Caprelsa

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Caprelsa 100 mg film-coated tablets 
Caprelsa 300 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Caprelsa 100 mg tablets 
Each film-coated tablet contains 100 mg of vandetanib. 
 
Caprelsa 300 mg tablets 
Each film-coated tablet contains 300 mg of vandetanib. 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Caprelsa 100 mg tablets 
The Caprelsa 100 mg tablet is a round, biconvex, white film-coated tablet with ‘Z100’ impressed on 
one side. 
 
Caprelsa 300 mg tablets 
The Caprelsa 300 mg tablet is an oval-shaped, biconvex, white film-coated tablet with ‘Z300’ 
impressed on one side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Caprelsa is indicated for the treatment of aggressive and symptomatic medullary thyroid cancer 
(MTC) in patients with unresectable locally advanced or metastatic disease.  
 
Caprelsa is indicated in adults, children and adolescents aged 5 years and older. 
 
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 
important information in sections 4.4 and 5.1). 
 
4.2 Posology and method of administration 
 
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). 
 
Only one supply per prescription is allowed. For a further supply, a new prescription is required. 
 
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. 



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Patients treated with Caprelsa must be given the patient alert card and be informed about the risks of 
Caprelsa (see also package leaflet).  
 
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.  
 
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 
BSA (m2) Start dose (mg)a Dose increase (mg)b  

when tolerated well  
after 8 weeks at starting 
dose 

Dose reduction (mg) c 

0.7 - <0.9 100 every other day 100 daily - 
0.9 - <1.2 100 daily 7 day schedule: 

100-200-100-200-100-
200-100 

100 every other day 

1.2 - <1.6 7 day schedule: 
100-200-100-200-100-
200-100 

200 daily 100 daily 

≥ 1.6 200 daily 300 daily 7 day schedule: 
100-200-100-200-100-
200-100 

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 



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 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. 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 (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 could 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 
 
 
 



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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 
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. 
 
4.3 Contraindications 
 
 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 Congenital long QTc syndrome. 
 Patients with a QTc interval over 480 msec.  
 Concomitant use of vandetanib with the following medicinal products known to also prolong 

the QTc interval and/or induce Torsades de pointes: Arsenic, cisapride, erythromycin 
intravenous (IV), toremifene, mizolastine, moxifloxacin, Class IA and III antiarrhythmics (see 
section 4.5). 

 Breast-feeding (see section 4.6). 
 
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. 
 
 



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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. 
 
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 (see sections 4.1 and 5.1). 
 
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. For more severe skin reactions (such as Stevens-Johnson syndrome), referral of the 
patient to seek urgent medical advice is recommended.  
 
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. 
 
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 



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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).  
 
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. 
 
Patients with renal impairment 
Vandetanib is not recommended for use in adult and paediatric patients with moderate or severe renal 
impairment since there is limited data, and safety and efficacy have not been established (see 
sections 4.2, 5.1, and 5.2). 
 
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. 
 
Patient Alert Card  



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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.  
 
 
 
Paediatric population 
Based on height measurements at all visits, all children and adolescents in a paediatric study 
demonstrated linear growth while receiving vandetanib. However, long term safety data in paediatric 
patients are not available. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Pharmacokinetic interactions 
Effect of vandetanib on other medicinal products 
In healthy subjects, the exposure for midazolam (CYP3A4 substrate) was not affected when given 
together with a single dose of vandetanib at 800 mg. 
 
Vandetanib is an inhibitor of the organic cation 2 (OCT2) transporter. In healthy subjects with wild 
type for OCT2, the AUC(0-t) and Cmax for metformin (OCT2 substrate) were increased by 74% and 
50%, respectively and CLR of metformin was decreased by 52% when given together with vandetanib. 
Appropriate clinical and/or laboratory monitoring is recommended for patients receiving concomitant 
metformin and vandetanib, and such patients may require a lower dose of metformin. 
 
In healthy subjects, the AUC(0-t) and Cmax for digoxin (P-gp substrate) were increased by 23% and 29% 
respectively, when given together due to P-gp inhibition by vandetanib. Furthermore, the bradycardiac 
effect of digoxin may increase the risk of vandetanib QTc interval prolongation and Torsade de 
Pointes. Therefore, an appropriate clinical (e.g. ECG) and/or laboratory monitoring is recommended 
for patients receiving concomitant digoxin and vandetanib, and such patients may require a lower dose 
of digoxin. (For vandetanib monitoring, see section 4.2 Posology and Method of administration and 
section 4.4 Special warnings and precautions for use). 
 
As regards other P-gp substrates such as dabigatran, a clinical monitoring is recommended in case of 
combination with vandetanib. 
 
Effect of other medicinal products on vandetanib 
In healthy subjects, no clinically significant interaction was shown between vandetanib (a single dose 
of 300mg) and the potent CYP3A4 inhibitor, itraconazole (repeated doses of 200mg once daily). In 
healthy male subjects, the exposure to vandetanib was reduced by 40% when given together with the 
potent CYP3A4 inducer, rifampicin. Administration of vandetanib with potent CYP3A4 inducers 
should be avoided. 
 
In healthy subjects, the Cmax for vandetanib was decreased by 15% while the AUC(0-t)  for vandetanib 
was not affected when given together with omeprazole. Neither the Cmax nor the AUC(0-t) for 
vandetanib was affected when given together with ranitidine. Therefore, no change in dose of 
vandetanib is required when vandetanib is given with either omeprazole or ranitidine. 
 
Pharmacodynamic interactions 
Biliary excretion of unchanged vandetanib is one of the excretion pathways for vandetanib. 
Vandetanib is not a substrate of multidrug resistance protein 2 (MRP2), p-glycoprotein (P-gp) or 
breast cancer resistance protein (BCRP). 
 
Medicinal products known to prolong QTc interval 
Vandetanib has been shown to prolong the ECG QTc interval; Torsades de pointes have been 
uncommonly reported. Therefore, the concomitant use of vandetanib with medicinal products known 



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to also prolong the QTc interval and/or induce Torsades de pointes is either contraindicated or not 
recommended depending on existing alternative therapies. 
 
 Combinations contraindicated (see section 4.3): Cisapride, erythromycin intravenous (IV), 

toremifene, mizolastine, moxifloxacin, arsenic, Class IA and III antiarrhythmics  
 Combinations not recommended: Methadone, haloperidol, amisulpride, chlorpromazine, 

sulpiride, zuclopenthixol, halofantrine, pentamidine and lumefantrine. 
 
If there is no appropriate alternative therapy, not recommended combinations with vandetanib may be 
made with additional ECG monitoring of the QTc interval, evaluation of electrolytes and further 
control at onset or worsening of diarrhoea.  
 
Results of a pharmacodynamic and pharmacokinetic interaction study indicated that co-administration 
with ondansetron in healthy patients appeared to have little effect on the pharmacokinetics of 
vandetanib, but had a small additive effect on the prolongation of the QTc interval of approximately 
10 ms. Therefore, the concomitant use of ondansetron with vandetanib is not recommended. If 
ondansetron is administered with vandetanib, closer monitoring of serum electrolytes and ECGs and 
aggressive management of any abnormalities is required. 
 
Vitamin K antagonists 
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation is frequent. In 
consideration of the high intra-individual variability of the response to anticoagulation, and the 
possibility of interaction between vitamin K antagonists and chemotherapy, an increased frequency of 
the INR (International Normalised Ratio) monitoring is recommended, if it is decided to treat the 
patient with vitamin K antagonists. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
Women of childbearing potential must use effective contraception during therapy and for at least four 
months following the last dose.  
 
Pregnancy 
There is a limited amount of data on the use of vandetanib during pregnancy. As expected from its 
pharmacological actions, vandetanib has shown significant effects on all stages of female reproduction 
in rats (see section 5.3). 
 
If vandetanib is used during pregnancy or if the patient becomes pregnant while receiving vandetanib, 
she should be apprised of the potential for foetal abnormalities or loss of the pregnancy. Treatment 
should only be continued in pregnant women if the potential benefit to the mother outweighs the risk 
to the foetus.  
 
Breast-feeding 
There are no data on the use of vandetanib in breast-feeding women. Vandetanib and/or its metabolites 
is excreted into milk in rats and found in plasma of pups following dosing to lactating rats (see 
section 5.3). 
 
Breast-feeding is contraindicated while receiving vandetanib therapy. 
 
Fertility 
In rats, vandetanib had no effect on male fertility but impaired female fertility (see section 5.3). 
 
Effects on reproduction in paediatric patients treated with vandetanib are not known. 
 
4.7 Effects on ability to drive and use machines 
 



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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. 
 
 
 
 
 
4.8 Undesirable effects 
 
Summary of the safety profileThe most commonly reported adverse drug reactions have been 
diarrhoea, rash, nausea, hypertension, and headache. 
 
Tabulated list of adverse reactions 
The following adverse reactions have been identified in clinical studies with patients receiving 
vandetanib as treatment for MTC. Their frequency is presented in Table 2, adverse reactions using 
Council for International Organizations of Medical Sciences (CIOMS III), listed by MedDRA System 
Organ Class (SOC) and at the preferred term level and then by frequency classification. Frequencies of 
occurrence of undesirable effects are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); 
uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and not 
known (cannot be estimated from the available data). This section includes only data derived from 
completed studies where patient exposure is known.  
 
Table 2: Adverse reactions and system organ class  
System Organ 
Class 

Very common Common Uncommon Not 
known 

Infection and 
infestation 
disorders 

Nasopharyngitis 
bronchitis, upper 
respiratory tract 
infections, urinary 
tract infections 

Pneumonia, sepsis, 
influenza, cystitis, 
sinusitis, laryngitis, 
folliculitis, furuncle, 
fungal infection, 
pyelonephritis 

Appendicitis, 
staphylococcal 
infection, 
diverticulitis, 
cellulitis, abdominal 
wall abscess 

 

Endocrine 
disorders 

 Hypothyroidism   

Metabolism and  
nutrition 
disorders 

Appetite decreased, 
Hypocalcaemia  

Hypokalaemia, 
hypercalcaemia, 
hyperglycemia, 
dehydration, 
hyponatremia 

Malnutrition  

Psychiatric 
disorders 

Insomnia, 
Depression 

Anxiety   

Nervous system 
disorders 

Headache, 
paraesthesia, 
dysaesthesia, 
dizziness  

Tremor, lethargy, loss 
of consciousness, 
balance disorders, 
dysgeusia 

Convulsion, clonus, 
brain oedema 

 

Eye disorders Vision blurred, 
corneal structural 
change (including 
corneal deposits 
and corneal 
opacity) 

Visual impairment, 
halo vision, photopsia, 
glaucoma, 
conjunctivitis, dry eye, 
keratopathy 

Cataract, 
accommodation 
disorders 

 

Cardiac 
disorders 
 
 

Prolongation of 
ECG QTc 
interval(*) (**) 

 Heart failure, acute 
heart failure, rate and 
rhythm disorders, 
cardiac conduction 
disorders, ventricular 

 



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arrhythmia and 
cardiac arrest 

Vascular 
disorders 

Hypertension Hypertensive crisis, 
ischaemic 
cerebrovascular 
conditions 

 Aneurysms 
and artery 
dissections 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Epistaxis, 
haemoptysis, 
pneumonitis 

Respiratory failure, 
pneumonia 
aspiration 

 

Gastrointestinal 
disorders 

Abdominal pain, 
diarrhoea, nausea, 
vomiting, 
dyspepsia 

Colitis, dry mouth, 
stomatitis, dysphagia, 
constipation, gastritis, 
gastrointestinal 
haemorrhage 

Pancreatitis, 
peritonitis, ileus, 
intestinal perforation, 
faecal incontinence 

 

Hepatobiliary 
disorders 

 Cholelithiasis   

Skin and 
subcutaneous 
tissue disorders 

Photosensitivity 
reaction, rash and 
other skin rections 
(including acne, 
dry skin, 
dermatitis, 
pruritus), nail 
disorders 

Palmar-plantar 
erythrodysaesthiesia 
syndrome, alopecia 
 

Bullous dermatitis 
 

 

Renal and 
urinary 
disorders 

Proteinuria, 
nephrolithiasis 

Dysuria, hematuria, 
renal failure, 
pollakiuria, 
micturition urgency 

Chromaturia, anuria  

General 
disorders and 
administration 
site conditions 

Asthenia, fatigue, 
pain, oedema 

Pyrexia Impaired healing  

Investigations 
 

ECG QTc interval 
prolonged  
 

Increase of serum 
ALT and AST, weight 
decreased blood 
creatinine increased  

Increased 
haemoglobin,serum 
amylase increased 
 

 

* 13.4% vandetanib patients had QTc (Bazett’s) ≥ 500 ms compared with 1.0% placebo patients. QTcF 
prolongation was > 20 ms in over 91% of patients, > 60 ms in 35%, > 100 ms in 1.7%. Eight percent of patients 
had a dose reduction due to QTc prolongation. 
** including two deaths in patients with QTc > 550 ms (one due to sepsis and one due to heart failure) 
 
Description of selected adverse reactions 
Events such as Torsades de pointes, Stevens-Johnson syndrome, erythema multiforme, interstitial lung 
disease (sometimes fatal) and PRES (RPLS) have occurred in patients treated with vandetanib 
monotherapy. It is expected that these would be uncommon adverse reactions in patients receiving 
vandetanib for MTC. 
 
Ocular events such as blurred vision are common in patients who received vandetanib for MTC. 
Scheduled slit lamp examinations have revealed corneal opacities (vortex keratopathies) in treated 
patients; however, routine slit lamp examinations are not required for patients receiving vandetanib. 
 
At various exposure durations, median haemoglobin levels in patients treated with vandetanib were 
increased by 0.5-1.5 g/dl compared to baseline. 
 
Reporting of suspected adverse reactions 



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Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
Paediatric population 
Paediatric clinical trial data with vandetanib in MTC (see section 5.1) obtained during drug 
development is limited to 16 patients aged 9 years to 17 years with hereditary medullary thyroid 
carcinoma (Study IRUSZACT0098). Whilst the study size is small owing to the rarity of MTC in 
children, it is considered representative of the target population. The safety findings in this study are 
consistent with the safety profile of vandetanib in adult patients with MTC. Long term safety data in 
paediatric patients are not available. 
 
 
 
 
4.9 Overdose 
 
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). 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic Group: antineoplastic agent, protein kinase inhibitor, ATC Code: L01XE12 
 
Mechanism of action and pharmacodynamic effects 
Vandetanib is a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2 also 
known as kinase insert domain containing receptor [KDR]), epidermal growth factor receptor (EGFR) 
and RET tyrosine kinases. Vandetanib is also a sub-micromolar inhibitor of vascular endothelial 
receptor-3 tyrosine kinase. 
 
Vandetanib inhibits VEGF-stimulated endothelial cell migration, proliferation, survival and new blood 
vessel formation in in vitro models of angiogenesis. In addition, vandetanib inhibits epidermal growth 
factor (EGF)-stimulated EGF receptor tyrosine kinase in tumour cells and endothelial cells. 
Vandetanib inhibits EGFR-dependent cell proliferation and cell survival in vitro. Vandetanib also 
inhibits both wild type and the majority of mutated, activated forms of RET, and significantly inhibits 
the proliferation of MTC cell lines in vitro. 
 
In vivo vandetanib administration reduced tumour cell-induced angiogenesis, tumour vessel 
permeability, tumour microvessel density, and inhibited tumour growth of a range of human xenograft 
tumour models in athymic mice. Vandetanib also inhibited the growth of MTC xenograft tumours in 
vivo. 
 
The precise mechanism of action of vandetanib in locally advanced or metastatic MTC is unknown. 



13 

 
Clinical efficacy in adults 
 
Clinical data from MTC  
A randomised, double-blind, placebo-controlled study (Study 58) was conducted to demonstrate safety 
and efficacy of vandetanib 300 mg versus placebo. This study included 331 patients with unresectable 
locally advanced or metastatic MTC. Only patients with CTN ≥ 500 pg/mL (conventional units) or 
≥ 146.3 pmol/L (international standard units) were enrolled. Of the patients enrolled in the study 
10 patients on vandetanib and 4 on placebo (4% of all patients) had a World Health Organization 
performance status (WHO PS) score of ≥ 2 and 28 (12.1%) patients on vandetanib and 10 (10.1%) on 
placebo had cardiac impairment. Cardiac impairment was defined as patients with previous 
cardiovascular abnormality. 
 
The primary objective of this study was to demonstrate an improvement in progression-free survival 
(PFS) with vandetanib compared to placebo. The secondary endpoints were evaluation of overall 
objective response rate (ORR), disease control rate (DCR) defined as, partial response (PR) or 
complete response (CR) or stable disease (SD) lasting at least 24 weeks, duration of response (DOR), 
time to worsening of pain based on Brief Pain Inventory (BPI) worst pain scale, and overall survival 
(OS). The PFS primary endpoint, ORR and DCR were based on centralized, independent blinded 
review of the imaging data. Biochemical response with vandetanib as compared to placebo as 
measured by CTN and CEA was also assessed as secondary endpoints. 
 
Patients were treated with vandetanib or placebo until they reached objective disease progression. 
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 vandetanib. Twenty-eight of 
the 231 patients (12.1%) on vandetanib and 3 of the 99 (3.0%) on placebo discontinued treatment 
because of an adverse event. Fourteen of the 28 patients (50%) who stopped vandetanib for an adverse 
event discontinued without a dose reduction. Five out of 6 patients (83%) with moderate renal failure 
who were treated with vandetanib had a dose reduction to 200 mg for adverse reaction; 1 patient 
required a further reduction to 100 mg. 
 
The result of the primary analysis of PFS showed a statistically significant improvement in PFS for 
patients randomised to vandetanib compared to placebo (Hazard Ratio (HR) = 0.46; 95% Confidence 
Interval (CI) = 0.31-0.69; p=0.0001). 
 
The median PFS for patients randomised to vandetanib has not been reached; however, based on 
statistical modelling of data observed up to the 43rd percentile, the median PFS is predicted to be 
30.5 months with 95% confidence interval 25.5 to 36.5 months. The median PFS for patients 
randomised to placebo was 19.3 months. At 12 months, the proportion of patients alive and 
progression-free was 192 (83%) for patients randomised to vandetanib and 63 (63%) for patients 
randomised to placebo. In the vandetanib arm, a total of 73 (32%) patients progressed: 64 (28%) by 
response evaluation criteria in solid tumours (RECIST) progression and 9 (4%) by death in the 
absence of progression. The remaining 158 patients (68%) were censored in the analysis of PFS. In the 
placebo arm, a total of 51 (51%) of patients had progressed: 46 (46%) by RECIST progression and 5 
(5%) by death in the absence of progression. The remaining 49 patients (49%) were censored in the 
analysis of PFS. 
 
Figure 1: Kaplan Meier plot of PFS  



14 

 
 
months  0  6  12  18  24  30  36  

n-vandetanib  231  196  169  140  40  1  0  

n-placebo  100  71  57  45  13  0  0  
 
____ vandetanib 300 mg, ------ placebo, y-axis=PFS, x-axis=time in months, n-vandetanib=number of patients at 
risk-vandetanib, n-placebo=number of patients at risk-placebo 
 
HR = 0.46, 95%CI (0.31-0.69), p = 0.0001 
PFS N Median PFS HR 95% CI p-value 
Vandetanib 300 mg 73/231 

(32%) 
Not reached 
(predicted 
30.5 months) 

 
 
0.46 

 
 
0.31, 0.69 

 
 
0.0001 

Placebo 51/100 
(51%) 

19.3 months    

 
Survival status and the median final overall survival (81.6 months in the vandetanib arm and 80.4 
months in the placebo arm) were similar across both treatment arms. There was no statistically 
significant difference in final OS (HR 0.99, 95.002% CI 0.72, 1.38, p=0.9750). Results should be 
interpreted with caution due to the high percentage of patients in the placebo arm switching to open-
label vandetanib (79.0% [79/100] of patients). 
 
Most (95% of the patients) had metastatic disease. Fourteen patients treated with vandetanib, and 3 
with placebo had unresectable locally advanced disease only. There is limited clinical experience with 
vandetanib in patients with unresectable locally advanced disease and without metastasis.  
 
Statistically significant advantages were seen for vandetanib for the secondary endpoints of response 
rate, disease control rate, and biochemical response. 
 
Table 3: Summary of other efficacy findings in study 58 
ORRa N Response rate ORb 95% CI p-value 

 Vandetanib 300 mg 104/231 45% 
5.48 2.99, 10.79 < 0.0001 

 Placebo 13/100 13% 

DCRa N Response rate ORb 95% CI p-value 



15 

 Vandetanib 300 mg 200/231 87% 
2.64 1.48, 4.69 0.001 

 Placebo 71/100 71% 

CTN Response 
 

N 
Response rate ORb 95% CI p-value 

 Vandetanib 300 mg 160/231 69% 
72.9 26.2, 303.2 < 0.0001 

 Placebo 3/100 3% 

CEA Response  N Response rate ORb 95% CI p-value 

 Vandetanib 300 mg 119/231 52% 
52.0 16.0, 320.3 < 0.0001 

 Placebo 2/100 2% 

OVERALL SURVIVAL  N Median OS  HRc 95% CI p-value 

 Vandetanib 300 mg 116/231 81.6 months 0.99 
0.72, 1.38 

 
0.9750  Placebo 52/100 80.4 months 

      
a  Overall response rate = complete + partial responses. Disease control rate = response rate + stable disease at 24 weeks. 

Intent-to-treat (ITT) analysis includes patients who received open-label vandetanib before progression according to the 
central read. 

b  OR=Odds Ratio. A value > 1 favors vandetanib. The analysis was performed using a logistic regression model with  
treatment as the only factor. 

c HR= Hazard Ratio. A value <1 favors vandetanib. The analysis was performed using a log rank test with 
treatment as the only factor. 
N=Number of events/number of randomised patients  
 
A statistically significant advantage was seen for vandetanib for the secondary endpoint of time to 
worsening of pain (derived as a composite endpoint using the worst pain score from BPI and patient 
reported opioid analgesic use) (vandetanib 49%, placebo 57%, HR 0.61, 97.5%CI 0.43-0.87, p< 0.006: 
8 vs. 3 months). There were no statistically significant differences observed for the exploratory 
endpoint of diarrhoea (reported as stool frequency). 
 
RET mutation status in Study 58 
In Study 58, RET mutation testing was performed by using the polymerase chain reaction (PCR) based 
Amplification Refractory Mutation System (ARMS) assay for the M918T mutation, and direct 
sequencing of DNA for mutations in exons 10, 11, 13, 14, 15 and 16 (site of M918T mutation) on all 
sporadic patients where DNA was available (297/298).  
 
However, RET status could not be tested in a large proportion of patients (mainly because of 
unavailable results for direct sequencing of DNA) and response rate was somewhat lower in the 
patients with unknown RET status compared with RET mutation positive status: 51.8% vs. 35.9 % 
respectively. In the blinded comparison of vandetanib vs. placebo, only 2 patients known to be RET 
negative at all 6 exons received vandetanib and none demonstrated responses. 
 
A post-hoc subgroup analysis of RET negative status based on absence of M918T mutation of the 
pivotal study 58 was performed. A patient was considered to have a RET mutation if either an M918T 
mutation by the ARMS assay, or a RET mutation in any exons sequenced was present in the tumour. 
Actually 79 patients were identified by absence of an M918T mutation and no RET mutation 
identified at any of the other 6 exons tested but in 71 of such patients sequencing of the 6 exons was 
incomplete. M918T mutation is the most frequent mutation observed in patients with sporadic MTC; 
however it cannot be ruled out that some patients tested RET negative for M918T mutation might be 
positive for mutation on other exons. 
 
Results according to RET status (positive, unknown and RET M918T mutation negative definition) 
are presented in Table 4. 



16 

 
Table 4: Summary of efficacy findings in a segment of patients according to RET mutation 
status 
 

 Patients with 
documented RET 
mutation  
(n=187)  

Patients with no 
M918T mutation 
and other 
mutations not 
tested or negative 
(n=79)* 

Objective response rate 
(vandetanib arm)  

52%  35%  

Efficacy endpoint 
PFS HR (95%) 
confidence interval  

0.45 (0.26, 0.78)  0.57 (0.29, 1.13)  

*RET mutation status was obtained at the time of diagnosis in a majority of patients and could have changed 
since. 
 
Clinical efficacy in paediatric patients: 
A Phase I/II single-center open-label, single-arm study (Study IRUSZACT0098) assessed the activity 
of vandetanib in 16 patients with unresectable locally advanced or metastatic hereditary MTC. 
Characteristics of the patients at study entry were the following: mean age 14.2 years (range 9-17 
years), 50% female, 50% male, 93.8% White, 26.7% Hispanic and 6.3% were Black. Most patients 
(81.3%) had undergone partial or total thyroidectomy prior to study entry. Starting vandetanib dose 
was 100mg/m2/day for all patients except for one who started at 150mg/m2/day. After having well 
tolerated the first 1 or 2 cycles of therapy (1 cycle = 28 days), the remaining patients continued on 100 
mg/m2 of treatment. The primary efficacy outcome was ORR according to RECIST v 1.0. The 
objective response rate observed was 43.8%, all of which were partial responses. 31.3% of patients 
had stable disease for at least 8 weeks. Disease Control Rate including best response or Stable Disease 
>24 weeks was 75.0%. There is no experience with Caprelsa in patients 5-8 years of age in this study. 
 
This medicinal product has been authorized under a so-called “conditional approval” scheme. This 
means that further evidence on this medicinal product is awaited. The European Medicines Agency 
(EMA) will review new information on the product every year and this SmPC will be updated as 
necessary. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
Following oral administration of vandetanib absorption is slow with peak plasma concentrations 
typically achieved at a median of 6 hours, range 4-10 hours, after dosing. Vandetanib accumulates 
approximately 8-fold on multiple dosing with steady state achieved from approximately 2 months. 
 
Distribution 
Vandetanib binds to human serum albumin and alpha-1-acid-glycoprotein with in vitro protein binding 
being approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady state 
exposure after 300 mg once daily, the mean percentage protein binding was 93.7% (range 92.2 to 
95.7%). The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterised by 
a volume of distribution of approximately 7450 l.  
 
Biotransformation 
Following oral dosing of 14C- vandetanib, unchanged vandetanib and metabolites vandetanib N-oxide 
and N-desmethyl vandetanib were detected in plasma, urine and feces. A glucuronide conjugate was 
seen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by 



17 

CYP3A4, and vandetanib-N-oxide by flavin-containing monooxygenase enzymes (FM01 and FMO3). 
N-desmethyl-vandetanib and vandetanib-N-oxide circulate at concentrations of approximately 11% 
and 1.4% of those of vandetanib. 
 
Elimination 
The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterised by a 
clearance of approximately 13.2 l/h. and plasma half-life of approximately 19 days. Within a 21 day 
collection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% in 
faeces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days would 
be expected based on the plasma half-life. 
 
Special populations 
Renal impairment 
A single dose pharmacokinetic study in volunteers indicated that exposure to vandetanib is enhanced 
(up to 1.5, 1.6 and 2-fold) in mild, moderate and severe renal impaired subjects respectively compared 
to subjects with normal renal function (see sections 4.2, 4.4 and 4.5). 
 
Hepatic impairment 
A single dose pharmacokinetic study in volunteers indicated that hepatic impairment did not affect 
exposure to vandetanib. There is limited data in patients with hepatic impairment (serum bilirubin 
greater than 1.5 times upper limit of normal (see sections 4.2 and 4.4). 
 
Food effect 
Exposure to vandetanib is not affected by food. 
 
Pharmacokinetics in paediatric population 
The pharmacokinetic parameters of vandetanib in paediatrics MTC patients aged 9-17 years were 
similar to those in adults. Vandetanib exposure in children between 5-8 years old with glioma-related 
indications was comparable to MTC patients aged 9-18 years. Dosing at 100mg/m2/day of the 
indicated posology (function of BSA) in paediatrics delivers similar exposure to that achieved in 
adults at 300 mg daily. 
 
 
5.3 Preclinical safety data 
 
Vandetanib has shown no mutagenic or clastogenic potential. 
 
In repeat-dose toxicity studies of up to 9 months duration, effects included emesis, body weight loss 
and diarrhoea in dogs and physeal dysplasia in young dogs and rats with open growth plates. In rats, 
effects on teeth, kidney and skin were noted. These findings occurred at clinically-relevant plasma 
concentrations, were largely reversible within 4 weeks of cessation of dosing and were attributable to 
inhibition of vascular endothelial growth factor receptor (VEGFR) or EGFR.  
 
Effects noted in other studies included inhibition of human ether-à-go-go related gene (hERG) current 
and prolongation of QTc interval in dogs. Elevation of systolic and diastolic blood pressure was 
observed in rats and dogs. In mice, vandetanib was shown to delay but not prevent wound healing. 
Vandetanib also showed evidence of phototoxic potential in an in vitro cytotoxicity assay. In an 
animal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strength 
compared with controls. This suggests that vandetanib slows but does not prevent wound healing. The 
appropriate interval between discontinuation of vandetanib and subsequent elective surgery required to 
avoid the risks of impaired wound healing has not been determined. In clinical studies, a small number 
of patients had surgery while receiving vandetanib and there were no reported wound healing 
complications. 
 
Reproductive toxicology 
Vandetanib had no effect on fertility in male rats. In a female fertility study, there was a trend towards 
increased oestrus cycle irregularity, a slight reduction in pregnancy incidence and increase in 



18 

implantation loss. In a repeat-dose toxicity study in rats, there was a decrease in the number of 
corpora lutea in the ovaries of rats given vandetanib for 1 month. 
 
In rats, embryofoetal toxicity was evident as foetal loss, delayed foetal development, heart vessel 
abnormalities and precocious ossification of some skull bones. In a rat pre- and post-natal 
development study, at doses producing maternal toxicity during gestation and/or lactation, vandetanib 
increased pre-birth loss and reduced post-natal pup growth. Vandetanib was excreted into milk in rat 
and found in plasma of pups following dosing to lactating rats. 
 
Carcinogenicity 
 Vandetanib has shown no carcinogenic potential effect in a 6 month carcinogenicity study in 
rasH2 transgenic mice. A 2-year carcinogenicity study in rats was impaired by low survival in 
the high dose female group and limited exposure of the animals to vandetanib; however, no 
carcinogenic effects were observed in the remaining animals.  
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Calcium hydrogen phosphate dihydrate 
Microcrystalline cellulose 
Crospovidone (type A) 
Povidone (K 29-32) 
Magnesium stearate 
 
Film-coating 
Hypromellose 
Macrogol (300) 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
4 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C.  
 
6.5 Nature and contents of container  
 
PVC/ PVDC/Alu blisters, sealed with aluminium foil, each containing 30 film-coated tablets. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands 
 
 



19 

8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/749/001 
EU/1/11/749/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 February 2012 
 
Date of latest renewal: 15 January 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

  



20 

 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
E.  SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE CONDITIONAL MARKETING AUTHORISATION  
 



21 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
AstraZeneca UK Ltd. 
Silk Road Business Park 
Macclesfield, Cheshire SK10 2NA 
United Kingdom 
 
Or 
 
Genzyme Ltd. 
37 Hollands Road 
Haverhill  
Suffolk, CB9 8PU 
United Kingdom 
 
Or 
 
Genzyme Ireland Ltd. 
IDA Industrial Park, 
Old Kilmeaden Road, 
Waterford  
Ireland 
 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION 
 
 Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
 EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 



22 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
 
 Additional risk minimisation measures 

 
Prior to launch of CAPRELSA in each Member State the Marketing Authorisation Holder (MAH) 
must agree about the content and format of the educational programme, including communication 
media, distribution modalities, and any other aspects of the programme, with the National Competent 
Authority.  
The MAH shall ensure that in each Member State where CAPRELSA is marketed, all healthcare 
professionals (HCPs) and patients / caregivers who are expected to prescribe, dispense and use 
CAPRELSA have access to/are provided with an educational package containing: 
 
HCPs 

 The summary of Product Characteristics (SmPC); 
 The educational material, including: 

o Information about the risks associated with CAPRELSA: 
- QTc prolongation and Torsades de pointes 
- Posterior reversible encephalopathy syndrome (PRES); 
- Teeth and bone development abnormalities in pediatric patients 
- Medication errors in the pediatric population 

o The Physicians’ dosing and monitoring guide for paediatric patients; 
 The dosing and monitoring guide for paediatric patients and patient’s caregivers; 
 The Patient Leaflet; 
 The Patient Alert Card. 

 
Patients / caregivers 

 The dosing and monitoring guide for paediatric patients and patient’s caregivers; 
 The Patient Leaflet; 
 The Patient Alert Card. 

 
 
The HCPs educational materials should include the following key elements: 
 

QTc prolongation and Torsades de pointes 
 CAPRELSA prolongs the QTc interval and can cause Torsades de pointes and sudden death  
 CAPRELSA treatment must not be started in patients: 

o Whose ECG QTc interval is greater than 480 msec; 
o Who have congenital long QTc syndrome; 
o Who have a history of Torsades de pointes unless all risk factors that contributed to 

Torsades de pointes have been corrected; 
 The need for an ECG, and serum levels of potassium, calcium and magnesium and thyroid 

stimulating hormone (TSH) and the times and situations when it should be performed; 
 Patients who develop a single value of corrected ECG QTc interval of at least 500 msec should 

stop taking CAPRELSA. Dosing can be resumed at a reduced dose after return of the ECG QTc 
interval to pre-treatment status has been confirmed and correction of possible electrolyte 
imbalance has been made; 

 If QTc increases markedly but stays below 500 msec, the advice of a cardiologist should be 
sought; 

 Details of medicinal products where the co-administration of CAPRELSA is either 
contraindicated or not recommended; 

 The role and use of the Patient Alert Card. 



23 

 
 

 
Posterior reversible encephalopathy syndrome (PRES) also known as reversible posterior 
leukoencephalopathy syndrome (RPLS) 
 PRES should be considered in any patient presenting with seizures, headache, visual 

disturbances, confusion or altered mental function. A brain MRI should be performed in any 
patient presenting with seizures, confusion or altered mental status; 

 The need to counsel patients about the risk of prolonged QTc and PRES and inform them of 
what symptoms and signs to be aware of and the actions to take; 

 The role and use of the Patient Alert Card. 
 
 

Teeth and bone development abnormalities in pediatric patients 
 Vandetanib was found not to impair linear growth in clinical trials conducted in children and 

adolescents; 
 Vandetanib has demonstrated adverse effect on growing tissue that relies on vascularization 

such as teeth and growth plates in non-clinical studies; 
 The need to closely monitor teeth and bone abnormalities in the paediatric population; 

 
 

Medication errors in the paediatric population 
 
The Physicians’ dosing and monitoring guide for paediatric patients should contain the 
following key elements: 
 How CAPRELSA dose for infants and adolescents is calculated; 
 The posology regimens according to patient’s body surface area (BSA), including a visual 

representation of the two-week posology regimen per BSA; 
 How CAPRELSA is used / administered; 
 Instructions on how to use the dosing and monitoring guide and the daily tracker for paediatric 

patients and caregivers. 
 
 

The dosing and monitoring guide for patients and patient’s caregivers should contain the 
following key elements: 

 What CAPRELSA is, what it treats, how it is administered; 
 How CAPRELSA dose is calculated; 
 What are the side effects associated with CAPRELSA and which monitoring is requested; 
 How to use the daily tracker table (including examples of a completed daily tracker); 
 The general daily tracker for 14 days and blank copies of the daily tracker. 

 
 

The Patient Alert Card should include the following key elements: 
 Information about the risks of QTc prolongation and Torsades de pointes, and Posterior 

reversible encephalopathy syndrome (PRES); 
 Signs or symptoms of the safety concerns and when to seek attention from a HCP; 
 Not to stop taking CAPRELSA, or change the dose, without consulting the prescriber; 
 Contact details of the CAPRELSA prescriber. 

 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 
 FOR  THE CONDITIONAL MARKETING AUTHORISATION  
 
This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) No 
726/2004, the MAH shall complete, within the stated timeframe, the following measures:  
 



24 

 
 
 
 
Description Due date 
In order to confirm the efficacy and safety of Caprelsa in RET-negative patients, 
the MAH should submit: 
 
- the clinical study report of study D4200C00104, an observational study 
including a retrospective arm to evaluate the Benefit/Risk of vandetanib 
(Caprelsa) 300 mg in RET mutation negative and RET mutation positive patients 
with symptomatic, aggressive, sporadic, unresectable, locally advanced/metastatic 
thyroid cancer (MTC). 
 
- The re-evaluation of treatment efficacy in RET-negative patients based on the 
re-analysis of archived tumour samples from the pivotal study D4200C00058. 

3Q 2020 

 
  



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
  



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



27 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON OF CAPRELSA 100 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Caprelsa 100 mg film-coated tablets 
vandetanib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg vandetanib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



28 

 
Genzyme Europe B.V.,  
Paasheuvelweg 25 
1105 BP Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/749/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Caprelsa 100 mg 
 
 
17.  UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
  



29 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF CAPRELSA 100 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Caprelsa 100 mg tablets 
vandetanib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Genzyme Europe B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
  



30 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON OF CAPRELSA 300 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Caprelsa 300 mg film-coated tablets 
vandetanib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 300 mg vandetanib. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



31 

 
Genzyme Europe B.V.,  
Paasheuvelweg 25 
1105 BP Amsterdam 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/11/749/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Caprelsa 300 mg 
 
 
17.  UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18.  UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



32 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF CAPRELSA 300 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Caprelsa 300 mg tablets 
vandetanib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Genzyme Europe B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



34 

Package leaflet: Information for the patient  
Caprelsa 100 mg film-coated tablets 
Caprelsa 300 mg film-coated tablets 

vandetanib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
In addition to this leaflet you will be given the Patient Alert Card, which contains important safety 
information that you need to know before you are given Caprelsa and during treatment with Caprelsa. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet and the patient alert card. You may need to read it again. 
- It is important that you keep the Alert Card with you during treatment.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
1. What Caprelsa is and what it is used for 
2. What you need to know before you take Caprelsa 
3. How to take Caprelsa 
4. Possible side effects 
5. How to store Caprelsa 
6. Contents of the pack and other information 
 
 
1. What Caprelsa is and what it is used for 
 
Caprelsa is a treatment for adults and children aged 5 years and above with: 
 
Medullary thyroid cancer that cannot be removed by surgery or has spread to other parts of the body. 
 
Caprelsa works by slowing down the growth of new blood vessels in tumours (cancers). This cuts off 
the supply of food and oxygen to the tumour. Caprelsa may also act directly on cancer cells to kill 
them or slow down their growth. 
 
 
2. What you need to know before you take Caprelsa 
 
Do not take Caprelsa: 
- if you are allergic to vandetanib or any of the other ingredients of this medicine (listed in 

Section 6). 
- if you have a heart problem that you were born with called ‘congenital long QTc syndrome’. 

This is seen on an electrocardiogram (ECG). 
- if you are breast-feeding. 
- if you are taking any of the following medicines: arsenic, cisapride (used to treat heartburn), 

erythromycin intravenous and moxifloxacin (used to treat infection), toremifene (used to treat 
breast cancer), mizolastine (used to treat allergies), Class IA and III antiarrhythmics (used to 
control heart rhythm). 

 
Do not take Caprelsa if any of the above applies to you. If you are not sure, talk to your doctor. 
 



35 

Warnings and precautions 
Talk to your doctor or pharmacist before taking Caprelsa: 
 If you are sensitive to the sun. Some people who are taking Caprelsa become more sensitive to 

the sun. This can cause sunburn. While you are taking Caprelsa, protect yourself when you go 
outside by always using sunscreen and wearing clothes to avoid exposure to the sun.  

 If you have high blood pressure. 
 If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a 

tear in a blood vessel wall. 
 
Monitoring of your blood and your heart: 
Your doctor or nurse should perform tests to check the levels of your blood potassium, calcium, 
magnesium, and thyroid-stimulating hormone (TSH) as well as the electrical activity of your heart 
with a test called an electrocardiogram (ECG). You should have these tests:  
 Before starting Caprelsa  
 Regularly during Caprelsa treatment  
 1, 3 and 6 weeks after starting Caprelsa  
 12 weeks after starting Caprelsa  
 Every 3 months thereafter 
 If your doctor or pharmacist changes your dose of Caprelsa 
 If you start taking medicines that affect your heart 
 As instructed by your doctor or pharmacist 
 
Children  
Caprelsa should not be given to children below 5 years of age. 
 
Other medicines and Caprelsa 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines that you buy without a prescription and herbal medicines. This is 
because Caprelsa can affect the way some medicines work and some medicines can have an effect on 
Caprelsa. 
 
Tell your doctor or pharmacist if you are taking any of the following medicines: 
 itraconazole, ketoconazole, ritonavir, clarithromycin, rifampicin and moxifloxacin (medicines 

used to treat infections) 
 carbamazepine and phenobarbital (used to control seizures) 
 ondansetron (used to treat nausea and vomiting) 
 cisapride (used to treat heart burn), pimozide (used to treat uncontrolled repeated movements of 

the body and verbal outbursts) and halofantrine and lumefantrine (used to treat malaria)  
 methadone (used to treat addiction), haloperidol, chlorpromazine, sulpiride, amisulpride, and 

zuclopenthixol, (used to treat mental illness)  
 pentamidine (used to treat infection) 
 vitamin K antagonists and dabigatran often referred to as ‘blood thinners’ 
 cyclosporine and tacrolimus (used to treat transplant rejection), digoxin (used to treat irregular 

heart rate), and metformin (used to control your blood sugar) 
 proton pump inhibitors (used to treat heartburn) 
 
You will also find this information in the Patient Alert Card you have been given by your doctor. It is 
important that you keep this Alert Card and show it to your partner or caregivers. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. This is because Caprelsa may harm an unborn 
child. Your doctor will discuss with you the benefits and risks of taking Caprelsa during this time. 
 If you may become pregnant you must use effective contraception when you are taking Caprelsa 

and for at least four months after the last dose of Caprelsa. 
You must not breast-feed during treatment with Caprelsa for the safety of your baby. 



36 

 
 
Driving and using machines 
Use caution before driving or using machines. Keep in mind Caprelsa may make you feel tired, weak, 
or cause blurred vision. 
 
 
3. How to take Caprelsa 
 
Use in adults 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
 The recommended dose is 300 mg each day. 
 Take Caprelsa about the same time each day. 
 Caprelsa may be taken with or without food. 
 
Use in children  
The doctor will tell you how many tablets of Caprelsa to give to your child. The amount of Caprelsa 
given will depend on your child’s body weight and height. The total daily dose in children must not 
exceed 300 mg. The treatment may either be given to your child as a once-daily dose, an every other 
day dosing or a repeating 7-day schedule as indicated in the dosing guide that has been given to you 
by your doctor. It is important that you keep this dosing guide and show it to your caregiver. 
 
If you have trouble swallowing the tablet 
If you have trouble swallowing the tablet, you can mix it with water as follows: 
 Take half a glass of still (non-carbonated) water. Only use water, do not use any other liquids. 
 Put the tablet into the water. 
 Stir the tablet until it has dispersed into the water. This may take about 10 minutes. 
 Then drink it straight away. 
To make sure there is no medicine left, refill the glass halfway with water and drink it. 
 
If you get side effects 
If you get side effects always tell your doctor. Your doctor may tell you to take Caprelsa at a lower or 
increased dose (such as two 100 mg tablets or one 100 mg tablet). Your doctor may also prescribe 
other medicines to help control your side effects. The side effects of Caprelsa are listed in Section 4. 
 
If you take more Caprelsa than you should 
If you take more Caprelsa than you have been prescribed, talk to a doctor or go to a hospital straight 
away. 
 
If you forget to take Caprelsa 
What to do if you forget to take a tablet depends on how long it is until your next dose. 
 If it is 12 hours or more until your next dose: Take the missed tablet as soon as you 

remember. Then take the next dose at the normal time. 
 If it is less than 12 hours until your next dose: Skip the missed dose. Then take the next dose 

at the normal time. 
Do not take a double dose (two doses at the same time) to make up for a forgotten tablet. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. If you get 
side effects, your doctor may tell you to take Caprelsa at a lower dose. Your doctor may also prescribe 
other medicines to help control your side effects. 



37 

 
Tell your doctor straight away if you notice any of the following side effects – you may need 
urgent medical treatment: 
 Fainting, dizziness or heart rhythm changes. These may be signs of a change in the electrical 

activitiy of your heart. They are seen in 8% of people taking Caprelsa for medullary thyroid 
cancer. Your doctor may recommend you take Caprelsa at a lower dose or stop taking Caprelsa. 
Caprelsa has uncommonly been associated with life-threatening changes in heart rhythm. 

 Severe skin reactions affecting large areas of your body. The signs may include redness, pain, 
ulcers, blisters and shedding of the skin. The lips, nose, eyes and genitals may also be affected. 
These may be common (affecting less than 1 in 10 people) or uncommon (affects less than 1 in 
100 people) depending on the type of skin reaction. 

 Severe diarrhoea. 
 Serious breathlessness, or sudden worsening breathlessness, possibly with a cough or a high 

temperature (fever). This may mean that you have an inflammation of the lungs called 
‘interstitial lung disease’. This is uncommon (affects less than 1 in 100 people) but can be 
life-threatening. 

 Seizures, headache, confusion or finding it difficult to concentrate. These may be signs of a 
condition called RPLS (Reversible Posterior Leukoencephalopathy Syndrome). These usually 
go away when Caprelsa is stopped. RPLS is uncommon (affects less than 1 in 100 people). 

Tell your doctor straight away if you notice any of the side effects above.  
 
Other side effects include: 
Very common (affects more than 1 in 10 people): 
 Diarrhoea. Your doctor may prescribe a medicine to treat this. If it gets severe, tell your doctor 

straight away. 
 Abdominal pain. 
 Skin rash or acne. 
 Depression. 
 Tiredness. 
 Feeling sick (nausea). 
 Upset stomach (dyspepsia). 
 Nail disorders. 
 Being sick (vomiting). 
 Loss of appetite (anorexia). 
 Weakness (asthenia). 
 High blood pressure.Your doctor may prescribe a medicine to treat this. 
 Headache. 
 Fatigue. 
 Trouble sleeping (insomnia). 
 Inflammation of the nasal passages. 
 Inflammation of the main air passages to the lungs. 
 Upper respiratory tract infections. 
 Urinary tract infections. 
 Numbness or tingling of the skin. 
 Abnormal sensation of the skin. 
 Dizziness. 
 Pain. 
 Swelling caused by excess fluid (oedema). 
 Stones or calcium deposits in the urinary tract (nephrolithiasis). 
 Blurred vision, including mild changes in the eye which can lead to blurred vision (corneal 

opacity). 
 Sensitivity of the skin to sunlight. While you are taking Caprelsa, protect yourself when you go 

outside by always using sun cream and wearing clothes to avoid exposure to the sun. 
 
Common (affects less than 1 in 10 people) 



38 

 Dehydration. 
 Severe high blood pressure. 
 Weight loss. 
 Stroke or other conditions where the brain may not get enough blood. 
 A type of rash that affects the hands and feet (hand foot syndrome). 
 Sore mouth (stomatitis). 
 Dry mouth. 
 Pneumonia. 
 Toxins in the blood as a complication of infection. 
 Flu. 
 Inflammation of the urinary bladder. 
 Inflammation of the sinuses. 
 Inflammation of the voice box (larynx). 
 Inflammation of a follicle, especially a hair follicle. 
 Boil. 
 Fungal infection. 
 Kidney infection. 
 Loss of body fluid (dehydration). 
 Anxiety. 
 Tremor. 
 Drowsiness. 
 Fainting. 
 Feeling unsteady. 
 Increased pressure in the eye (glaucoma). 
 Coughing up of blood. 
 Inflammation of the lung tissue. 
 Difficulty swallowing. 
 Constipation. 
 Inflammation of the lining of the stomach (gastritis). 
 Gastrointestinal bleeding.  
 Gallstones (cholelithiasis). 
 Painful urination. 
 Kidney failure. 
 Frequent urination. 
 Urgent desire to urinate. 
 Fever. 
 Nose bleed (epistaxis). 
 Dry eye. 
 An irritation of the eyes (conjunctivitis). 
 Visual impairment. 
 Halo vision. 
 Seeing flashes of light (photopsia). 
 Disorder of the cornea of the eye (keratopathy). 
 A type of diarrhoea (colitis). 
 Loss of hair from the head or body (alopecia). 
 Changes in taste of foods (dysgeusia). 
 
Uncommon (affects less than 1 in 100 people) 
 Heart failure. 
 Inflammation of the appendix (appendicitis). 
 Bacterial infection. 
 Inflammation of the diverticula (small bulging pouches that can form in your digestive system).  
 Bacterial skin infection. 
 Abdominal wall abscess. 



39 

 Malnutrition. 
 Involuntary muscle contraction (convulsions). 
 Rapidly alternating muscular contraction and relaxation (clonus). 
 Swelling of the brain.  
 Clouding of the lens of the eye. 
 Heart rate and rhythm disorders. 
 Loss of heart function. 
 Failure of the lungs to function properly. 
 Pneumonia that happens when you breathe in foreign matter into your lungs. 
 Bowel obstruction. 
 Hole in your bowel. 
 Inability to control your bowel movements. 
 Abnormal color of urine. 
 Lack of urine. 
 Inability to heal properly. 
 Inflammation of the pancreas (pancreatitis). 
 Blistering of skin (bullous dermatitis). 
 
Frequency: Not known 
An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and 
artery dissections). 
 
The following side effects may be shown in tests that may be carried out by your doctor: 
 Protein or blood in your urine (shown in a urine test). 
 Heart rhythm changes (shown in an ECG). Your doctor may tell you to stop taking Caprelsa or 

take Caprelsa at a lower dose. 
 Abnormalities in your liver or pancreas (shown in blood tests). These do not usually cause 

symptoms but your doctor may want to monitor them. 
 Decreased levels of calcium in your blood. Your doctor may need to prescribe or change your 

thyroid hormone treatment. 
 Decreased levels of potassium in your blood. 
 Increased levels of calcium in your blood. 
 Increased levels of glucose in your blood. 
 Decreased levels of sodium in your blood. 
 Decrease in thyroid function.  
 Increased levels of red cells in your blood. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist straight away.  
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Caprelsa 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP. 
The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 



40 

 
Do not throw away medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Caprelsa contains  
 The active substance is vandetanib. Each tablet contains 100 or 300 mg of vandetanib. 
 The other ingredients are calcium hydrogen phosphate dihydrate, microcrystalline cellulose, 

crospovidone (type A), povidone (K29-32), magnesium stearate, hypromellose, macrogol and 
titanium dioxide (E171). 

 
What Caprelsa looks like and contents of the pack 
Caprelsa 100 mg is a white round film-coated tablet with “Z100” imprinted on one side. 
Caprelsa 300 mg is a white oval-shaped film-coated tablet with “Z300” imprinted on one side. 
 
Caprelsa comes in blister packs of 30 tablets. 
 
Marketing Authorisation Holder 
Genzyme Europe B.V.,  
Paasheuvelweg 25 
1105 BP Amsterdam 
The Netherlands 
 
 
Manufacturer 
AstraZeneca UK Limited, Macclesfield, Cheshire, SK10 2NA, United Kingdom 
 
Or 
 
Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk, CB9 8PU, United Kingdom 
 
Or 
 
Genzyme Ireland Ltd., IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien/ 
Luxembourg/Luxemburg 
Sanofi Belgium 
Tél/Tel: + 32 (0)2 710 54 00 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel: +36 1 505 0050 

 

България 
SANOFI BULGARIA EOOD  
Tел: +359 (0)2 970 53 00 
 

Malta 
Sanofi  S.p.A 
Tel:  +39 02 39394275 
 

 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Nederland 
Genzyme Europe B.V. 
Tel: +31  20 245 4000 

 

Danmark 
Sanofi A/S 

Norge 
sanofi-aventis Norge AS 

 



41 

Tlf: +45 45 16 70 00 
 

Tlf: + 47 67 10 71 00 
 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel.: 0800 04 36 996 
Tel. aus dem Ausland: +49 69 305 70 13 
 

Österreich 
sanofi-aventis GmbH 
Tel: + 43 1 80 185 - 0 

 

Eesti 
sanofi-aventis Estonia OÜ 
Tel. +372 627 34 88 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 

 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 

Portugal 
Sanofi – Produtos Farmacêuticos, Lda.  
Tel: +351 21 35 89 400 
 

 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
  

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 

 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 3 4 00 
 
Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel.:  +421 2 33 100 100 
 
 
 
 

 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: + 358 (0) 201 200 300 
 

 

Italia 
Sanofi S.p.A. 
Tel: +39 059 349 811 
 
Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi 
Tel: +44 (0)845 372 7101 
 

 

Lietuva 
UAB „SANOFI-AVENTIS LIETUVA“ 
Tel. +370 5 2755224 
 

  

   
 
This leaflet was last revised in  
 



42 

This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine.  
The European Medicines Agency will review new information on the medicine at least every year and 
this leaflet will be updated as necessary. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  

 


	ANNEX ISUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET