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VANDETANIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Vandetanib is a tyrosine kinase inhibitor. It inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells, and vascular endothelial cell growth factor (VEGF)-stimulated tyrosine kinase phosphorylation in endothelial cells.

Specific Substances

    1) AZD-6474
    2) ZD-6474
    3) CAS 338992-00-0

Available Forms Sources

    A) FORMS
    1) Vandetanib is available as 100 mg and 300 mg film-coated tablets (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) USES
    1) Vandetanib is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients who have locally advanced or metastatic disease that is unresectable (Prod Info CAPRELSA(R) oral tablets, 2011).
    2) Vandetanib is only available through the Vandetanib Risk Evaluation and Mitigation Strategy (REMS) program, a restricted distribution program, due to the risk of developing QT prolongation, torsade de pointes and sudden death in patients who are taking this medication (Prod Info CAPRELSA(R) oral tablets, 2011).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Vandetanib is used to treat symptomatic or progressive medullary thyroid cancer in patients who have locally advanced or metastatic disease that is unresectable.
    B) PHARMACOLOGY: Inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells, and vascular endothelial cell growth factor (VEGF)-stimulated tyrosine kinase phosphorylation in endothelial cells.
    C) EPIDEMIOLOGY: Overdose is rare. Vandetanib is only available through the Vandetanib Risk Evaluation and Mitigation Strategy (REMS) program, a restricted distribution program.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%).
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include prolonged QT interval, dry skin, photosensitivity reaction, pruritus, vomiting, asthenia, insomnia, hypocalcemia, proteinuria, increased serum creatinine, increased liver enzymes, bleeding, neutropenia, thrombocytopenia, and depression.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Rash, diarrhea, and hypertension were reported in patients and in healthy volunteers who received multiple doses at and above 300 mg.
    2) SEVERE TOXICITY: Severe toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses, and may include fatigue, severe skin rashes, hypertension, QT interval prolongation, torsades de pointes, and death.
    0.2.20) REPRODUCTIVE
    A) Vandetanib is classified as FDA pregnancy category D. Animal studies, conducted in rats, have shown vandetanib to be embryotoxic, fetotoxic, and teratogenic at doses equivalent to or lower than the recommended human dose of 300 mg/day.

Laboratory Monitoring

    A) Monitor serum electrolytes, including calcium and magnesium, in patients with significant overdose.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    C) Monitor renal function and liver enzymes after significant overdose.
    D) Monitor CBC with differential and platelets.
    E) Monitor vital signs.
    F) Obtain a chest X-ray in patients with respiratory symptoms to evaluate for evidence of interstitial lung disease.
    G) Serum vandetanib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) QT prolongation and torsades de pointes have been reported with therapeutic doses and may occur following overdose. Treat torsades de pointes with IV magnesium sulfate and correct electrolyte abnormalities; overdrive pacing. Hemorrhagic events have been observed. Transfusions as needed for severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in patients who are awake and able to protect their airway.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain their airway or if the airway is protected.
    D) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect their airway, or if unstable dysrhythmias develop.
    E) ANTIDOTE
    1) None.
    F) TORSADES DE POINTES
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium, isoproterenol, and/or atrial overdrive pacing. Correct electrolyte abnormalities (hypomagnesemia, hypokalemia, hypocalcemia). MAGNESIUM SULFATE/DOSE: ADULT: 2 g IV over 1 to 2 min, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr if dysrhythmias recur. CHILD: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 min. OVERDRIVE PACING: Begin at 130 to 150 beats/min, decrease as tolerated. Avoid class Ia (quinidine, disopyramide, procainamide), class Ic (flecainide, encainide, propafenone) and most class III antidysrhythmics (N-acetylprocainamide, sotalol).
    G) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be effective due to high protein binding (90%) and large volume of distribution.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions of one or two extra doses can be monitored at home.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients demonstrating severe fluid and electrolyte imbalance, QTc prolongation or cardiovascular instability should be admitted.
    4) CONSULT CRITERIA: Consult with an oncologist, medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) When managing a suspected vandetanib overdose, the possibility of multi-drug involvement should be considered. Toxic effects may be prolonged due to long plasma half-life (19 days).
    J) PHARMACOKINETICS
    1) Protein binding is approximately 90%, volume of distribution is 7450 L. Following a single radiolabeled dose, 69% was recovered, with 25% recovered from urine and 44% recovered from feces. Mean plasma half-life, following oral administration of 300 mg daily, was 19 days.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause myelosuppression (eg, pazopanib, sorafenib) or QT interval prolongation.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Rash, diarrhea, and hypertension were reported in patients and in healthy volunteers who received daily doses of 600 mg and 1200 mg vandetanib.
    B) THERAPEUTIC DOSE: The recommended adult dose is 300 mg orally daily. Safety and efficacy have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Vandetanib is used to treat symptomatic or progressive medullary thyroid cancer in patients who have locally advanced or metastatic disease that is unresectable.
    B) PHARMACOLOGY: Inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells, and vascular endothelial cell growth factor (VEGF)-stimulated tyrosine kinase phosphorylation in endothelial cells.
    C) EPIDEMIOLOGY: Overdose is rare. Vandetanib is only available through the Vandetanib Risk Evaluation and Mitigation Strategy (REMS) program, a restricted distribution program.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects include diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%).
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include prolonged QT interval, dry skin, photosensitivity reaction, pruritus, vomiting, asthenia, insomnia, hypocalcemia, proteinuria, increased serum creatinine, increased liver enzymes, bleeding, neutropenia, thrombocytopenia, and depression.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Rash, diarrhea, and hypertension were reported in patients and in healthy volunteers who received multiple doses at and above 300 mg.
    2) SEVERE TOXICITY: Severe toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses, and may include fatigue, severe skin rashes, hypertension, QT interval prolongation, torsades de pointes, and death.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) BLURRED VISION was reported in 9% of patients who received vandetanib compared with 1% of patients who received placebo for medullary thyroid cancer. Examination revealed corneal opacities (vortex keratopathies) in vandetanib-treated patients (Prod Info CAPRELSA(R) oral tablets, 2011).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, QT prolongation (all Grades) was reported in 14% (33 of 231) of patients who received vandetanib 300 mg compared with 1% (1 of 99) of patients who received placebo. Grade 3-4 QT prolongation was reported in 8% of vandetanib-treated patients compared with 1% of placebo-treated patients. Using Fridericia correction, QT prolongation of greater than 450 msec was reported in 69% of patients and QT prolongation of greater than 500 msec was reported in 7% of patients who received vandetanib. QT interval prolongation led to drug discontinuation in more than 1 vandetanib-treated patient (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, hypertension/hypertensive crisis/accelerated hypertension (all Grades) was reported in 33% (76 of 231) of patients who received vandetanib 300 mg compared with 5% (5 of 99) of patients who received placebo. Grade 3-4 hypertension/hypertensive crisis/accelerated hypertension was reported in 9% of vandetanib-treated patients compared with 1% of placebo-treated patients. Hypertension led to drug discontinuation in more than 1 vandetanib-treated patient (Prod Info CAPRELSA(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) Rash, diarrhea, and hypertension were reported in patients and in healthy volunteers who received multiple doses at and above 300 mg (Prod Info CAPRELSA(R) oral tablets, 2011).
    C) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Heart failure has been reported, with fatalities in some instances, in patients who have received vandetanib (Prod Info CAPRELSA(R) oral tablets, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) Cases of interstitial lung disease (ILD) or pneumonitis, some resulting in death, have been reported in patients who received vandetanib (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) Adverse reactions that resulted in death occurred in 5 patients who received vandetanib (n=231) and included respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrythmia, and sepsis in randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer (Prod Info CAPRELSA(R) oral tablets, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, headache (all Grades) was reported in 26% (59 of 231) of patients who received vandetanib 300 mg compared with 9% (9 of 99) of patients who received placebo. Grade 3-4 headache was reported in 1% of vandetanib-treated patients compared with 0% of placebo-treated patients (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, asthenia (all Grades) was reported in 15% (34 of 231) of patients who received vandetanib 300 mg compared with 11% (11 of 99) of patients who received placebo. Grade 3-4 asthenia was reported in 3% of vandetanib-treated patients compared with 1% of placebo-treated patients. Asthenia led to drug discontinuation in more than 1 vandetanib-treated patient (Prod Info CAPRELSA(R) oral tablets, 2011).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, insomnia was reported in 13% (30 of 231) of patients who received vandetanib 300 mg compared with 10% (10 of 99) of patients who received placebo (Prod Info CAPRELSA(R) oral tablets, 2011).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, fatigue (all Grades) was reported in 24% (55 of 231) of patients who received vandetanib 300 mg compared with 23% (23 of 99) of patients who received placebo. Grade 3-4 fatigue was reported in 6% of vandetanib-treated patients compared with 1% of placebo-treated patients. Fatigue led to drug discontinuation in more than 1 vandetanib-treated patient (Prod Info CAPRELSA(R) oral tablets, 2011).
    E) ISCHEMIC STROKE
    1) WITH THERAPEUTIC USE
    a) Vandetanib has been associated with ischemic cerebrovascular events, including some fatalities. In the randomized medullary thyroid cancer study, ischemic cerebrovascular events (none fatal) were reported in 1.3% of patients who received vandetanib 300 mg (n=231) compared with 0% of patients who received placebo (n=99) (Prod Info CAPRELSA(R) oral tablets, 2011).
    F) POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
    1) WITH THERAPEUTIC USE
    a) Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in patients who received vandetanib. RPLS may present as headache, seizure, visual disturbances, confusion, or altered mental function. Hypertension was also present in 3 of the 4 vandetanib-treated patients (including one pediatric patient) who developed RPLS during clinical trial (Prod Info CAPRELSA(R) oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, diarrhea/colitis (all Grades) was reported in 57% (132 of 231) of patients who received vandetanib 300 mg compared with 27% (27 of 99) of patients who received placebo. Grade 3-4 diarrhea/colitis was reported in 11% of vandetanib-treated patients compared with 2% of placebo-treated patients. Diarrhea led to drug discontinuation in more than 1 vandetanib-treated patient (Prod Info CAPRELSA(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) Rash, diarrhea, and hypertension were reported in patients and in healthy volunteers who received multiple doses at and above 300 mg (Prod Info CAPRELSA(R) oral tablets, 2011)
    B) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, nausea (all Grades) was reported in 33% (77 of 231) of patients who received vandetanib 300 mg compared with 16% (16 of 99) of patients who received placebo. Grade 3-4 nausea was reported in 1% of vandetanib-treated patients compared with 0% of placebo-treated patients (Prod Info CAPRELSA(R) oral tablets, 2011).
    b) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, vomiting (all Grades) was reported in 15% (34 of 231) of patients who received vandetanib 300 mg compared with 7% (7 of 99) of patients who received placebo. Grade 3-4 vomiting was reported in 1% of vandetanib-treated patients compared with 0% of placebo-treated patients (Prod Info CAPRELSA(R) oral tablets, 2011).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, abdominal pain (all Grades) was reported in 21% (48 of 231) of patients who received vandetanib 300 mg compared with 11% (11 of 99) of patients who received placebo. Grade 3-4 abdominal pain was reported in 3% of vandetanib-treated patients compared with 0% of placebo-treated patients. Abdominal pain included reports of both upper and lower abdominal pain and abdominal discomfort (Prod Info CAPRELSA(R) oral tablets, 2011).
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, decreased appetite (all Grades) was reported in 21% (49 of 231) of patients who received vandetanib 300 mg compared with 12% (12 of 99) of patients who received placebo. Grade 3-4 decreased appetite was reported in 4% of vandetanib-treated patients compared with 0% of placebo-treated patients (Prod Info CAPRELSA(R) oral tablets, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, an increase in the ALT (all Grades) was reported in 51% (118 of 231) of patients who received vandetanib 300 mg compared with 19% (19 of 99) of patients who received placebo. Grade 3-4 increased ALT was reported in 2% of vandetanib-treated patients compared with 0% of placebo-treated patients. Vandetanib therapy was continued in 16 of 22 patients with Grade 2 elevation in ALT, and levels returned to normal within 6 months in 7 of those patients (Prod Info CAPRELSA(R) oral tablets, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PROTEINURIA
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, proteinuria was reported in 10% (23 of 231) of patients who received vandetanib 300 mg compared with 2% (2 of 99) of patients who received placebo (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, an increase in the serum creatinine concentration was reported in 16% (38 of 231) of patients who received vandetanib 300 mg compared with 1% (1 of 99) of patients who received placebo (Prod Info CAPRELSA(R) oral tablets, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) In the randomized portion of the medullary thyroid cancer study, Grade 1-2 bleeding events were reported in 14% of patients who received vandetanib compared with 7% of patients who received placebo. In the 300-mg monotherapy safety program, Grade 1-2 bleeding events were reported in 13% of patients who received vandetanib (Prod Info CAPRELSA(R) oral tablets, 2011).
    b) Serious hemorrhage, including some fatal cases, has been reported in patients who received vandetanib. Although, in the randomized medullary thyroid cancer study, no fatal bleeding events were reported in patients who received vandetanib 300 mg (n=231) or in patients who received placebo (n=99), fatal bleeding events were reported in 3 vandetanib-treated patients in other clinical studies (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) DECREASED PLATELET COUNT
    1) WITH THERAPEUTIC USE
    a) In the randomized portion of the medullary thyroid cancer study, a decrease in platelets (all grades) was reported in 9% (18 of 231) of patients who received vandetanib compared with 3% (3 of 99) of patients who received placebo (Prod Info CAPRELSA(R) oral tablets, 2011).
    C) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, a decrease in neutrophils (all Grades) was reported in 10% (21 of 231) of patients who received vandetanib 300 mg compared with 5% (5 of 99) of patients who received placebo (Prod Info CAPRELSA(R) oral tablets, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, rash (all Grades) was reported in 53% (123 of 231) of patients who received vandetanib 300 mg compared with 12% (12 of 99) of patients who received placebo. Grade 3-4 rash was reported in 5% of vandetanib-treated patients compared with 0% of placebo-treated patients. Rash included erythematous, generalized, macular, maculopapular, papular, pruritic, exfoliative, dermatitis, bullous dermatitis, generalized erythema, and eczema. Rash led to drug discontinuation in more than 1 vandetanib-treated patient (Prod Info CAPRELSA(R) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) Rash, diarrhea, and hypertension were reported in patients and in healthy volunteers who received multiple doses at and above 300 mg (Prod Info CAPRELSA(R) oral tablets, 2011)
    B) ACNE
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, dermatitis acneiform/acne (all Grades) was reported in 35% (81 of 231) of patients who received vandetanib 300 mg compared with 7% (7 of 99) of patients who received placebo. Grade 3-4 acne was reported in 1% of vandetanib-treated patients compared with 0% of placebo-treated patients (Prod Info CAPRELSA(R) oral tablets, 2011).
    C) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, photosensitivity reaction (all Grades) was reported in 13% (31 of 231) of patients who received vandetanib 300 mg compared with 0% of patients who received placebo (n=99). Grade 3-4 photosensitivity reaction was reported in 2% of vandetanib-treated patients compared with 0% of placebo-treated patients (Prod Info CAPRELSA(R) oral tablets, 2011).
    D) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome, with some fatal cases, has been reported in patients who received vandetanib (Prod Info CAPRELSA(R) oral tablets, 2011).
    E) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, dry skin was reported in 15% (35 of 231) of patients who received vandetanib 300 mg compared with 5% (5 of 99) of patients who received placebo (Prod Info CAPRELSA(R) oral tablets, 2011).
    F) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, pruritus (all Grades) was reported in 11% (25 of 231) of patients who received vandetanib 300 mg compared with 4% (4 of 99) of patients who received placebo. Grade 3-4 pruritus was reported in 1% of vandetanib-treated patients compared with 0% of placebo-treated patients (Prod Info CAPRELSA(R) oral tablets, 2011).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) DECREASED GLUCOSE LEVEL
    1) WITH THERAPEUTIC USE
    a) In randomized clinical trials of unresectable locally advanced or metastatic medullary thyroid cancer, decreased glucose was reported in 24% (55 of 231) of patients who received vandetanib 300 mg compared with 7% (7 of 99) of patients who received placebo (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) In the randomized medullary thyroid cancer study, thyroid replacement therapy dose increases were required in 49% of patients who received vandetanib 300 mg (n=231) compared with 17% of patients who received placebo (n=99). Of all study subjects, 90% had a prior thyroidectomy (Prod Info CAPRELSA(R) oral tablets, 2011).

Reproductive

    3.20.1) SUMMARY
    A) Vandetanib is classified as FDA pregnancy category D. Animal studies, conducted in rats, have shown vandetanib to be embryotoxic, fetotoxic, and teratogenic at doses equivalent to or lower than the recommended human dose of 300 mg/day.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Administration of vandetanib 1, 10 and 25 mg/kg/day (approximately 0.03, 0.4 and 1 times the Cmax in patients with cancer at the recommended human dose, respectively) during organogenesis indicated delayed fetal development with malformations of the heart vessels and delayed skull, vertebrae, and sternum ossification (Prod Info CAPRELSA(R) oral tablets, 2011).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Vandetanib is classified as FDA pregnancy category D (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) ANIMAL STUDIES
    1) Administration of vandetanib to female rats prior to mating and for the first week of pregnancy resulted in increased pre- and post-implantation loss, as well as post-implantation loss and embryofetal death when administered during organogenesis. Complete litter loss was seen at doses of 25 mg/kg/day only. Additionally, maternal toxicity was seen in rats during pre- and postnatal development animal studies with doses of 1 and 10 mg/kg/day with a decrease in pup survival, and reduced postnatal pup growth (Prod Info CAPRELSA(R) oral tablets, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether vandetanib is excreted in human milk (Prod Info CAPRELSA(R) oral tablets, 2011).
    B) ANIMAL STUDIES
    1) Animal studies have shown that vandetanib is excreted in the milk of lactating rats and has been found in the plasma of pups with relatively constant exposure in pups due to the long half-life of the drug (Prod Info CAPRELSA(R) oral tablets, 2011).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In a study involving male rats, there appeared to be no decrease in the fertility rate when undosed females were mated with males who were receiving vandetanib at doses of 1, 5, or 20 mg/kg/day; however, there was an increase in preimplantation loss at doses of 5 mg/kg/day or more, and a slight decrease in the number of live embryos occurred at the 20 mg/kg/day dose (Prod Info CAPRELSA(R) oral tablets, 2011).
    2) In a fertility study involving female rats, there was an increase in estrus cycle irregularity, a slight decrease in the incidence of pregnancy, and an increase in implantation loss. During a repeat dose toxicity study, vandetanib administration to female rats at a dose of 75 mg/kg/day for a month resulted in a decrease in the number of corpora lutea within the ovaries (Prod Info CAPRELSA(R) oral tablets, 2011).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, carcinogenicity studies have not been conducted (Prod Info CAPRELSA(R) oral tablets, 2011).

Genotoxicity

    A) Vandetanib was not mutagenic in vitro with the bacterial reverse mutation (Ames) assay. Vandetanib was also not clastogenic in vitro with a cytogenetic assay using human lymphocytes and in vivo with the rat micronucleus assay (Prod Info CAPRELSA(R) oral tablets, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, including calcium and magnesium, in patients with significant overdose.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    C) Monitor renal function and liver enzymes after significant overdose.
    D) Monitor CBC with differential and platelets.
    E) Monitor vital signs.
    F) Obtain a chest X-ray in patients with respiratory symptoms to evaluate for evidence of interstitial lung disease.
    G) Serum vandetanib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4.1.2) SERUM/BLOOD
    A) Monitor serum electrolytes, including calcium and magnesium, in patients with significant overdose.
    B) Monitor renal function and liver enzymes after significant overdose.
    C) Monitor CBC with differential and platelets.
    D) Serum vandetanib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation. QT interval prolongation and torsades de pointes have been reported with therapy and may occur with overdose (Prod Info CAPRELSA(R) oral tablets, 2011).
    2) CHEST RADIOGRAPH
    a) Obtain a chest X-ray in patients with respiratory symptoms. Interstitial lung disease has been reported (Prod Info CAPRELSA(R) oral tablets, 2011).
    3) MONITORING
    a) Monitor vital signs.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients demonstrating severe fluid and electrolyte imbalance, QTc prolongation or cardiovascular instability should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestions of one or two extra doses can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult with an oncologist, medical toxicologist, and/or poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions should be observed in a healthcare facility.

Monitoring

    A) Monitor serum electrolytes, including calcium and magnesium, in patients with significant overdose.
    B) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    C) Monitor renal function and liver enzymes after significant overdose.
    D) Monitor CBC with differential and platelets.
    E) Monitor vital signs.
    F) Obtain a chest X-ray in patients with respiratory symptoms to evaluate for evidence of interstitial lung disease.
    G) Serum vandetanib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. There is no known antidote.
    B) MONITORING OF PATIENT
    1) Monitor serum electrolytes including calcium and magnesium in patients with significant overdose.
    2) Institute continuous cardiac monitoring and obtain serial ECGs to evaluate for evidence of QT prolongation.
    3) Monitor renal function and liver enzymes after significant overdose.
    4) Monitor CBC with differential and platelets.
    5) Monitor vital signs.
    6) Obtain a chest X-ray in patients with respiratory symptoms to evaluate for evidence of interstitial lung disease.
    7) Serum vandetanib concentrations are not clinically useful in guiding management following overdose, or widely available in clinical practice.
    C) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is unlikely to be effective due to high protein binding (90%) and large volume of distribution.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Rash, diarrhea, and hypertension were reported in patients and in healthy volunteers who received daily doses of 600 mg and 1200 mg vandetanib.
    B) THERAPEUTIC DOSE: The recommended adult dose is 300 mg orally daily. Safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) Recommended dose: 300 mg orally once daily (Prod Info CAPRELSA(R) oral tablets, 2014).
    B) Do NOT crush vandetanib tablets (Prod Info CAPRELSA(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric or adolescent patients have not been established (Prod Info CAPRELSA(R) oral tablets, 2014).

Maximum Tolerated Exposure

    A) Rash, diarrhea, and hypertension were reported in patients and in healthy volunteers who received daily doses of vandetanib of 300 mg to 1200 mg. In a phase 1 clinical trial, a limited number of patients received vandetanib daily doses of 600 mg and healthy volunteers received daily doses of up to 1200 mg (Prod Info CAPRELSA(R) oral tablets, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Vandetanib is a kinase inhibitor that has been shown to inhibit epidermal growth factor receptor (EGRF)-dependent cell survival in vitro. It inhibits epidermal growth factor (EGF)-stimulated receptor tyrosine kinase phosphorylation in tumor cells and endothelial cells, and vascular endothelial cell growth factor (VEGF)-stimulated tyrosine kinase phosphorylation in endothelial cells. In models of angiogenesis, it has been shown to inhibit endothelial cell migration, proliferation, survival, and new blood vessel formation (Prod Info CAPRELSA(R) oral tablets, 2011).

References

General Bibliography

    1) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    2) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    8) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    9) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    10) Keren A, Tzivoni D, & Gavish D: Etiology, warning signs and therapy of torsade de pointes: a study of 10 patients. Circulation 1981; 64:1167-1174.
    11) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
    12) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    13) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    14) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    15) Perticone F, Ceravolo R, & Cuccurullo O: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
    16) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    17) Product Information: CAPRELSA(R) oral tablets, vandetanib oral tablets. AstraZeneca Pharmaceuticals LP (Per Manufacturer), Wilmington, DE, 2011.
    18) Product Information: CAPRELSA(R) oral tablets, vandetanib oral tablets. AstraZeneca Pharmaceuticals LP (per FDA), Wilmington, DE, 2014.
    19) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    20) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    21) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    22) Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.