Caprelsa Drug Information
Generic name: VANDETANIB
Kinase Inhibitor [EPC]
Uses of Caprelsa
CAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.
Dosage & Administration of Caprelsa
The recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable toxicity occurs. CAPRELSA may be taken with or without food. Do not take a missed dose within 12 hours of the next dose.
Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion.
Swallow immediately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow. The dispersion can also be administered through nasogastric or gastrostomy tubes. 300 mg once daily.
Dosage reduction may be necessary in the event of severe toxicities or QTc interval prolongation. Interrupt CAPRELSA for the following: Corrected QT interval, Fridericia (QTcF) greater than 500 ms: Resume at a reduced dose when the QTcF returns to less than 450 ms. CTCAE Grade 3 or greater toxicity: Resume at a reduced dose when the toxicity resolves or improves to CTCAE Grade 1.
For recurrent toxicities, reduce the dose of CAPRELSA to 100 mg after resolution or improvement to CTCAE Grade 1 severity, if continued treatment is warranted. Adverse events including QT interval prolongation should be monitored closely as they may not resolve fully until approximately three plasma half-lives of the drug. Monitor appropriately.
For Patients with Renal Impairment Reduce the starting dose to 200 mg in patients with moderate (creatinine clearance ≥30 to <50 mL/min) renal impairment. For Patients with Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment.
Side Effects of Caprelsa
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with unresectable locally advanced or metastatic medullary thyroid cancer were treated with CAPRELSA 300 mg (n=231) or Placebo (n=99). The population exposed to CAPRELSA was 58% male, 94% white, and had a median age of 50 years.
The data described below reflect a median exposure to CAPRELSA for 607 days. The most commonly reported adverse drug reactions which occurred in >20% of CAPRELSA-treated patients and with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea/colitis, rash, acneiform dermatitis, hypertension, nausea, headache, upper respiratory tract infection, decreased appetite, and abdominal pain. Blurred vision was commonly reported (9% vs 1%) in this trial.
Scheduled slit lamp examinations revealed corneal opacities (vortex keratopathies) in treated patients, which can lead to halos and decreased visual acuity. Perform ophthalmologic examination, including slit lamp examination, in patients who report visual changes. Table 2: Per-Patient Incidence of Selected Laboratory Abnormalities in Patients with MTC Occurring at a Higher Incidence in CAPRELSA-Treated Patients (Between-Arm Difference of ≥5% CTCAE version 3 was used to grade laboratory abnormalities. ) No patient with a Grade 3 to 4 ALT elevation had a concomitant increase in bilirubin in the MTC study.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of CAPRELSA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Vascular disorders: Arterial (including aortic) aneurysms, dissections, and rupture Musculoskeletal and connective tissue disorders: Osteonecrosis General disorders: Impaired wound healing
| System Organ Class | CAPRELSA 300 mg | Placebo | ||
|---|---|---|---|---|
| Preferred Term | N=231 | N=99 | ||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Gastrointestinal Disorders | ||||
| Diarrhea/Colitis | 57 | 11 | 27 | 2 |
| Nausea | 33 | 1 | 16 | 0 |
| Abdominal Pain Includes abdominal pain, abdominal pain upper, lower abdominal pain, and abdominal discomfort. | 21 | 3 | 11 | 0 |
| Vomiting | 15 | 1 | 7 | 0 |
| Dyspepsia | 11 | 0 | 4 | 0 |
| Dry Mouth | 9 | 0 | 3 | 0 |
| Skin and Cutaneous Disorders | ||||
| Rash Includes rash, rash (erythematous, generalized, macular, maculopapular, papular, pruritic, and exfoliative), dermatitis, dermatitis bullous, generalized erythema, and eczema. | 53 | 5 | 12 | 0 |
| Dermatitis Acneiform/Acne | 35 | 1 | 7 | 0 |
| Dry Skin | 15 | 0 | 5 | 0 |
| Photosensitivity Reaction | 13 | 2 | 0 | 0 |
| Pruritus | 11 | 1 | 4 | 0 |
| Nail abnormalities Includes nail disorder, nail bed inflammation, nail bed tenderness, paronychia, nail bed infection, and nail infection. | 9 | 0 | 0 | 0 |
| Alopecia | 8 | N/A | 0 | N/A |
| Vascular Disorders | ||||
| Hypertension/Hypertensive Crisis/Accelerated Hypertension | 33 | 9 | 5 | 1 |
| Nervous System Disorders | ||||
| Headache | 26 | 1 | 9 | 0 |
| Dysgeusia | 8 | 0 | 3 | 0 |
| General Disorders | ||||
| Fatigue Included in Table 1 due to the increased incidence of severe fatigue in the CAPRELSA group compared to the placebo group. | 24 | 6 | 23 | 1 |
| Infections | ||||
| Upper Respiratory Tract Infections Includes laryngitis, nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, acute sinusitis, rhinitis, and tracheitis. | 23 | 0 | 16 | 0 |
| Metabolic and Nutritional Disorders | ||||
| Decreased Appetite | 21 | 4 | 12 | 0 |
| Hypocalcemia | 11 | 2 | 3 | 0 |
| Investigations | ||||
| ECG QT Prolonged 69% had QT prolongation >450 ms and 7% had QT prolongation >500 ms by ECG using Fridericia correction. | 14 | 8 | 1 | 1 |
| Eye Disorders | ||||
| Corneal Abnormalities Includes corneal edema, corneal opacity, corneal dystrophy, corneal pigmentation, keratopathy, arcus lipoides, corneal deposits, and acquired corneal dystrophy. | 13 | 0 | 1 | 0 |
| Blurred Vision | 9 | 0 | 1 | 0 |
| Renal Disorders | ||||
| Proteinuria | 10 | 0 | 2 | 0 |
| Psychiatric Disorders | ||||
| Depression | 10 | 2 | 3 | 0 |
| Endocrine Disorders | ||||
| Hypothyroidism | 6 | 0 | 0 | 0 |
| Musculoskeletal Disorders | ||||
| Muscle Spasms | 6 | 0 | 1 | 0 |
| Laboratory Abnormalities | CAPRELSA 300 mg N=231 | Placebo N=99 | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Chemistries | ||||
| Hypocalcemia | 57 | 6 | 25 | 3 |
| ALT Increased | 51 | 2 | 19 | 0 |
| Hypoglycemia | 24 | 0 | 7 | 1 |
| Creatinine Increased | 16 | 0 | 1 | 0 |
| Hypomagnesemia | 7 | <1 | 2 | 0 |
| Hematologic | ||||
| Neutropenia | 10 | <1 | 5 | 2 |
| Thrombocytopenia | 9 | 0 | 3 | 0 |
Warnings & Cautions for Caprelsa
QT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA. Do not start CAPRELSA treatment in patients whose QTcF interval is greater than 450 ms.
Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function.
Reduce the starting dose to 200 mg in patients with moderate renal impairment and monitor QT interval frequently. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above.
Maintain serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium levels within normal ranges to reduce the risk of QT prolongation. Avoid using CAPRELSA with drugs known to prolong the QT interval. If such drugs are given to patients already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more frequently.
Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose.
Severe Skin Reactions Severe and sometimes fatal skin reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, have occurred in patients treated with CAPRELSA. Permanently discontinue CAPRELSA for severe skin reactions and refer the patient for urgent medical evaluation. Systemic therapies such as corticosteroids may be required.
Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation.
Interstitial Lung Disease Interstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms. Interrupt CAPRELSA for acute or worsening pulmonary symptoms.
Discontinue CAPRELSA if ILD is confirmed.
Ischemic Cerebrovascular Events
Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied.
Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event.
Hemorrhage
Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage.
Heart Failure
Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure.
Heart failure may not be reversible upon stopping CAPRELSA.
Diarrhea Diarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early detection of QT prolongation resulting from dehydration. Interrupt CAPRELSA for severe diarrhea.
Upon improvement, resume CAPRELSA at a reduced dose.
Hypothyroidism In the randomized
MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-treated patients. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly.
Hypertension
Hypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary.
If hypertension cannot be controlled, do not resume CAPRELSA.
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension.
Discontinue CAPRELSA treatment in patients with RPLS.
Drug Interactions
Avoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide).
Renal Failure
Renal failure occurred in patients treated with CAPRELSA. Withhold, reduce the dose or permanently discontinue based on severity. Vandetanib is not recommended for use in patients with severe renal impairment (clearance below 30 mL/min).
There is no information available for patients with end-stage renal disease requiring dialysis.
Hepatic Impairment CAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established.
Impaired Wound Healing
Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Impaired wound healing has occurred in patients treated with CAPRELSA. Withhold CAPRELSA for at least 1 month prior to elective surgery.
Do not administer CAPRELSA for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment with CAPRELSA after resolution of wound healing complications has not been established.
Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, CAPRELSA can cause fetal harm when administered to a pregnant woman. In rats, vandetanib was embryotoxic, fetotoxic, and induced fetal malformations at exposures equivalent to or lower than those expected at the 300 mg clinical dose and had adverse effects on female fertility, embryofetal development, and postnatal development of pups. Advise patients of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with CAPRELSA and for 4 months after the last dose.
Osteonecrosis
Osteonecrosis, including osteonecrosis of the jaw (ONJ), has occurred during treatment with CAPRELSA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to and periodically during treatment with CAPRELSA.
Advise patients regarding good oral hygiene practices. Avoid invasive dental procedures while on CAPRELSA treatment, particularly in patients at higher risk. Withhold CAPRELSA for at least one month prior to scheduled dental surgery or invasive dental procedures.
Permanently discontinue CAPRELSA if ONJ develops.
Drug Interactions with Caprelsa
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.
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.
Effect of CAPRELSA on Digoxin
CAPRELSA increased plasma concentrations of digoxin.
Drugs that Prolong the QT Interval
Avoid concomitant use of CAPRELSA with agents that may prolong the QT interval.
Pregnancy Safety for Caprelsa
Pregnancy Risk Summary Based on its mechanism of action and findings in animals, CAPRELSA can cause fetal harm when administered to a pregnant woman. There are no available human data on CAPRELSA use in pregnant women to inform a drug-associated risk. Vandetanib is embryotoxic, fetotoxic, and induced fetal malformations in rats at exposures less than or equal to those expected at the recommended human dose of 300 mg/day.
Advise patients of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal data In reproductive toxicity studies, administration of vandetanib to female rats prior to mating and through the first week of pregnancy at a dose of 25 mg/kg/day (approximately equal to the human exposure at the 300 mg clinical dose based on C max ), there were increases in pre-implantation loss and post-implantation loss resulting in a reduction in the number of live embryos.
During organogenesis, vandetanib caused an increase in post-implantation loss, including occasional total litter loss at a dose of 25 mg/kg/day. At doses greater than 10 mg/kg/day (approximately 0.4 times the human C max at the 300 mg clinical dose) treatment with vandetanib resulted in increases in late embryofetal death and decreases in fetal birth weight. A no-effect level for malformations was not identified in this study.
Administration of vandetanib at doses greater than or equal to 1 mg/kg/day (approximately 0.03 times the human C max at the 300 mg clinical dose) resulted in dose dependent increases in both malformations of the heart vessels and skeletal variations including delayed ossification of the skull, vertebrae, and sternum, indicating delayed fetal development. In a rat prenatal and postnatal development study, at doses (1 and 10 mg/kg/day) producing mild maternal toxicity during gestation and/or lactation, vandetanib decreased pup survival and reduced postnatal pup growth. Reduced postnatal pup growth was associated with a delay in physical development.
Pediatric Use of Caprelsa
Pediatric Use Safety and efficacy of CAPRELSA in pediatric patients have not been established.
Contraindications for Caprelsa
Do not use in patients with congenital long QT syndrome.
Overdosage Information for Caprelsa
In the event of an overdose, monitor patients closely for QTc prolongation. Adverse events including QT interval prolongation should be monitored closely as they may not resolve fully until approximately three plasma half-lives of the drug.
Clinical Studies of Caprelsa
Clinical Trial in Patients with Medullary Thyroid Cancer
A double-blind, placebo-controlled study (Study D4200C00058, NCT00410761) randomized patients with unresectable locally advanced or metastatic medullary thyroid cancer to CAPRELSA 300 mg (n=231) versus placebo (n=100). The major efficacy outcome measure was progression-free survival (PFS) with CAPRELSA compared to placebo. Other efficacy outcome measures included evaluation of overall survival (OS) and overall objective response rate (ORR).
Centralized, independent blinded review of the imaging data was used in the assessment of PFS and ORR. Upon objective disease progression based on the investigator's assessment, patients were discontinued from blinded study treatment and given the option to receive open-label CAPRELSA. Forty-seven percent (109/231) of the patients initially randomized to CAPRELSA opted to receive open-label CAPRELSA after disease progression, and 79% (79/100) of the patients initially randomized to placebo opted to receive open-label CAPRELSA after disease progression.
The result of the PFS analysis, based on the central review RECIST assessment, showed a statistically significant improvement in PFS for patients randomized to CAPRELSA (Hazard Ratio (HR) = 0.35; 95% Confidence Interval (CI) = 0.24-0.53; p<0.0001). Analyses in the subgroups of patients who were symptomatic or had progressed within 6 months prior to their enrollment showed similar PFS results (HR = for symptomatic patients; HR = for patients who had progressed within 6 months prior to enrollment). Median final OS were similar across both treatment arms.
The overall objective response rate (ORR) for patients randomized to CAPRELSA was 44% compared to 1% for patients randomized to placebo. All objective responses were partial responses. Figure 1: Kaplan-Meier Curves for Progression Free Survival in Study D4200C00058 Table 3: Efficacy Results in Study D4200C00058 Figure 1
| Vandetanib 300 mg (N=231) | Placebo (N=100) | |
|---|---|---|
| Progression Free Survival | ||
| Events (%) | 59 (26.0) | 41 (41.0) |
| Median, months | NR Not reached | 16.4 |
| (95% CI) | (22.6, NE Not estimable ) | (8.3, 19.7) |
| Hazard Ratio (95% CI) | 0.35 (0.24, 0.53) | |
| p-value | <0.0001 | |
| Overall Survival | ||
| Deaths (%) | 116 (50.2) | 52 (52.0) |
| Median, months | 81.6 | 80.4 |
| (95% CI) | (64.6, 98.5) | (52.5, NE) |
| Hazard Ratio (95% CI) | 0.99 (0.72, 1.38) | |
| p-value | 0.975 | |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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