Caprelsa

If your next dose is due in 12 hours or more, take the missed dose as soon as you remember it. However, if the next dose will be taken in less than 12 hours, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Vandetanib may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• heartburn
• loss of appetite
• weight loss
• stomach pain
• runny nose
• extreme tiredness
• weakness
• difficulty falling asleep or staying asleep
• depression

Some side effects can be serious. If you experience any of these symptoms or those listed in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• diarrhea
• rash or acne
• dry, peeling, or itchy skin
• blisters or sores on the skin or in the mouth
• redness of the face, hands, or soles of the feet
• muscle or joint aches
• fever
• chest pain (which may get worse with deep breaths or cough)
• hiccups or rapid breathing
• sudden shortness of breath
• persistent cough
• swelling of the hands, feet, ankles, or lower legs
• sudden weight gain
• numbness or weakness of the face, arm, or leg, especially on one side of the body
• sudden confusion
• difficulty speaking or understanding
• sudden trouble seeing in one or both eyes
• sudden trouble walking or balancing
• sudden severe headache
• seizures
• unusual bruising or bleeding

Vandetanib may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid taking an herbal supplement containing St. John's wort at the same time you are taking vandetanib.

Avoid exposure to sunlight or tanning beds. Vandetanib can make you sunburn more easily, for up to 4 months after you stop taking the medicine. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

This medicine can pass into body fluids (urine, feces, vomit). Caregivers should wear rubber gloves while cleaning up a patient's body fluids, handling contaminated trash or laundry or changing diapers. Wash hands before and after removing gloves. Wash soiled clothing and linens separately from other laundry.

Many drugs can interact with vandetanib. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with vandetanib, especially:

• anagrelide, arsenic trioxide, droperidol, methadone;
• an antibiotic--azithromycin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, pentamidine, rifampicin;
• an antidepressant--citalopram, escitalopram;
• anti-malaria medication--chloroquine, halofantrine;
• heart medicine--amiodarone, digoxin, disopyramide, dofetilide, dronedarone, flecainide, ibutilide, procainamide, quinidine, sotalol;
• medicine to prevent nausea and vomiting--dolasetron, ondansetron, granisetron; or
• medicine to treat a psychiatric disorder--chlorpromazine, haloperidol, pimozide, thioridazine.

This list is not complete and many other drugs can interact with vandetanib. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

In the event of an overdose, monitor patients closely for QTc prolongation. Because of the 19-day halflife, adverse reactions may not resolve quickly.

Dosage Forms & 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

Safety and efficacy not established

Caprelsa is part of the drug class:

• Protein kinase inhibitors

Caprelsa can cause a change in the electrical activity of your heart called QT prolongation, which can cause irregular heartbeats and that may lead to death. You should not take Caprelsa if you have had a condition called long QT syndrome since birth.

Your healthcare provider should perform tests to check the levels of your blood potassium, calcium, magnesium, and thyroid-stimulating hormone (TSH) as well as the electrical activity of your heart with a test called an electrocardiogram (ECG). You should have these tests:

• Before starting Caprelsa 
• Regularly during Caprelsa treatment:
• 2 to 4 weeks after starting Caprelsa 
• 8 to 12 weeks after starting Caprelsa 
• Every 3 months thereafter
• If your healthcare provider changes your dose of Caprelsa 
• If you start taking medicine that causes QT prolongation
• As instructed by your healthcare provider

Your healthcare provider may stop your Caprelsa treatment for a while and restart you at a lower dose if you have QT prolongation.

Call your healthcare provider right away if you feel faint, light-headed, or feel your heart beating irregularly while taking Caprelsa. These may be symptoms related to QT prolongation.

• Limit exposure to the sun. Caprelsa can make your skin sensitive to the sun. While taking Caprelsa and for 4 months after stopping your Caprelsa treatment, use sun block and wear clothes that cover your skin, including your head, arms and legs when you go outdoors.

• Use caution before driving or using machinery. Keep in mind Caprelsa may make you feel tired, weak, or cause blurred vision.

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Caprelsa passes into your breast milk. You and your healthcare provider should decide if you will take Caprelsa or breastfeed. You should not do both.

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.1 2 4 5 6 7 10

• A copy of the manufacturer’s patient information (medication guide) for vandetanib must be provided to all patients with each prescription of the drug.20 (See REMS and see also Restricted Distribution Program under Dosage and Administration.) Importance of patients reading the medication guide prior to initiation of therapy and each time the prescription is refilled.1

• Importance of not crushing vandetanib tablets.1 Importance of avoiding direct contact of crushed tablets with the skin or mucous membranes.1

• If a dose is missed, importance of not taking the missed dose if it is <12 hours before the next dose.1

• Risk of QT interval prolongation, torsades de pointes, ventricular tachycardia, and sudden death.1 Importance of regular monitoring of ECG and serum electrolytes.1 Importance of contacting clinician promptly if feelings of lightheadedness or faintness or an irregular heartbeat occurs.1

• Risk of photosensitivity/phototoxicity reactions.1 Importance of using sunscreen and protective clothing and limiting sun exposure during therapy and for at least 4 months after discontinuance of the drug.1

• Risk of severe adverse dermatologic effects.1 Importance of contacting clinician promptly if dermatologic manifestations (e.g., rash; acne; dry skin; itching; blisters on skin or in mouth; peeling; fever; muscle or joint aches; redness or swelling of face, hands, or soles of feet) occur.1

• Risk of interstitial lung disease.1 Importance of promptly reporting new or worsening respiratory manifestations (e.g., shortness of breath, persistent cough, fever).1

• Risk of diarrhea.1 Importance of using antidiarrheal drugs to manage symptoms; importance of contacting clinician if diarrhea becomes persistent or severe.1 Importance of contacting clinician for regular monitoring of serum electrolytes.1

• Risk of RPLS.1 Importance of contacting clinician promptly if seizures, headache, visual disturbances, confusion, or difficult thinking occurs.1

• Importance of women using an effective method of contraception while receiving vandetanib and for at least 4 months after discontinuance.1 Importance of discontinuing nursing while receiving vandetanib therapy.1

• Risk of blurred vision.1 Importance of avoiding driving a vehicle or operating machinery if blurred vision occurs.1

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., hepatic or renal impairment, cardiovascular disease).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of vandetanib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of vandetanib in the elderly.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Amisulpride
• Bepridil
• Cisapride
• Dronedarone
• Fluconazole
• Ketoconazole
• Mesoridazine
• Nelfinavir
• Pimozide
• Piperaquine
• Saquinavir
• Sparfloxacin
• Terfenadine
• Thioridazine
• Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfuzosin
• Amiodarone
• Amitriptyline
• Anagrelide
• Apomorphine
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Artemether
• Asenapine
• Astemizole
• Atazanavir
• Azithromycin
• Bedaquiline
• Buserelin
• Carbamazepine
• Ceritinib
• Chloroquine
• Chlorpromazine
• Ciprofloxacin
• Citalopram
• Clarithromycin
• Clomipramine
• Clozapine
• Crizotinib
• Cyclobenzaprine
• Dabrafenib
• Dasatinib
• Degarelix
• Delamanid
• Desipramine
• Deslorelin
• Deutetrabenazine
• Digoxin
• Disopyramide
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Doxepin
• Droperidol
• Ebastine
• Efavirenz
• Enzalutamide
• Eribulin
• Erythromycin
• Escitalopram
• Famotidine
• Felbamate
• Fingolimod
• Flecainide
• Fluoxetine
• Foscarnet
• Fosphenytoin
• Galantamine
• Gatifloxacin
• Gemifloxacin
• Gonadorelin
• Goserelin
• Granisetron
• Halofantrine
• Haloperidol
• Histrelin
• Hydroquinidine
• Hydroxychloroquine
• Hydroxyzine
• Ibutilide
• Idelalisib
• Iloperidone
• Imipramine
• Itraconazole
• Ivabradine
• Lapatinib
• Leuprolide
• Levofloxacin
• Lumefantrine
• Mefloquine
• Metformin
• Methadone
• Metronidazole
• Mifepristone
• Mitotane
• Mizolastine
• Moxifloxacin
• Nafarelin
• Nilotinib
• Norfloxacin
• Octreotide
• Ofloxacin
• Olanzapine
• Ondansetron
• Paliperidone
• Panobinostat
• Paroxetine
• Pasireotide
• Pazopanib
• Pentamidine
• Perphenazine
• Phenytoin
• Pimavanserin
• Pitolisant
• Posaconazole
• Primidone
• Probucol
• Procainamide
• Prochlorperazine
• Promethazine
• Propafenone
• Protriptyline
• Quetiapine
• Quinidine
• Quinine
• Ranolazine
• Ribociclib
• Rifabutin
• Rifampin
• Rifapentine
• Rilpivirine
• Risperidone
• Ritonavir
• Sertindole
• Sevoflurane
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Solifenacin
• Sorafenib
• Sotalol
• St John's Wort
• Sulpiride
• Sunitinib
• Tacrolimus
• Tamoxifen
• Telaprevir
• Telavancin
• Telithromycin
• Tetrabenazine
• Tizanidine
• Tolterodine
• Toremifene
• Trazodone
• Trimipramine
• Triptorelin
• Vardenafil
• Vemurafenib
• Venlafaxine
• Vinflunine
• Voriconazole
• Vorinostat
• Zuclopenthixol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bleeding problems or
• Diarrhea or
• Heart failure or
• Hypertension (high blood pressure) or
• Hypothyroidism (an underactive thyroid) or
• Lung disease (eg, interstitial lung disease, pneumonitis)—Use with caution. May make these conditions worse.

• Bradyarrhythmia (abnormally slow heartbeat) or
• Congenital long QT syndrome (heart disorder), or history of or
• Hemoptysis (spitting or coughing up blood), recent history of or
• Torsade de pointes (abnormal heart rhythm), history of—Should not be used in patients with these conditions.

• Hypocalcemia (low calcium in the blood) or
• Hypokalemia (low potassium in the blood) or
• Hypomagnesemia (low magnesium in the blood)—Use with caution. May cause side effects to be worse.

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach cramps or pain
• bleeding gums
• blurred vision
• body aches or pain
• chest pain
• cloudy urine
• confusion
• convulsions
• cough
• coughing up blood
• difficulty with breathing or swallowing
• dizziness
• ear congestion
• fainting
• fever or chills
• headache
• increased menstrual flow or vaginal bleeding
• irregular heartbeat recurrent
• loss of voice
• muscle cramps in the hands, arms, feet, legs, or face
• nervousness
• nosebleeds
• numbness and tingling around the mouth, fingertips, or feet
• paralysis
• pounding in the ears
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• slow or fast heartbeat
• sneezing
• sore throat
• stuffy or runny nose
• tenderness
• tightness in the chest
• tremor
• troubled breathing
• unusual tiredness or weakness (severe)
• watery or bloody diarrhea

• Blue lips, fingernails, or skin
• chest pain or discomfort
• dilated neck veins
• extreme fatigue
• foreign substance into the lungs
• infection from breathing
• irregular breathing
• irregular heartbeat
• irregular, fast or slow, or shallow breathing
• lightheadedness
• no breathing
• swelling of the face, fingers, feet, or lower legs
• weight gain

• Bloating
• constipation
• darkened urine
• decreased urine output
• indigestion
• loss of appetite
• nausea
• pains in the stomach, side, or abdomen, possibly radiating to the back
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• blemishes on the skin
• blindness
• blistering, crusting, irritation, itching, or reddening of the skin
• change in taste
• cracked, dry, or scaly skin
• cracks in the skin
• decreased appetite
• decreased vision
• decreased weight
• depression
• discoloration of the fingernails or toenails
• dry mouth
• dry skin
• hair loss or thinning of the hair
• heartburn
• increased sensitivity of the skin to sunlight
• itching skin
• lack or loss of strength
• loosening of the fingernails
• loss of heat from the body
• loss of taste
• muscle aches or spasms
• pimples
• rash with flat lesions or small raised lesions on the skin
• red, swollen skin
• redness or other discoloration of the skin
• redness or soreness around the fingernails
• severe sunburn
• stomach discomfort or upset
• swelling
• trouble sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about Caprelsa (vandetanib), please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Caprelsa. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Caprelsa.

Review Date: October 4, 2017

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.

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.

Because of the 19-day half-life, adverse reactions including a prolonged QT interval may not resolve quickly. 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) and severe (creatinine clearance <30 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)].

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

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)].

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)].

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)].

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)].

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.14)]

Risk Summary

Based on its mechanism of action, Caprelsa can cause fetal harm when administered to a pregnant woman. Vandetanib is embryotoxic, fetotoxic, and teratogenic in rats, at exposures less than or equal to those expected at the recommended human dose of 300 mg/day. If Caprelsa is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal data

When vandetanib was administered 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 recommended dose based on Cmax), there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of live embryos.

During organogenesis, a vandetanib dose of 25 mg/kg administered to rats caused an increase in post-implantation loss, including occasional total litter loss. At doses greater than 10 mg/kg (approximately 0.4 times the human exposure at the recommended dose by Cmax) 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 Cmax in patients with cancer at the recommended 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 pre- and post-natal development study, at doses producing mild maternal toxicity (1 and 10 mg/kg/day) during gestation and/or lactation, vandetanib decreased pup survival and/or reduced post-natal pup growth. Reduced post-natal pup growth was associated with a delay in physical development.

Nursing Mothers

In nonclinical studies, vandetanib was excreted in rat milk and found in plasma of pups following dosing to lactating rats. Vandetanib transfer in breast milk resulted in relatively constant exposure in pups due to the long half-life of the drug. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Caprelsa, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and efficacy of Caprelsa in pediatric patients have not been established.

Geriatric Use

The MTC study of Caprelsa did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently compared to younger patients.

Renal Impairment

Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment [see Dosage and Administration (2.1), Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)].

Hepatic Impairment

The pharmacokinetics of Caprelsa were evaluated after a single dose of 800 mg in subjects with mild (n=8), moderate (n=7), and severe (n=6) hepatic impairment and normal hepatic function (n=5). Subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment had comparable mean AUC and clearance values to those with normal hepatic function.

There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). Caprelsa is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration (2.1) and Warnings and Precautions (5.13)].

Females and Males of Reproductive Potential

Contraception

Females of reproductive potential should avoid pregnancy.

Use effective contraception during treatment and up to 4 months after the last dose of Caprelsa.

Infertility

There are no data on the effect of Caprelsa on human fertility. Results from animal studies indicate that vandetanib can impair male and female fertility [see Nonclinical Toxicology (13.1)].

Mechanism of Action

In vitro studies have shown that vandetanib inhibits the tyrosine kinase activity of the EGFR and VEGFR families, RET, BRK, TIE2, and members of the EPH receptor and Src kinase families. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. In addition, the N-desmethyl metabolite of the drug, representing 7 to 17.1% of vandetanib exposure, has similar inhibitory activity to the parent compound for VEGF receptors (KDR and Flt-1) and EGFR.

In vitro, vandetanib inhibited epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells and VEGF-stimulated tyrosine kinase phosphorylation in endothelial cells.

In vivo, vandetanib administration reduced tumor cell-induced angiogenesis, tumor vessel permeability, and inhibited tumor growth and metastasis in mouse models of cancer.

Pharmacodynamics

Cardiac Electrophysiology

In 231 patients with medullary thyroid cancer randomized to receive Caprelsa 300 mg once daily in the phase 3 clinical trial. Caprelsa was associated with sustained plasma concentration-dependent QT prolongation. Based on the exposure-response relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 35 (33–36) ms for the 300 mg dose. The ΔQTcF remained above 30 ms for the duration of the trial (up to 2 years). In addition, 36% of patients experienced greater than 60 ms increase in ΔQTcF and 4.3% of patients had QTcF greater than 500 ms. Cases of Torsades de pointes and sudden death have occurred [see Boxed Warning and Warnings and Precautions (5.1), (5.11)].

. Pharmacokinetics

A population pharmacokinetic analysis of Caprelsa was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of Caprelsa at the 300 mg dose in MTC patients are characterized by a mean clearance of approximately 13.2 L/h, a mean volume of distribution of approximately 7450 L, and a median plasma half-life of 19 days.

Absorption

Following oral administration of Caprelsa, absorption is slow with peak plasma concentrations typically achieved at a median of 6 hours, range 4-10 hours, after dosing. Vandetanib accumulates approximately 8-fold on multiple dosing with steady state achieved in approximately 3 months.

Exposure to vandetanib is unaffected by food

Distribution

Vandetanib binds to human serum albumin and α1-acid-glycoprotein with in vitro protein binding being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state exposure after 300 mg once daily, the mean percentage protein binding was 94%.

Metabolism

Following oral dosing of 14C-vandetanib, unchanged vandetanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was seen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by CYP3A4 and vandetanib-N-oxide by flavin–containing monooxygenase enzymes FMO1 and FMO3. N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 7–17% and 1.4–2.2%, respectively, of those of vandetanib.

Excretion

Within a 21-day collection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% in feces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would be expected based on the plasma half-life.

Vandetanib was not a substrate of hOCT2 expressed in HEK293 cells. Vandetanib inhibits the uptake of the selective OCT2 marker substrate 14C-creatinine by HEK-OCT2 cells, with a mean IC50 of 2.1 μg/mL. This is higher than vandetanib plasma concentrations (0.81 μg/mL) observed after multiple dosing at 300 mg. Inhibition of renal excretion of creatinine by vandetanib provides an explanation for increases in plasma creatinine seen in human subjects receiving vandetanib.

Specific Populations

Effects of Age and Gender

In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance of vandetanib and patient age or gender.

Ethnicity

Based on a cross-study comparison in a limited number of patients, Japanese (N=3) and Chinese (N=7) patients had average exposures of vandetanib that were higher than Caucasian (N=7) patients receiving the same dose of Caprelsa.

Pediatric

The pharmacokinetics of vandetanib has not been evaluated in pediatric patients.

Effect of Renal Impairment

The pharmacokinetics of vandetanib were evaluated after a single Caprelsa dose of 800 mg in six subjects with mild (creatinine clearance = 50 to < 80 mL/min), eight subjects with moderate (creatinine clearance ≥30 to <50 mL/min), six subjects with severe (creatinine clearance < 30 mL/min) renal impairment and ten subjects with normal (creatinine clearance > 80 mL/min) renal function. Subjects with mild renal impairment had a comparable mean AUC of vandetanib to that with normal renal function. In subjects with moderate or severe renal impairment, the average AUC of vandetanib increased by 39% and 41%, respectively, compared to patients with normal renal function [see Dosage and Administration (2.1), Warnings and Precautions (5.12) and Use in Specific Populations (8.6)].

Drug Interactions

Effect of Other Drugs on Caprelsa

Strong CYP3A4 inducers: In a cross-over study in 12 healthy volunteers, a single oral 300 mg dose of Caprelsa was administered alone on day 1 and on day 10 in combination with daily doses of 600 mg of rifampicin (a strong CYP3A4 inducer) given on days 1–31. The coadministration of rifampicin with Caprelsa decreased the geometric mean AUC0–504h of vandetanib by 40% (90% confidence interval (CI): 56%, 63%) compared to vandetanib alone. No clinically meaningful change in the mean Cmax of vandetanib was observed. The geometric mean AUC0–504h and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively, in the presence of rifampicin compared with vandetanib alone [see Drug Interactions (7.1)].

Strong CYP3A4 inhibitors: In a cross-over study in 14 healthy volunteers, a single oral 300 mg dose of Caprelsa was administered alone and on day 4 in combination with daily doses of 200 mg of itraconazole (a strong CYP3A4 inhibitor) given on days 1–24. No change was observed in the geometric mean AUC0–504h or Cmax of vandetanib when itraconazole was coadministered with Caprelsa.

Gastric pH elevating agents: In a cross-over study of 14 healthy volunteers, a single oral 300 mg dose of Caprelsa was administered alone and in combination with five daily doses of 40 mg omeprazole (a proton pump inhibitor). No clinically meaningful change was observed in the geometric mean AUC0–504h and Cmax of vandetanib when omeprazole was coadministered with Caprelsa.

In a cross-over study of 16 healthy volunteers, a single 300 mg oral dose of Caprelsa was administered alone and after two oral doses of 150 mg of ranitidine (a H2 receptor antagonist) administered about 12 hours apart. No change was observed in the geometric mean AUC0–504h and Cmax of vandetanib when ranitidine was coadministered with Caprelsa.

Effect of Caprelsa on Other Drugs

Sensitive CYP3A4 substrates: In a cross-over study of 16 healthy volunteers, a single oral 7.5 mg dose of midazolam (as 2 mg/mL oral syrup), a sensitive CYP3A4 substrate, was administered alone and 8 days after receiving a single 800 mg oral dose of Caprelsa. No change was observed in the geometric mean Cmax and AUCinf of midazolam when Caprelsa was coadministered with midazolam.

Substrates of OCT2 transporter: In a cross-over study of 13 healthy volunteers, a single 1000 mg oral dose of metformin, a substrate of OCT2, was administered alone and 3 hours after receiving a single 800 mg oral dose of Caprelsa. The coadministration of Caprelsa with metformin increased the geometric mean AUCinf of metformin by 74% (90% CI: 58%, 92%) and geometric mean Cmax of metformin by 50% (90% CI: 34%, 67%) compared to metformin alone [see Drug Interactions (7.2)].

Substrates of P-glycoprotein transporter: In a cross-over study of 14 healthy volunteers, a single oral 0.25 mg dose of digoxin, a substrate of P-glycoprotein, was administered alone and in combination with a single 300 mg oral dose of Caprelsa. The coadministration of Caprelsa increased the geometric mean Cmax digoxin by 29% (90% CI: 10%, 52%) and the geometric mean of AUC0–t of digoxin by 23% (90% CI: 12%, 34%) compared to digoxin alone [see Drug Interactions (7.3)].

Take the missed dose as soon as you remember. Skip the missed dose if your next dose is less than 12 hours away. Do not take extra medicine to make up the missed dose.