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  • Caprelsa 100 mg
    / Sanofi


    Active Ingredient
    Vandetanib 100 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    30 x 100 mg

    partial basket chart 9652

    Related information


    Dosage

    The recommended dose is 300 mg 1 x day, taken with or without food at about the same time each day. If a dose is missed, it should be taken as soon as the patient remembers. If it is less than 12 hours to the next dose, the patient should not take the missed dose. Patients should not take a double dose (two doses at the same time) to make up for a forgotten dose. Patients must be given the patient alert card and be informed about the risks (see also package leaflet).
    QTc interval should be carefully assessed prior to initiation of treatment. In the event of common terminology criteria for adverse events (CTCAE) grade 3 or higher toxicity or prolongation of the ECG QTc interval, dosing with vandetanib should be at least temporarily stopped and resumed at a reduced dose when toxicity has resolved or improved to CTCAE grade 1. The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets), and then to 100 mg if necessary. The patient must be monitored appropriately. Due to the 19-day half-life, adverse reactions including a prolonged QTc interval may not resolve quickly. See prescribing information for full details.
    Pediatric population: The safety and efficacy in children have not been established.
    Elderly: No adjustment in starting dose is required for elderly patients. There is limited clinical data with vandetanib in patients with MTC aged over 75.
    Renal impairment: Clinical data suggest that no change in starting dose is required in patients with mild renal impairment. There is limited data with 300 mg in patients with moderate renal impairment: the dose needed to be lowered to 200 mg in 5 out of 6 patients. The starting dose could be reduced to 200 mg in patients with moderate renal impairment; safety and efficacy have however not been established with 200 mg. Vandetanib is not recommended for use in patients with severe renal impairment since there is limited data in patients with severe renal impairment, and safety and efficacy have not been established.
    Hepatic impairment: Vandetanib is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), since there is limited data in patients with hepatic impairment, and safety and efficacy have not been established. No change in starting dose is required in patients with mild, moderate or severe hepatic impairment. See prescribing information for full details.
    For patients who have difficulty swallowing, the tablets may be dispersed in half a glass of non-carbonated drinking water. No other liquids should be used.


    Indications

    Treatment of aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease. For patients in whom Rearranged during Transfection (RET) mutation is not known or is negative, a possible lower benefit should be taken into account before individual treatment decision.
    See prescribing information for full details.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients. Congenital long QTc syndrome. Patients with a QTc interval over 480 msec. Concomitant with the following medicdbinal products known to also prolong the QTc interval and/or induce Torsades de pointes: Arsenic, cisapride, erythromycine intravenous, toremifene, mizolastine, moxifloxacine, Class IA and III antiarrhythmics. Lactation.
    See prescribing information for full details.


    Special Precautions

    In view of the associated risks, it is important to limit treatment with vandetanib to patients who are in real need for treatment, i.e., with a symptomatic-aggressive course of the disease. Either symptomatic disease or progressive disease alone is not enough to prompt the need of treatment with vandetanib. Rate of change in biomarker levels such as of calcitonin (CTN) and/or carcinoembryonic antigen (CEA) as well as the rate of change of tumor volume during watchful waiting might help to identify not only patients in need for treatment but also the optimal moment to commence treatment with vandetanib. QTc prolongation and Torsades de Pointes Vandetanib at a dose of 300 mg is associated with a substantial and concentration dependent prolongation in QTc (mean 28 msec, median 35 msec). First QT prolongations occurred most often in the first 3 months of treatment, but continued to first occur after this time. The half-life of vandetanib (19 days) renders this prolongation in QTc interval particularly problematic. At a dose of 300 mg per day in MTC, ECG QTc prolongation to above 500 msec was observed in a phase III study in 11% of patients. ECG QTc prolongation appears to be dose-dependent. Torsades de pointes and ventricular tachycardia have been uncommonly reported in patients administered vandetanib 300 mg daily. The risk of torsades may be increased in patients with electrolyte imbalance. Vandetanib treatment must not be started in patients whose ECG QTc interval is greater than 480 msec. Vandetanib should not be given to patients who have a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. Vandetanib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. An ECG, and levels of serum potassium, calcium and magnesium and thyroid stimulating hormone (TSH) should be obtained at baseline, at 1, 3, 6 and 12 weeks after starting treatment and every 3 months for at least a year thereafter. This schedule should apply to the period after dose reduction due to QTc prolongation and after dose interruption for more than two weeks. ECGs and blood tests should also be obtained as clinically indicated during this period and afterwards. Frequent ECG monitoring of the QTc interval should be continued. Serum potassium, serum magnesium and serum calcium should be kept within normal range to reduce the risk of ECG QTc prolongation. Additional monitoring of QTc, electrolytes and renal function are required especially in case of diarrhoea, increase in diarrhoea/dehydration, electrolyte imbalance and/or impaired renal function. If QTc increases markedly but stays below 500 msec, cardiologist advice should be sought. The administration of vandetanib with substances known to prolong the ECG QTc interval is contraindicated or not recommended The concomitant use of vandetanib with ondansetron is not recommended. Patients who develop a single value of a QTc interval of 500 msec should stop taking vandetanib. Dosing can be resumed at a reduced dose after return of the QTc interval to pretreatment status has been confirmed and correction of possible electrolyte imbalance has been made. Posterior reversible encephalopathy syndrome, PRES (Reversible posterior leukoencephalopathy syndrome-RPLS) PRES is a syndrome of subcortical vasogenic edema diagnosed by a MRI of the brain, has been observed infrequently with vandetanib treatment in combination with chemotherapy. PRES has also been observed in patients receiving vandetanib as monotherapy. This syndrome should be considered in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Brain MRI should be performed in any patient presenting with seizures, confusion or altered mental status. Rearranged during transfection (RET) status Patients without RET mutation may have a decreased benefit from vandetanib treatment and the benefit/risk balance for this group of patients may therefore differ from that of the group with RET mutations. For patients whose RET mutation status could be negative, a possible lower benefit should be taken into account before individual treatment decisions and the use of vandetanib should be carefully considered because of the treatment related risks. Therefore RET mutation testing is recommended. When establishing RET mutation status, tissue samples should be obtained if possible at the time of initiation of treatment rather than at the time of diagnosis.Skin reactions Rash and other skin reactions (including photosensitivity reactions and palmar-plantar erythrodysaesthesia syndrome) have been observed in patients who have received vandetanib. Mild to moderate skin reactions can be managed by symptomatic treatment, or by dose reduction or interruption. More severe skin reactions (such as Stevens-Johnson syndrome) may require systemic glucocorticosteroids and permanent discontinuation of vandetanib. Care should be taken with sun exposure by wearing protective clothing and /or sunscreen due to the potential risk of phototoxicity reactions associated with vandetanib treatment. Diarrhea Diarrhea is a disease related symptom as well as a known undesirable effect of vandetanib. Routine anti-diarrheal agents are recommended for the treatment of diarrhea. QTc and serum electrolytes should be monitored more frequently. If severe diarrhea (CTCAE grade 3-4) develops, vandetanib should be stopped until diarrhea improves. Upon improvement, treatment should be resumed at a reduced dose. Hemorrhage Caution should be used when administering vandetanib to patients with brain metastases, as intracranial hemorrhage has been reported. Heart failure Heart failure has been observed in patients who received vandetanib. Temporary or permanent discontinuation of therapy may be necessary in patients with heart failure. It may not be reversible on stopping vandetanib. Some cases have been fatal. Hypertension Hypertension, including hypertensive crisis, has been observed in patients treated with vandetanib. Patients should be monitored for hypertension and controlled as appropriate. If high blood pressure cannot be controlled with medicdbal management, vandetanib should not be restarted until the blood pressure is controlled medicdbally. Reduction in dose may be necessary. Patients with renal impairment Vandetanib is not recommended for use in patients with moderate or severe renal impairment since there is limited data, and safety and efficacy have not been established. Patients with hepatic impairment Vandetanib is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), since there is limited data in patients with hepatic impairment, and safety and efficacy have not been established. Pharmacokinetic data from volunteers, suggests that no change in starting dose is required in patients with mild, moderate or severe hepatic impairment. Alanine aminotransferase elevations Alanine aminotransferase elevations occur commonly in patients treated with vandetanib. The majority of elevations resolve while continuing treatment, others usually resolve after a 1-2 week interruption in therapy. Periodic monitoring of alanine aminotransferase is recommended. Interstitial lung disease Interstitial Lung Disease (ILD) has been observed in patients receiving vandetanib and some cases have been fatal. If a patient presents with respiratory symptoms such as dyspnoea, cough and fever, vandetanib treatment should be interrupted and prompt investigation initiated. If ILD is confirmed, vandetanib should be permanently discontinued and the patient treated appropriately. CYP3A4 inducers. The concomitant use of vandetanib with strong CYP3A4 inducers (such as rifampicin, St Johns’Wort, carbamazepine, phenobarbital) should be avoided. CTN less than 500 pg/ml The benefit of vandetanib in patients with CTN less than 500 pg/ml has not been determined, therefore use in patients with CTN < 500 pg/ml should be carefully considered because of the treatment related risks of vandetanib.
    Patient Alert Card: All prescribers of Caprelsa must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of Caprelsa therapy with the patient. The patient will be provided with the Patient Alert Card with each prescription.


    Side Effects

    The most commonly reported adverse drug reactions have been diarrhea, rash, nausea, hypertension and headache. Nasopharyngitis, bronchitis, upper respiratory tract infections, urinary tract infections, decreased appetite, hypocalcemia, insomnia, depression, headache, paresthesia, dysaesthesia, dizziness, blurred vision, corneal structural change (including corneal deposits and corneal opacity), prolongation of ECG QTc interval, hypertension, abdominal pain, diarrhea, nausea, vomiting, dyspepsia, photosensitivity reaction, rash and other skin reactions (including acne, dry skin, dermatitis, pruritis), nail disorders, proteinuria, nephrolithiasis, asthenia, fatigue, pain, edema, ECG QTc interval prolonged.


    Drug interactions

    In vitro data suggest that vandetanib is a moderate CYP3A4 inducer. Therefore, since no clinical interaction studies have been performed, caution should be made when vandetanib is combined with CYP3A4 substrates, especially estroprogestatives, immunosuppressants like cyclosporine or tacrolimus, or antineoplastic agents like docetaxel and bortezomib. Vandetanib is a weak inhibitor of the efflux pump P-glycoprotein (P-gp). The coadministration of vandetanib and medicdbinal products excreted by P-gp, such as dabigatran or digoxin may result in increased plasma concentrations of these medicdbinalproducts. Patients receiving dabigatran or digoxin and vandetanib may require increased clinical and biological surveillance and appropriate dose adjustments, if needed. Vandetanib is an inhibitor of the organic cation transporter 2 (OCT2) transporter. Therefore vandetanib may have the potential to decrease the elimination of medicdbinal products known to be excreted by OCT2 and increase a patient’s exposure to these medicdbinal products. Metformin is a substrate of OCT2 and patients who are receiving vandetanib and metformin (or other substrate of OCT2) may require more careful monitoring, and possible dose adjustment of metformin. The effect of proton pump inhibitors on the gastrointestinal absorption of vandetanib has not been determined. Vandetanib demonstrates pH dependent solubility; therefore the co-administration of vandetanib with proton pump inhibitors may reduce a patient’s exposure to vandetanib. The concomitant use with these therapeutic classes is therefore not recommended. In a clinical study performed with healthy volunteers, the co-dministration of vandetanib (a single dose of 300 mg) with itraconazole (repeated-doses of 200 mg, once daily), a potent CYP3A4 inhibitor, increases vandetanib plasma exposure about 9%. Since the itraconazole dose was under the minimal recommended dose to inhibit CYP3A4, (i.e 400 mg once day) caution should be made when itraconazole, and other potent CYP3A4 inhibitors (e.g. ketocoanzole, ritonavir and clarithromycin) are combined with vandetanib. In a clinical study performed with healthy male subjects, the exposure to vandetanib was reduced by 40% when given together with the potent CYP3A4 inducer, rifampicin. Therefore, administration of vandetanib with rifampicin and other potent CYP3A4 inducers (e.g. carbamazepine, phenobarbital and St. John’s Wort) should be avoided.


    Manufacturer
    Genzyme Europe
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