when administering CAPRELSA with drugs that are transported by OCT2 [see Clinical Pharmacology (12.3) ] . 7.3 Effect of CAPRELSA on Digoxin CAPRELSA increased plasma concentrations of digoxin. Use caution and closely monitor for toxicities when administering CAPRELSA with digoxin [see Clinical Pharmacology (12.3) ] . 7.4 Drugs that Prolong the QT Interval Avoid concomitant use of CAPRELSA with agents that may prolong the QT interval [see Warnings and Precautions (5.11) ] .

Contraindications

4 CONTRAINDICATIONS Do not use in patients with congenital long QT syndrome [see Boxed Warning ] . Do not use in patients with congenital long QT syndrome. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on its mechanism of action and findings in animals, CAPRELSA can cause fetal harm when administered to a pregnant woman. There are no available human data on CAPRELSA use in pregnant women to inform a drug-associated risk. Vandetanib is embryotoxic, fetotoxic, and induced fetal malformations in rats at exposures less than or equal to those expected at the recommended human dose of 300 mg/day. Advise patients of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data In reproductive toxicity studies, administration of vandetanib to female rats prior to mating and through the first week of pregnancy at a dose of 25 mg/kg/day (approximately equal to the human exposure at the 300 mg clinical dose based on C max ), there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of live embryos. During organogenesis, vandetanib caused an increase in post-implantation loss, including occasional total litter loss at a dose of 25 mg/kg/day. At doses greater than 10 mg/kg/day (approximately 0.4 times the human C max at the 300 mg clinical dose) treatment with vandetanib resulted in increases in late embryofetal death and decreases in fetal birth weight. A no-effect level for malformations was not identified in this study. Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times the human C max at the 300 mg clinical dose) resulted in dose dependent increases in both malformations of the heart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicating delayed fetal development. In a rat prenatal and postnatal development study, at doses (1 and 10 mg/kg/day) producing mild maternal toxicity during gestation and/or lactation,...

Overdosage

10 OVERDOSAGE In the event of an overdose, monitor patients closely for QTc prolongation. Adverse events including QT interval prolongation should be monitored closely as they may not resolve fully until approximately three plasma half-lives of the drug.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 100 mg Tablets available in bottles containing 30 tablets (NDC 58468-7820-3). 300 mg Tablets available in bottles containing 30 tablets (NDC 58468-7840-3). 16.1 Storage and Handling CAPRELSA tablets should be stored at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted to 59°F–86°F (15°C-30°C) [See USP controlled room temperature]. Procedures for proper handling and disposal of anticancer drugs should be considered. A guideline on this subject has been published. 1 Do not crush CAPRELSA tablets.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.