CAPRELSA Film-coated tablet Ref.[8958] Active ingredients: Vandetanib

Treatment should be initiated and supervised by a physician experienced in treatment of MTC and in the use of anticancer medicinal products and experienced in the assessment of electrocardiogram (ECG).

Rearranged during transfection (RET) status

Since the activity of Caprelsa, based on available data, is considered insufficient in patients with no identified RET mutation, the presence of a RET mutation should be determined by a validated test prior to initiation of treatment with Caprelsa. 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.

Posology for MTC in adult patients

The recommended dose is 300 mg once a 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.

Dose adjustments in adult patients with MTC

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 (see section 4.4). 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 section 4.4).

Posology in paediatric patients with MTC

Dosing for paediatric patients should be on the basis of BSA in mg/m². Paediatric patients treated with Caprelsa and patients' caregivers must be given the dosing guide and be informed on the correct dose to be taken with the initial prescription and each subsequent dose adjustment. Recommended dosing regimens and dose modifications are presented in Table 1.

Table 1. Dosing nomogram for paediatric patients with MTC:

^a The starting dose is the dose at which treatment should be initiated.
^b Higher vandetanib doses than 150 mg/m² have not been used in clinical studies in paediatric patients.
^c Patients with an adverse reaction requiring a dose reduction should stop taking vandetanib for at least a week. Dosing can be resumed at a reduced dose thereafter when fully recovered from adverse reactions.

Dose adjustments in paediatric patients with MTC

• In the event of 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.
• Patients who are on the starting dose (^a in Table 1), should be recommenced at the reduced dose (^c in Table 1).
• Patients who are on the increased dose (^b in Table 1), should be recommenced at the starting dose (^a in Table 1). If another event of common terminology criteria for adverse events (CTCAE) grade 3 or higher toxicity or prolongation of the ECG QTc interval occurs, dosing with Caprelsa should be at least temporarily stopped and resumed at a reduced dose (^c in Table 1) when toxicity has resolved or improved to CTCAE grade 1.
• If a further event of CTCAE grade 3 or higher toxicity or prolongation of the ECG QTc interval occurs, dosing with vandetanib should be permanently stopped.

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 section 4.4).

Duration

Vandetanib may be administered until disease progression or until the benefits of treatment continuation do no longer outweigh its risk, thereby considering the severity of adverse events (see sections 4.8) in relation to the degree of clinical stabilization of the tumour status.

Special patient populations

Paediatric population

Caprelsa should not be given to children below 5 years of age. The safety and efficacy of Caprelsa in children below 5 years of age have not been established. No data are available. There is no experience in paediatric patients with hereditary MTC below 9 years of age (see section 5.1). Patients aged 5-18 years should be dosed according to the nomogram in Table 1. Vandetanib doses higher than 150 mg/m² have not been used in clinical studies in paediatric patients.

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 in adult patients with MTC

A pharmacokinetic study in volunteers with mild, moderate and severe renal impairment shows that exposure to vandetanib after single dose is increased up to 1.5, 1.6 and 2-fold respectively in patients with mild, moderate (creatinine clearance ≥30 to <50 ml/min) and severe (clearance below 30 ml/min) renal impairment at baseline (see section 5.2). 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 due to an adverse reaction of QT prolongation. The starting dose should be reduced to 200 mg in patients with moderate renal impairment; safety and efficacy have however not been established with 200 mg (see section 4.4). 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.

Renal impairment in paediatric patients with MTC

There is no experience with the use of vandetanib in paediatric patients with renal impairment. Considering the data available in adult patients with renal impairment:

• No change in starting dose is recommended in paediatric patients with mild renal impairment
• The reduced dose as specified in Table 1 should be used in paediatric patients with moderate renal impairment. Individual patient management will be required by the physician, especially in paediatric patients with low BSA.
• Vandetanib is not recommended in paediatric patients with severe renal impairment.

Hepatic impairment

Vandetanib is not recommended for use in adult and paediatric patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of reference range (ULRR), this criterion does not apply to patients with Gilbert’s Disease and alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) greater than 2.5 times ULRR, or greater than 5.0 times ULRR if judged by the physician to be related to liver metastases), since there is limited data in patients with hepatic impairment, and safety and efficacy have not been established (see section 4.4).

Pharmacokinetic data from volunteers, suggests that no change in starting dose is required in patients with mild, moderate or severe hepatic impairment (see section 5.2).

Method of administration

Caprelsa is for oral use. For patients who have difficulty swallowing, vandetanib tablets may be dispersed in half a glass of non-carbonated drinking water. No other liquids should be used. The tablet is to be dropped in water, without crushing, stirred until dispersed (approximately 10 minutes) and the resultant dispersion swallowed immediately. Any residues in the glass are to be mixed with half a glass of water and swallowed. The liquid can also be administered through nasogastric or gastrostomy tubes.

There is no specific treatment in the event of overdose with vandetanib and possible symptoms of overdose have not been established. An increase in the frequency and severity of some adverse reactions, like rash, diarrhoea and hypertension was observed at multiple doses at and above 300 mg in healthy volunteer studies and in patients. In addition, the possibility of QTc prolongation and Torsades de pointes should be considered. Vandetanib doses higher than 150 mg/m² have not been used in clinical studies in paediatric patients.

Adverse reactions associated with overdose are to be treated symptomatically; in particular, severe diarrhoea must be managed appropriately. In the event of an overdose, further doses must be interrupted, and appropriate measures taken to assure that an adverse event has not occurred, i.e. ECG within 24 hours to determine QTc prolongation. Adverse reactions associated with overdose may be prolonged due to the long half-life of vandetanib (see section 5.2).

4 years.

Do not store above 30°C.

PVC/PVDC/Alu blisters, sealed with aluminium foil, each containing 30 film-coated tablets.

No special requirements.