CAPRELSA 100mg tablets medication leaflet

Caprelsa 100 mg film-coated tablets

Caprelsa 300 mg film-coated tablets

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.

Caprelsa 100 mg tablets

The Caprelsa 100 mg tablet is a round, biconvex, white film-coated tablet with ‘Z100’ impressed onone 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.

Caprelsa is indicated for the treatment of aggressive and symptomatic Rearranged during Transfection(RET) mutant medullary thyroid cancer (MTC) in patients with unresectable locally advanced ormetastatic disease.

Caprelsa is indicated in adults, children and adolescents aged 5 years and older.

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

Rearranged during transfection (RET) status

Since the activity of Caprelsa, based on available data, is considered insufficient in patients with noidentified RET mutation, the presence of a RET mutation should be determined by a validated testprior to initiation of treatment with Caprelsa. When establishing RET mutation status, tissue samplesshould be obtained if possible at the time of initiation of treatment rather than at the time of diagnosis.

Posology for MTC in adult patients

The recommended dose is 300 mg once a day, taken with or without food at about the same time eachday.

If a dose is missed, it should be taken as soon as the patient remembers. If it is less than 12 hours tothe next dose, the patient should not take the missed dose. Patients should not take a double dose (twodoses at the same time) to make up for a forgotten dose.

Dose adjustments in adult patients with MTC

QTc interval should be carefully assessed prior to initiation of treatment. In the event of commonterminology 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 areduced dose when toxicity has resolved or improved to CTCAE grade 1 (see section 4.4). The300 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 aprolonged 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 doseto be taken with the initial prescription and each subsequent dose adjustment. Recommended dosingregimens 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 Dose reduction (mg) cwhen tolerated wellafter 8 weeks at startingdose0.7 - <0.9 100 every other day 100 daily -0.9 - <1.2 100 daily 7 day schedule: 100 every other day100-200-100-200-100-200-1001.2 - <1.6 7 day schedule: 200 daily 100 daily100-200-100-200-100-200-100≥ 1.6 200 daily 300 daily 7 day schedule:100-200-100-200-100-200-100a The starting dose is the dose at which treatment should be initiatedb Higher vandetanib doses than 150 mg/m2 have not been used in clinical studies in paediatric patientsc Patients with an adverse reaction requiring a dose reduction should stop taking vandetanib for at least a week. Dosing can beresumed at a reduced dose thereafter when fully recovered from adverse reactions

Dose adjustments in paediatric patients with MTC

* In the event of CTCAE grade 3 or higher toxicity or prolongation of the ECG QTc interval,dosing with vandetanib should be at least temporarily stopped and resumed at a reduced dosewhen 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 startingdose (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, dosingwith Caprelsa should be at least temporarily stopped and resumed at a reduced dose (c in Table1) 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 intervaloccurs, dosing with vandetanib should be permanently stopped.

The patient must be monitored appropriately. Due to the 19-day half-life, adverse reactions including aprolonged QTc interval may not resolve quickly (see section 4.4).

Duration

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

Caprelsa should not be given to children below 5 years of age. The safety and efficacy of Caprelsa inchildren 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 section5.1). Patients aged 5-18 years should be dosed according to the nomogram in Table 1. Vandetanibdoses higher than 150 mg/m2 have not been used in clinical studies in paediatric patients.

No adjustment in starting dose is required for elderly patients. There is limited clinical data withvandetanib 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 thatexposure to vandetanib after single dose is increased up to 1.5, 1.6 and 2-fold respectively in patientswith mild, moderate (creatinine clearance ≥ 30 to < 50 ml/min) and severe (clearance below30 ml/min) renal impairment at baseline (see section 5.2). Clinical data suggest that no change instarting dose is required in patients with mild renal impairment. There is limited data with 300 mg inpatients with moderate renal impairment: the dose needed to be lowered to 200 mg in 5 out of 6patients due to an adverse reaction of QT prolongation. The starting dose should be reduced to 200 mgin patients with moderate renal impairment; safety and efficacy have however not been establishedwith 200 mg (see section 4.4). Vandetanib is not recommended for use in patients with severe renalimpairment since there is limited data in patients with severe renal impairment, and safety and efficacyhave not been established.

Renal impairment in paediatric patients with MTC

There is no experience with the use of vandetanib in paediatric patients with renal impairment.

Considering the data available in adult patients with renal impairment:

* No change in starting dose is recommended in paediatric patients with mild renal impairment

* The reduced dose as specified in Table 1 should be used in paediatric patients with moderaterenal impairment. Individual patient management will be required by the physician, especiallyin paediatric patients with low BSA.

* Vandetanib is not recommended in paediatric patients with severe renal 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 notapply to patients with Gilbert’s Disease and alanine aminotransferase (ALT), aspartateaminotransferase (AST), or alkaline phosphatase (ALP) greater than 2.5 times ULRR, or greater than5.0 times ULRR if judged by the physician to be related to liver metastases), since there is limited datain patients with hepatic impairment, and safety and efficacy have not been established (seesection 4.4).

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

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

* 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 prolongthe QTc interval and/or induce Torsades de pointes: Arsenic, cisapride, erythromycinintravenous (IV), toremifene, mizolastine, moxifloxacin, Class IA and III antiarrhythmics (seesection 4.5).

* Breast-feeding (see section 4.6).

In view of the associated risks, it is important to limit treatment with vandetanib to patients who are inreal need for treatment, i.e. with a symptomatic-aggressive course of the disease. Either symptomaticdisease 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 identifynot only patients in need for treatment but also the optimal moment to commence treatment withvandetanib.

QTc prolongation and Torsades de Pointes

Vandetanib at a dose of 300 mg is associated with a substantial and concentration dependentprolongation in QTc (mean 28 msec, median 35 msec). First QTc prolongations occurred most often inthe 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 adose 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 depointes and ventricular tachycardia have been uncommonly reported in patients administeredvandetanib 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 than480 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 myocardialinfarction.

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 every3 months for at least a year thereafter. This schedule should apply to the period after dose reductiondue to QTc prolongation and after dose interruption for more than two weeks. ECGs and blood testsshould also be obtained as clinically indicated during this period and afterwards. Frequent ECGmonitoring of the QTc interval should be continued.

Serum potassium, serum magnesium and serum calcium should be kept within normal range to reducethe risk of ECG QTc prolongation. Additional monitoring of QTc, electrolytes and renal function arerequired especially in case of diarrhoea, increase in diarrhoea/dehydration, electrolyte imbalanceand/or impaired renal function. If QTc increases markedly but stays below 500 msec, cardiologistadvice should be sought.

The administration of vandetanib with substances known to prolong the ECG QTc interval iscontraindicated or not recommended (see sections 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 takingvandetanib. Dosing can be resumed at a reduced dose after return of the QTc interval topretreatment status has been confirmed and correction of possible electrolyte imbalance hasbeen made.

Posterior reversible encephalopathy syndrome, PRES (Reversible posterior leukoencephalopathysyndrome-RPLS)

PRES is a syndrome of subcortical vasogenic oedema diagnosed by a MRI of the brain, has beenobserved infrequently with vandetanib treatment in combination with chemotherapy. PRES has alsobeen observed in patients receiving vandetanib as monotherapy. This syndrome should be consideredin any patient presenting with seizures, headache, visual disturbances, confusion or altered mentalfunction. Brain MRI should be performed in any patient presenting with seizures, confusion or alteredmental status.

Severe Cutaneous Adverse Reactions (SCARs) and other skin reactions

SCARs, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), which canbe life-threatening or fatal, have been reported in association with vandetanib treatment. At the time ofprescription patients should be advised of the signs and symptoms and monitored closely for skinreactions. For suspected SJS or TEN, vandetanib should be withheld and the patient should be referredto a specialised unit for assessment and treatment. If SJS or TEN is confirmed, vandetanib should bepermanently discontinued and an alternative treatment considered (as appropriate).

Photosensitivity reactions have been observed in patients who have received vandetanib. Care shouldbe taken with sun exposure by wearing protective clothing and/or sunscreen due to the potential risk ofphototoxicity reactions associated with vandetanib treatment.

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

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

Caution should be used when administering vandetanib to patients with brain metastases, asintracranial haemorrhage has been reported.

Heart failure has been observed in patients who received vandetanib. Temporary or permanentdiscontinuation of therapy may be necessary in patients with heart failure. It may not be reversible onstopping vandetanib. Some cases have been fatal.

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 pressurecannot be controlled with medical management, vandetanib should not be restarted until the bloodpressure is controlled medically. Reduction in dose may be necessary (see section 4.8).

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

Cases of osteonecrosis, including cases of osteonecrosis of the jaw, have been reported in patientstreated with vandetanib. Some cases were reported in patients who had received prior or concomitanttreatment with antiresorptive bone therapy. An oral examination should be performed prior toinitiation of vandetanib and periodically during vandetanib therapy. Patients should be advisedregarding oral hygiene practice. If possible, vandetanib treatment should be held at least 4 weeks priorto scheduled dental surgery or invasive dental procedures, especially in patients receiving agentsassociated with osteonecrosis, such as bisphosphonates. Vandetanib discontinuation should beconsidered in patients who experience osteonecrosis (see section 4.8).

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

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

Vandetanib exposure is increased in patients with impaired renal function. Vandetanib starting doseshould 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 below30 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.

Vandetanib is not recommended for use in patients with hepatic impairment (serum bilirubin greaterthan 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 thatno 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. Themajority of elevations resolve while continuing treatment, others usually resolve after a 1-2 weekinterruption in therapy. Periodic monitoring of alanine aminotransferase is recommended.

Interstitial Lung Disease (ILD) has been observed in patients receiving vandetanib and some caseshave 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.

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, thereforeuse in patients with CTN < 500 pg/ml should be carefully considered because of the treatment relatedrisks of vandetanib.

Based on height measurements at all visits, all children and adolescents in a paediatric studydemonstrated linear growth while receiving vandetanib. However, long term safety data in paediatricpatients are not available.

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 willbe provided with the Patient Alert Card with each prescription.

Effect of vandetanib on other medicinal products

In healthy subjects, the exposure for midazolam (CYP3A4 substrate) was not affected when giventogether with a single dose of vandetanib at 800 mg.

Vandetanib is an inhibitor of the organic cation 2 (OCT2) transporter. In healthy subjects with wildtype for OCT2, the AUC(0-t) and Cmax for metformin (OCT2 substrate) were increased by 74% and50%, 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 concomitantmetformin 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 bradycardiaceffect 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 recommendedfor patients receiving concomitant digoxin and vandetanib, and such patients may require a lower doseof digoxin. (For vandetanib monitoring, see sections 4.2 and section 4.4).

As regards other P-gp substrates such as dabigatran, a clinical monitoring is recommended in case ofcombination with vandetanib.

Effect of other medicinal products on vandetanib

In healthy subjects, no clinically significant interaction was shown between vandetanib (a single doseof 300mg) and the potent CYP3A4 inhibitor, itraconazole (repeated doses of 200mg once daily). Inhealthy male subjects, the exposure to vandetanib was reduced by 40% when given together with thepotent CYP3A4 inducer, rifampicin. Administration of vandetanib with potent CYP3A4 inducersshould be avoided.

In healthy subjects, the Cmax for vandetanib was decreased by 15% while the AUC(0-t) for vandetanibwas not affected when given together with omeprazole. Neither the Cmax nor the AUC(0-t) forvandetanib was affected when given together with ranitidine. Therefore, no change in dose ofvandetanib is required when vandetanib is given with either omeprazole or ranitidine.

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) orbreast 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 beenuncommonly reported. Therefore, the concomitant use of vandetanib with medicinal products knownto also prolong the QTc interval and/or induce Torsades de pointes is either contraindicated or notrecommended 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 bemade with additional ECG monitoring of the QTc interval, evaluation of electrolytes and furthercontrol at onset or worsening of diarrhoea.

Results of a pharmacodynamic and pharmacokinetic interaction study indicated that co-administrationwith ondansetron in healthy patients appeared to have little effect on the pharmacokinetics ofvandetanib, but had a small additive effect on the prolongation of the QTc interval of approximately10 ms. Therefore, the concomitant use of ondansetron with vandetanib is not recommended. Ifondansetron is administered with vandetanib, closer monitoring of serum electrolytes and ECGs andaggressive management of any abnormalities is required.

Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation is frequent. Inconsideration of the high intra-individual variability of the response to anticoagulation, and thepossibility of interaction between vitamin K antagonists and chemotherapy, an increased frequency ofthe INR (International Normalised Ratio) monitoring is recommended, if it is decided to treat thepatient with vitamin K antagonists.

Women of childbearing potential must use effective contraception during therapy and for at least fourmonths following the last dose.

There is a limited amount of data on the use of vandetanib during pregnancy. As expected from itspharmacological actions, vandetanib has shown significant effects on all stages of female reproductionin 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. Treatmentshould only be continued in pregnant women if the potential benefit to the mother outweighs the riskto the foetus.

There are no data on the use of vandetanib in breast-feeding women. Vandetanib and/or its metabolitesis excreted into milk in rats and found in plasma of pups following dosing to lactating rats (seesection 5.3).

Breast-feeding is contraindicated while receiving vandetanib therapy.

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.

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

The most commonly reported adverse drug reactions have been diarrhoea, rash, nausea, hypertension,and headache.

The following adverse reactions have been identified in clinical studies with patients receivingvandetanib as treatment for MTC and in post-marketing setting. Their frequency is presented in Table2, 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 frequencyclassification. 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); veryrare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 2: Adverse reactions and system organ class

System Organ Very common Common Uncommon Not known

Class

Infection and Nasopharyngitis Pneumonia, sepsis, Appendicitis,infestation bronchitis, influenza, cystitis, staphylococcaldisorders upper sinusitis, laryngitis, infection,respiratory tract folliculitis, furuncle, diverticulitis,infections, fungal infection, cellulitis,urinary tract pyelonephritis abdominal wallinfections abscess

Endocrine Hypothyroidismdisorders

Metabolism and Appetite Hypokalaemia, Malnutritionnutrition decreased, hypercalcaemia,disorders Hypocalcaemia hyperglycaemia,dehydration,hyponatremia

Psychiatric Insomnia, Anxietydisorders Depression

Nervous system Headache, Tremor, lethargy, Convulsion,disorders paraesthesia, loss of clonus, braindysaesthesia, consciousness, oedemadizziness balance disorders,dysgeusia

Eye disorders Vision blurred, Visual impairment, Cataract,corneal halo vision, accommodationstructural photopsia, glaucoma, disorderschange conjunctivitis, dry(including eye, keratopathycorneal depositsand cornealopacity)

Cardiac Prolongation of Heart failure,disorders ECG QTc acute heart failure,interval(*) (**) rate and rhythmdisorders, cardiacconductiondisorders,ventriculararrhythmia andcardiac arrest

Vascular Hypertension Hypertensive crisis, Aneurysms anddisorders ischaemic arterycerebrovascular dissectionsconditions

Respiratory, Epistaxis, Respiratorythoracic and haemoptysis, failure, pneumoniamediastinal pneumonitis aspirationdisorders

Gastrointestinal Abdominal pain, Colitis, dry mouth, Pancreatitis,disorders diarrhoea, stomatitis, dysphagia, peritonitis, ileus,nausea, constipation, intestinalvomiting, gastritis, perforation, faecaldyspepsia gastrointestinal incontinencehaemorrhage

Hepatobiliary Cholelithiasisdisorders

Skin and Photosensitivity Palmar-plantar Bullous dermatitis Stevens-subcutaneous reaction, rash erythrodysesthesia Johnsontissue disorders and other skin syndrome, alopecia syndrome/Toxireactions c epidermal(including acne, necrolysisdry skin, (***),dermatitis, erythemapruritus), nail multiformedisorders

Musculoskeletal Osteonecrosis,and connective osteonecrosistissue disorders of the jaw

Renal and Proteinuria, Dysuria, haematuria, Chromaturia,urinary nephrolithiasis renal failure, anuriadisorders pollakiuria,micturition urgency

General Asthenia, Pyrexia Impaired healingdisorders and fatigue, pain,administration oedemasite conditions

Investigations ECG QTc Increase of serum Increasedinterval ALT and AST, haemoglobin,prolonged weight decreased serum amylaseblood creatinine increasedincreased

* 13.4% vandetanib patients had QTc (Bazett’s) ≥ 500 ms compared with 1.0% placebo patients. QTcFprolongation was > 20 ms in over 91% of patients, > 60 ms in 35%, > 100 ms in 1.7%. Eight percent of patientshad 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)

*** See section 4.4

Events such as Torsades de pointes, interstitial lung disease (sometimes fatal) and PRES (RPLS) haveoccurred in patients treated with vandetanib monotherapy. It is expected that these would beuncommon 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 treatedpatients; however, routine slit lamp examinations are not required for patients receiving vandetanib.

At various exposure durations, median haemoglobin levels in patients treated with vandetanib wereincreased by 0.5-1.5 g/dl compared to baseline.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Paediatric clinical trial data with vandetanib in MTC (see section 5.1) obtained during drugdevelopment is limited to 16 patients aged 9 years to 17 years with hereditary medullary thyroidcarcinoma (Study IRUSZACT0098). Whilst the study size is small owing to the rarity of MTC inchildren, it is considered representative of the target population. The safety findings in this study areconsistent with the safety profile of vandetanib in adult patients with MTC. Long term safety data inpaediatric patients are not available.

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

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

Pharmacotherapeutic Group: antineoplastic agent, protein kinase inhibitor, ATC Code: L01EX04

Mechanism of action and pharmacodynamic effects

Vandetanib is a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2 alsoknown 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 endothelialreceptor-3 tyrosine kinase.

Vandetanib inhibits VEGF-stimulated endothelial cell migration, proliferation, survival and new bloodvessel formation in in vitro models of angiogenesis. In addition, vandetanib inhibits epidermal growthfactor (EGF)-stimulated EGF receptor tyrosine kinase in tumour cells and endothelial cells.

Vandetanib inhibits EGFR-dependent cell proliferation and cell survival in vitro. Vandetanib alsoinhibits both wild type and the majority of mutated, activated forms of RET, and significantly inhibitsthe proliferation of MTC cell lines in vitro.

In vivo vandetanib administration reduced tumour cell-induced angiogenesis, tumour vesselpermeability, tumour microvessel density, and inhibited tumour growth of a range of human xenografttumour models in athymic mice. Vandetanib also inhibited the growth of MTC xenograft tumours invivo.

The precise mechanism of action of vandetanib in locally advanced or metastatic MTC is unknown.

Clinical data from MTC

A randomised, double-blind, placebo-controlled study (Study 58) was conducted to demonstrate safetyand efficacy of vandetanib 300 mg versus placebo. This study included 331 patients with unresectablelocally 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 study10 patients on vandetanib and 4 on placebo (4% of all patients) had a World Health Organizationperformance status (WHO PS) score of ≥ 2 and 28 (12.1%) patients on vandetanib and 10 (10.1%) onplacebo had cardiac impairment. Cardiac impairment was defined as patients with previouscardiovascular 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 overallobjective response rate (ORR), disease control rate (DCR) defined as, partial response (PR) orcomplete 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 blindedreview of the imaging data. Biochemical response with vandetanib as compared to placebo asmeasured 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 discontinuedfrom blinded study treatment and given the option to receive open-label vandetanib. Twenty-eight ofthe 231 patients (12.1%) on vandetanib and 3 of the 99 (3.0%) on placebo discontinued treatmentbecause of an adverse event. Fourteen of the 28 patients (50%) who stopped vandetanib for an adverseevent discontinued without a dose reduction. Five out of 6 patients (83%) with moderate renal failurewho were treated with vandetanib had a dose reduction to 200 mg for adverse reaction; 1 patientrequired a further reduction to 100 mg.

The result of the primary analysis of PFS showed a statistically significant improvement in PFS forpatients 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 onstatistical modelling of data observed up to the 43rd percentile, the median PFS is predicted to be30.5 months with 95% confidence interval 25.5 to 36.5 months. The median PFS for patientsrandomised to placebo was 19.3 months. At 12 months, the proportion of patients alive andprogression-free was 192 (83%) for patients randomised to vandetanib and 63 (63%) for patientsrandomised to placebo. In the vandetanib arm, a total of 73 (32%) patients progressed: 64 (28%) byresponse evaluation criteria in solid tumours (RECIST) progression and 9 (4%) by death in theabsence of progression. The remaining 158 patients (68%) were censored in the analysis of PFS. In theplacebo 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 theanalysis of PFS.

Figure 1: Kaplan Meier plot of PFSmonths 0 6 12 18 24 30 36n-vandetanib 231 196 169 140 40 1 0n-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 atrisk-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 Not reached(32%) (predicted30.5 months) 0.46 0.31, 0.69 0.0001

Placebo 51/100 19.3 months(51%)

Survival status and the median final overall survival (81.6 months in the vandetanib arm and80.4 months in the placebo arm) were similar across both treatment arms. There was no statisticallysignificant difference in final OS (HR 0.99, 95.002% CI 0.72, 1.38, p=0.9750). Results should beinterpreted 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 3with placebo had unresectable locally advanced disease only. There is limited clinical experience withvandetanib in patients with unresectable locally advanced disease and without metastasis.

Statistically significant advantages were seen for vandetanib for the secondary endpoints of responserate, 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

Vandetanib 300 mg 200/231 87%2.64 1.48, pct. 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 0.990.72, 1.38

Placebo 52/100 80.4 months 0.9750a 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 thecentral read.

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

c HR= Hazard Ratio. A value <1 favours vandetanib. The analysis was performed using a log rank test withtreatment 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 toworsening of pain (derived as a composite endpoint using the worst pain score from BPI and patientreported 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 exploratoryendpoint of diarrhoea (reported as stool frequency).

RET mutation status

RET mutation status reanalysis in Study 58

In Study 58, RET mutation testing was initially performed by using the polymerase chain reaction(PCR) based Amplification Refractory Mutation System (ARMS) assay for the M918T mutation, anddirect 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). For reanalysis of samples lacking

M918T mutation, the RET sequences were enriched using a custom Agilent SureSelect reagent andsequenced on an Illumina sequencer. Data processing and automated calling of RET variants werecarried out using the Broad Genome Analysis ToolKit (GATK) pipeline with manual curation of anydifficult cases using Broad Integrative Genomics Viewer (IGV).

Initially, 79 patients had no M918T mutation identified. Of these 79 patients, 69 had enough tissuesample to allow a post-hoc reanalysis of RET mutation status based on new available assays. Mostpatients were reclassified as RET mutant (52/69) and 17/69 patients had no RET mutation (M918T orother) detected (11 with vandetanib and 6 with a placebo). Patients reclassified as RET mutant (N =52) were pooled with those 187 patients initially identified as RET mutant, leading to a total numberof 239 RET mutant patients (172 treated with vandetanib and 67 treated with a placebo). Results werebased on a blinded central review of imaging.

Table 4: Efficacy end-points in RET mutant patients

Efficacy end-point (Vandetanib vs placebo) Patients with RET mutation(n=239)

Objective response rate 51.7% vs 14.9%

Efficacy endpoint 0.46 (0.29, 0.74)

PFS HR (95% confidence interval)2-year PFS rate 55.7% vs 40.1%

Clinical efficacy in paediatric patients:

A Phase I/II single-center open-label, single-arm study (Study IRUSZACT0098) assessed the activityof 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 (range9-17 years), 50% female, 50% male, 93.8% White, 26.7% Hispanic and 6.3% were Black. Mostpatients (81.3%) had undergone partial or total thyroidectomy prior to study entry. Starting vandetanibdose was 100mg/m2/day for all patients except for one who started at 150mg/m2/day. After havingwell tolerated the first 1 or 2 cycles of therapy (1 cycle = 28 days), the remaining patients continued on100 mg/m2 of treatment. The primary efficacy outcome was ORR according to RECIST v 1.0. Theobjective response rate observed was 43.8%, all of which were partial responses. 31.3% of patientshad 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.

Following oral administration of vandetanib absorption is slow with peak plasma concentrationstypically achieved at a median of 6 hours, range 4-10 hours, after dosing. Vandetanib accumulatesapproximately 8-fold on multiple dosing with steady state achieved from approximately 2 months.

Vandetanib binds to human serum albumin and alpha-1-acid-glycoprotein with in vitro protein bindingbeing approximately 90%. In ex vivo plasma samples from colorectal cancer patients at steady stateexposure after 300 mg once daily, the mean percentage protein binding was 93.7% (range 92.2 to95.7%). The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterised bya volume of distribution of approximately 7450 l.

Following oral dosing of 14C- vandetanib, unchanged vandetanib and metabolites vandetanib N-oxideand N-desmethyl vandetanib were detected in plasma, urine and faeces. A glucuronide conjugate wasseen as a minor metabolite in excreta only. N-desmethyl-vandetanib is primarily produced by

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.

The pharmacokinetics of vandetanib at the 300 mg dose in MTC patients are characterised by aclearance of approximately 13.2 l/h. and plasma half-life of approximately 19 days. Within a 21 daycollection period after a single dose of 14C-vandetanib, approximately 69% was recovered with 44% infaeces and 25% in urine. Excretion of the dose was slow and further excretion beyond 21 days wouldbe expected based on the plasma half-life.

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 comparedto subjects with normal renal function (see sections 4.2, pct. 4.4 and 4.5).

A single dose pharmacokinetic study in volunteers indicated that hepatic impairment did not affectexposure to vandetanib. There is limited data in patients with hepatic impairment (serum bilirubingreater than 1.5 times upper limit of normal (see sections 4.2 and 4.4).

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 weresimilar to those in adults. Vandetanib exposure in children between 5-8 years old with glioma-relatedindications was comparable to MTC patients aged 9-18 years. Dosing at 100mg/m2/day of theindicated posology (function of BSA) in paediatrics delivers similar exposure to that achieved inadults at 300 mg daily.

Vandetanib has shown no mutagenic or clastogenic potential.

In repeat-dose toxicity studies of up to 9 months duration, effects included emesis, body weight lossand 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 plasmaconcentrations, were largely reversible within 4 weeks of cessation of dosing and were attributable toinhibition 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) currentand prolongation of QTc interval in dogs. Elevation of systolic and diastolic blood pressure wasobserved 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 ananimal model of wound-healing, mice dosed with vandetanib had reduced skin-breaking strengthcompared with controls. This suggests that vandetanib slows but does not prevent wound healing. Theappropriate interval between discontinuation of vandetanib and subsequent elective surgery required toavoid the risks of impaired wound healing has not been determined. In clinical studies, a small numberof patients had surgery while receiving vandetanib and there were no reported wound healingcomplications.

Vandetanib had no effect on fertility in male rats. In a female fertility study, there was a trend towardsincreased oestrus cycle irregularity, a slight reduction in pregnancy incidence and increase inimplantation loss. In a repeat-dose toxicity study in rats, there was a decrease in the number ofcorpora lutea in the ovaries of rats given vandetanib for 1 month.

In rats, embryofoetal toxicity was evident as foetal loss, delayed foetal development, heart vesselabnormalities and precocious ossification of some skull bones. In a rat pre- and post-nataldevelopment study, at doses producing maternal toxicity during gestation and/or lactation, vandetanibincreased pre-birth loss and reduced post-natal pup growth. Vandetanib was excreted into milk in ratand found in plasma of pups following dosing to lactating rats.

Vandetanib has shown no carcinogenic potential effect in a 6 month carcinogenicity study in rasH2transgenic mice. A 2-year carcinogenicity study in rats was impaired by low survival in the high dosefemale group and limited exposure of the animals to vandetanib; however, no carcinogenic effectswere observed in the remaining animals.

Calcium hydrogen phosphate dihydrate

Microcrystalline cellulose

Crospovidone (type A)

Povidone (K 29-32)

Magnesium stearate

Hypromellose

Macrogol (300)

Titanium dioxide (E171)

Not applicable.

4 years.

Do not store above 30°C.

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

No special requirements.

Sanofi B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands

EU/1/11/749/001

EU/1/11/749/002

Date of first authorisation: 17 February 2012

Date of latest renewal: 15 November 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu