Vandetanib

>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

Vandetanib is a prescription medicine used to treat medullary thyroid cancer that cannot be removed by surgery or that has spread to other parts of the body. 

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of vandetanib there are no specific foods that you must exclude from your diet when receiving vandetanib.

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 vandetanib, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to vandetanib 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 vandetanib, 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 vandetanib 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 vandetanib 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 vandetanib. 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.

Medicines used to treat cancer are very strong and can have many side effects. Before receiving vandetanib, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

Take vandetanib exactly as directed even if you feel well. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

vandetanib comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Swallow the tablet whole. Do not break, crush, or chew it. You may take the tablet with or without food.

If you have trouble swallowing the tablets:

• Dissolve the tablet in a glass containing 2 ounces of non-carbonated water. Do not use any other liquid.
• Stir the mixture for 10 minutes and swallow it right away.
• Rinse the glass with an additional 4 ounces of non-carbonated water and swallow the mixture to make sure you get the full dose of vandetanib.
• This mixture may also be given through a nasogastric or gastrostomy tubes.

Be careful not to handle crushed or broken tablets. If you have contact with broken or crushed tablets, wash your hands or skin with soap and water immediately.

Dosing

The dose of vandetanib will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of vandetanib. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For the treatment of medullary thyroid cancer:
    • Adults—300 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of vandetanib, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of vandetanib and it is less than 12 hours since your regular time, take it as soon as you can and take your next dose at the normal time. If you miss a dose and it is more than 12 hours since your regular time, skip the missed dose and take your next dose at the normal time. Do not use extra medicine to make up for a missed dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Use vandetanib as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• To gain the most benefit, do not miss doses.
• Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
• Take with or without food.
• Swallow whole. Do not chew, break, or crush.
• If needed, you may put your dose in 2 ounces (60 mL) of water. Mix for 10 minutes or until the drug is in very small pieces and drink. This drug will not melt all the way. Rinse the cup with 4 ounces (120 mL) of water and drink.
• If the tablet is crushed or broken, do not touch the contents. If you do touch the contents or get it in your eyes, wash hands or eyes right away.
• If you have upset stomach, throwing up, loose stools (diarrhea), or are not hungry, talk with your doctor. There may be ways to lower these side effects.
• Those who have feeding tubes may use vandetanib. Use as you have been told. Flush the feeding tube after this medicine is given.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is less than 12 hours until the next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Headache.
• Feeling tired or weak.
• Belly pain.
• Not hungry.
• Dry mouth.
• Change in nails.
• Hair loss.
• Change in taste.
• Muscle spasm.
• Signs of a common cold.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

. Medullary Thyroid Cancer (MTC)

Vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

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

. Mechanism of Action

Vandetanib is a tyrosine kinase inhibitor. In vitro studies have shown that Vandetanib inhibits the activity of tyrosine kinases including members of the epidermal growth factor receptor (EGFR) family, vascular endothelial cell growth factor (VEGF) receptors, rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, members of the EPH receptors kinase family, and members of the Src family of tyrosine kinases. Vandetanib inhibits endothelial cell migration, proliferation, survival and new blood vessel formation in in vitro models of angiogenesis. Vandetanib inhibits EGFR-dependent cell survival in vitro. In addition, Vandetanib inhibits 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.

There is no evidence of a relationship between RET mutations and efficacy with Vandetanib.

. Pharmacokinetics

A population pharmacokinetic analysis of Vandetanib was conducted in 231 patients with MTC following oral administration of 300 mg daily doses. The pharmacokinetics of Vandetanib 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 Vandetanib, 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 from 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 93.7% (range 92.2 to 95.7%).

Metabolism

Following oral dosing of 14C-Vandetanib, unchanged vandentanib 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 7-17.1% 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 approximately 2.1 μg/mL. This is higher than Vandetanib plasma concentrations (approximately 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.

Special Populations

Effects of Age and Gender

In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent between oral clearance 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 on average exposures that were higher than Caucasian (N=7) patients receiving the same dose.

Pediatric

The pharmacokinetics of Vandetanib have not been evaluated in pediatric patients.

QT Prolongation

In 231 medullary thyroid cancer patients randomized to receive Vandetanib 300 mg once daily in the phase 3 clinical trial, Vandetanib 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 been reported [see Warnings and Precautions (5.1, 5.11)].

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004 165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs: Am J Health-Syst Pharm. (2006) 63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L. O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Thyroid cancer, medullary (locally advanced or metastatic): Treatment of metastatic or unresectable locally-advanced medullary thyroid cancer (symptomatic or progressive)

Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer's labeling.

Moderate and severe impairment (Child-Pugh class B or C): Use is not recommended.

Concerns related to adverse effects:

• Dermatologic toxicity: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other serious skin reactions (including fatal reactions) have been reported. Mild to moderate skin reactions, including acne, dermatitis, dry skin, palmar-plantar erythrodysesthesia syndrome, pruritus, and rash have also been reported. Withhold treatment for dermatologic toxicity of grade 3 or higher; consider a reduced dose or permanent discontinuation upon improvement in symptoms. Discontinue permanently for severe dermatologic toxicity and refer patient for immediate evaluation. Systemic corticosteroids may be required. Grade 1 acneiform rash may be managed with topical corticosteroids and topical antibiotics; grade 2 may be managed with topical corticosteroids and systemic (oral) antibiotics; grade 3 or intolerable grade 2 acneiform rash may be managed with treatment interruption, topical corticosteroids and systemic (oral) antibiotics and systemic corticosteroids (Lacouture 2014). Increased risk of photosensitivity is associated with vandetanib; effective sunscreen and protective clothing are recommended during and for at least 4 months after treatment discontinuation.

• Gastrointestinal toxicity: Diarrhea may commonly occur. May cause electrolyte imbalance (closely monitor electrolytes and ECGs to detect QT prolongation resulting from dehydration). Withhold treatment until resolution for severe diarrhea; dose reduction is recommended when treatment is resumed. Antidiarrheal medication and/or other routine diarrhea management may be indicated.

• Heart failure: Heart failure (HF) has been reported; monitor for signs and symptoms of HF. May require discontinuation. HF may not be reversible upon discontinuation.

• Hemorrhage: Serious and sometimes fatal hemorrhagic events have been reported with use. Discontinue in patients with severe hemorrhage. Do not administer in patients with a recent history of hemoptysis with ≥2.5 mL of red blood.

• Hypertension: Hypertension and hypertensive crisis have been observed with vandetanib. Monitor blood pressure and initiate or adjust antihypertensive therapy as needed. May require vandetanib dosage adjustment or treatment interruption; discontinue vandetanib (permanently) if blood pressure cannot be adequately controlled.

• Hypothyroidism: Increased doses of thyroid replacement therapy have been required in patients with prior thyroidectomy. Obtain TSH at baseline, at 2 to 4 weeks, 8 to 12 weeks and every 3 months after vandetanib initiation. If signs and symptoms of hypothyroidism occur during treatment, evaluate thyroid hormone levels and adjust replacement therapy if needed.

• Ischemic events: Ischemic cerebrovascular events (some fatal) have been observed with vandetanib. Discontinue treatment in patients with severe ischemic events. The safety of resuming treatment after an ischemic event has not been studied.

• Pulmonary toxicity: Interstitial lung disease (ILD) or pneumonitis (including fatalities) has been reported with vandetanib. Patients should be advised to report any new or worsening respiratory symptoms; ILD should be suspected with nonspecific respiratory symptoms such as hypoxia, pleural effusion, cough or dyspnea. Interrupt therapy for acute or worsening pulmonary symptoms; discontinue if ILD diagnosis is confirmed.

• QT prolongation/sudden death: [US Boxed Warning]: May prolong the QT interval; torsade de pointes and sudden death have been reported. Do not use in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct electrolyte imbalance (hypocalcemia, hypokalemia, and/or hypomagnesemia) prior to initiating therapy. Monitor electrolytes periodically. Avoid the use of QT-prolonging agents. If concomitant use with QT-prolonging agents cannot be avoided, monitor ECG more frequently. Monitor electrolytes, TSH, and ECG at baseline, 2 to 4 weeks, and 8 to 12 weeks after therapy initiation, and then every 3 months or as clinically necessary (more frequently if clinically indicated). Vandetanib has a long half-life (19 days), therefore, adverse reactions (including QT prolongation) may resolve slowly; monitor appropriately. Ventricular tachycardia has also been reported. The potential for QT prolongation is dose dependent. Do not initiate treatment unless Fridericia-corrected QT interval (QTcF) is <450 msec. During treatment, if QTcF >500 msec, withhold vandetanib and resume at a reduced dose when QTcF is <450 msec. Do not use in patients with a history of torsade de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure. Patients with ventricular arrhythmias or recent MI were excluded from clinical trials. To reduce the risk of QT prolongation, maintain serum calcium and magnesium within normal limits and maintain serum potassium ≥4 mEq/L.

• Reversible posterior leukoencephalopathy syndrome (RPLS): RPLS been observed with vandetanib. Symptoms of RPLS include altered mental function, confusion, headache, seizure, or visual disturbances; generally associated with hypertension. Discontinue treatment if RPLS occurs.

Disease-related concerns:

• Hepatic impairment: Data is limited; a single-dose pharmacokinetic study demonstrated comparable mean vandetanib AUC and clearance between healthy patients and hepatically impaired (mild-severe) patients. Manufacturer labeling does not provide specific recommendations in mild impairment; not recommended for use in patients with moderate-to-severe hepatic impairment.

• Renal impairment: Dosage reduction is recommended in patients with moderate-to-severe renal impairment. Exposure is increased in patients with impaired renal function; closely monitor QT interval. Has not been studied in patients with end stage renal disease requiring dialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Due to the risk for serious treatment-related adverse events, use in patients whose disease is not progressive or symptomatic should be only be undertaken after careful consideration.

• Restricted access: [US Boxed Warning]: Vandetanib is only available through a restricted access program; prescribers and pharmacies must be certified with the restricted distribution program to prescribe and dispense vandetanib.

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

Use: For the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Mild renal impairment (CrCl 50 mL/min or greater): No dose adjustment recommended.
Moderate to severe renal impairment (CrCl less than 50 mL/min): Initial dose: 200 mg orally once daily.

Administration advice:
-May be taken with or without food.
-Do not crush or chew tablets; swallow whole with water.
-For patients who have difficulty swallowing tablets, a dispersion of the tablet in water may be used: Drop tablet in 2 ounces of non-carbonated water, stir for about 10 minutes (tablet will not completely dissolve); swallow the dispersion immediately; to ensure complete dosing, mix any remaining residue with 4 ounces of non-carbonated water and swallow. The dispersion may also be administered through nasogastric or gastrostomy tubes.
-If contact occurs with crushed tablet, wash affected area well with water.
-Missed dose: If a dose is missed, the missed dose should be skipped if it is less than 12 hours before the next scheduled dose. Patients should not take a double dose to make up for a missed dose.

General:
-For patients with indolent, asymptomatic, or slowly progressing disease, carefully consider treatment-related risks.
-Treatment should be initiated and supervised by a clinician experienced with the management of medullary thyroid cancer, use of anticancer medicinal products, and experienced in the assessment of ECGs.

Monitoring:
-Obtain an ECG, serum potassium, calcium, magnesium, and TSH, at baseline, at 2 to 4 weeks, at 8 to 12 weeks, and every 3 months thereafter; maintain potassium at 4 mEq/L or higher (within normal range).
-Monitor electrolytes and ECG more frequently as clinically indicated.
-Perform ophthalmologic examination, including slit lamp examination, in patients who experience visual changes.

Patient Advice:
-Advise patient to contact healthcare provider if they experience cardiac symptoms, skin reactions, respiratory symptoms, diarrhea, or CNS symptoms such as seizures, visual disturbances, or difficulty thinking.
-Advise patient to use effective contraception during therapy and for 4 months following the last dose; if pregnancy is suspected, patients should seek medical advice and counseling.
-Advise patient to use appropriate sun protection during therapy and for 4 months following the last dose.