Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
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 tumour 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 QTc 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 (see section 4.8). 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 (see section 4.8).

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 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 (see section 4.3 and 4.5).
The concomitant use of vandetanib with ondansetron is not recommended (see section 4.5) 
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 oedema 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.


Severe Cutaneous Adverse Reactions (SCARs) and other skin reactions
SCARs, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, have been reported in association with vandetanib treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. For suspected SJS or TEN, vandetanib should be withheld and the patient should be referred to a specialised unit for assessment and treatment. If SJS or TEN is confirmed, vandetanib should be permanently discontinued and an alternative treatment considered (as appropriate).

Photosensitivity reactions have been observed in patients who have received 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.

Mild to moderate skin reactions can be managed by symptomatic treatment, or by dose reduction or interruption.

Diarrhoea
Diarrhoea is a disease related symptom as well as a known undesirable effect of vandetanib.
Routine anti-diarrhoeal agents are recommended for the treatment of diarrhoea. QTc and serum electrolytes should be monitored more frequently. If severe diarrhoea (CTCAE grade 3-4) develops, vandetanib should be stopped until diarrhoea improves. Upon improvement, treatment should be resumed at a reduced dose (see sections 4.2 and 4.8).

Haemorrhage
Caution should be used when administering vandetanib to patients with brain metastases, as intracranial haemorrhage 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 medical management, vandetanib should not be restarted until the blood pressure is controlled medically. Reduction in dose may be necessary (see section 4.8).

Wound healing complications

No formal studies of the effect of vandetanib on wound healing have been conducted. Impaired would healing can occur in patients who receive drugs that inhibit the VEGF signalling pathway and has been reported in patients receiving vandetanib. Although evidence for an optimal duration of treatment interruption prior to scheduled surgery is very limited, temporary interruption of vandetanib should be considered for at least 4 weeks prior to elective surgery based on individual benefit-risk. The decision to resume vandetanib following a major surgical procedure should be based on clinical judgement of adequate wound healing.

Aneurysms and artery dissections
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating vandetanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.


Renal failure
Renal failure has been reported in patients treated with vandetanib (see section 4.8 Undesirable effects). Dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

Vandetanib exposure is increased in patients with impaired renal function. Vandetanib starting dose could be reduced to 200 mg in patients with moderate renal impairment (creatinine clearance ≥30 to <50 mL/min) and the QT interval should be closely monitored.
Vandetanib is not recommended for use in patients with severe renal impairment (clearance below 30 mL/min) (see sections 4.2, 5.1, and 5.2). There is no information available for patients with end-stage renal disease requiring dialysis.

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 (see sections 4.2 and 5.2).

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 John's Wort, carbamazepine, phenobarbital) should be avoided (see section 4.5).

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.

Effects on Driving

4.7    Effects on ability to drive and use machines

No studies to establish the effects of vandetanib on ability to drive and use machines have been conducted. However, fatigue and blurred vision have been reported and those patients who experience these symptoms should observe caution when driving or using machines.