4.1. Therapeutic indications

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 or metastatic disease.

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

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).

Rearranged during transfection (RET) status

Since the activity of Caprelsa, based on available data, is considered insufficient in patients with no identified RET mutation, the presence of a RET mutation should be determined by a validated test prior to initiation of treatment with Caprelsa. When establishing RET mutation status, tissue samples should be obtained if possible at the time of initiation of treatment rather than at the time of diagnosis.

Posology for MTC in adult patients

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

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

Dose adjustments in adult patients with MTC

QTc interval should be carefully assessed prior to initiation of treatment. In the event of common terminology criteria for adverse events (CTCAE) grade 3 or higher toxicity or prolongation of the ECG QTc interval, dosing with vandetanib should be at least temporarily stopped and resumed at a reduced dose when toxicity has resolved or improved to CTCAE grade 1 (see section 4.4). The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets), and then to 100 mg if necessary. The patient must be monitored appropriately. Due to the 19‑day half‑life, adverse reactions including a prolonged QTc interval may not resolve quickly (see section 4.4).

Posology in paediatric patients with MTC

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

Table 1: Dosing nomogram for paediatric patients with MTC

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

• In the event of CTCAE grade 3 or higher toxicity or prolongation of the ECG QTc interval, dosing with vandetanib should be at least temporarily stopped and resumed at a reduced dose when toxicity has resolved or improved to CTCAE grade 1.

• Patients who are on the starting dose (a in Table 1), should be recommenced at the reduced dose (c in Table 1).

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

• If a further event of CTCAE grade 3 or higher toxicity or prolongation of the ECG QTc interval occurs, dosing with vandetanib should be permanently stopped.

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

Duration

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

Special patient populations

Paediatric population

Caprelsa should not be given to children below 5 years of age. The safety and efficacy of Caprelsa in children below 5 years of age have not been established. No data are available.

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

Elderly

No adjustment in starting dose is required for elderly patients. There is limited clinical data with vandetanib in patients with MTC aged over 75.

Renal impairment in adult patients with MTC

A pharmacokinetic study in volunteers with mild, moderate and severe renal impairment shows that exposure to vandetanib after single dose is increased up to 1.5, 1.6 and 2‑fold respectively in patients with mild, moderate (creatinine clearance ≥ 30 to < 50 ml/min) and severe (clearance below 30 ml/min) renal impairment at baseline (see section 5.2). Clinical data suggest that no change in starting dose is required in patients with mild renal impairment. There is limited data with 300 mg in patients with moderate renal impairment: the dose needed to be lowered to 200 mg in 5 out of 6 patients due to an adverse reaction of QT prolongation. The starting dose should be reduced to 200 mg in patients with moderate renal impairment; safety and efficacy have however not been established with 200 mg (see section 4.4). Vandetanib is not recommended for use in patients with severe renal impairment since there is limited data in patients with severe renal impairment, and safety and efficacy have not been established.

Renal impairment in paediatric patients with MTC

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

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

• The reduced dose as specified in Table 1 should be used in paediatric patients with moderate renal impairment. Individual patient management will be required by the physician, especially in paediatric patients with low BSA.

• Vandetanib is not recommended in paediatric patients with severe renal impairment

Hepatic impairment

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

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

Method of administration

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

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.

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 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 taking vandetanib. Dosing can be resumed at a reduced dose after return of the QTc interval to pretreatment status has been confirmed and correction of possible electrolyte imbalance has been made.

Posterior reversible encephalopathy syndrome, PRES (Reversible posterior leukoencephalopathy syndrome‑RPLS)

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

Severe Cutaneous Adverse Reactions (SCARs) and other skin reactions

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

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

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

Diarrhoea

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

Haemorrhage

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

Heart failure

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

Hypertension

Hypertension, including hypertensive crisis, has been observed in patients treated with vandetanib. Patients should be monitored for hypertension and controlled as appropriate. If high blood pressure cannot be controlled with medical management, vandetanib should not be restarted until the blood pressure is controlled medically. Reduction in dose may be necessary (see section 4.8).

Wound healing complications

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

Osteonecrosis

Cases of osteonecrosis, including cases of osteonecrosis of the jaw, have been reported in patients treated with vandetanib. Some cases were reported in patients who had received prior or concomitant treatment with antiresorptive bone therapy. An oral examination should be performed prior to initiation of vandetanib and periodically during vandetanib therapy. Patients should be advised regarding oral hygiene practice. If possible, vandetanib treatment should be withheld at least 4 weeks prior to scheduled dental surgery or invasive dental procedures, especially in patients receiving agents associated with osteonecrosis, such as bisphosphonates. Vandetanib discontinuation should be considered in patients who experience osteonecrosis (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.

Renal failure

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

Vandetanib exposure is increased in patients with impaired renal function. Vandetanib starting dose should be reduced to 200 mg in patients with moderate renal impairment (creatinine clearance ≥30 to <50 mL/min) and the QT interval should be closely monitored.

Vandetanib is not recommended for use in patients with severe renal impairment (clearance below 30 mL/min) (see sections 4.2, 5.1, and 5.2). There is no information available for patients with end-stage renal disease requiring dialysis.

Patients with hepatic impairment

Vandetanib is not recommended for use in patients with hepatic impairment (serum bilirubin greater than 1.5 times upper limit of normal), since there is limited data in patients with hepatic impairment, and safety and efficacy have not been established. Pharmacokinetic data from volunteers, suggests that no change in starting dose is required in patients with mild, moderate or severe hepatic impairment (see sections 4.2 and 5.2).

Alanine aminotransferase elevations

Alanine aminotransferase elevations occur commonly in patients treated with vandetanib. The majority of elevations resolve while continuing treatment, others usually resolve after a 1‑2 week interruption in therapy. Periodic monitoring of alanine aminotransferase is recommended.

Interstitial lung disease

Interstitial Lung Disease (ILD) has been observed in patients receiving vandetanib and some cases have been fatal. If a patient presents with respiratory symptoms such as dyspnoea, cough and fever, vandetanib treatment should be interrupted and prompt investigation initiated. If ILD is confirmed, vandetanib should be permanently discontinued and the patient treated appropriately.

CYP3A4 inducers

The concomitant use of vandetanib with strong CYP3A4 inducers (such as rifampicin, St John's Wort, carbamazepine, phenobarbital) should be avoided (see section 4.5).

CTN less than 500 pg/ml

The benefit of vandetanib in patients with CTN less than 500 pg/ml has not been determined, therefore use in patients with CTN < 500 pg/ml should be carefully considered because of the treatment related risks of vandetanib.

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.

Patient alert card

All prescribers of Caprelsa must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of Caprelsa therapy with the patient. The patient will be provided with the Patient Alert Card with each prescription.

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 sections 4.2 and section 4.4).

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 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 / Contraception in males & females

Women of childbearing potential and fertile men 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

There are no data on the effect of vandetanib on human fertility. Results from animal studies indicate that vandetanib can impair male and 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

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 profile

The 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 and in post-marketing setting. 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).

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, hyperglycaemia, 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 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 reactions (including acne, dry skin, dermatitis, pruritus), nail disorders

Palmar‑plantar erythrodysesthesia syndrome, alopecia

Bullous dermatitis

Stevens-Johnson syndrome/Toxic epidermal necrolysis (***), erythema multiforme

Musculoskeletal and connective tissue disorders

Osteonecrosis, osteonecrosis of the jaw

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)

*** See section 4.4

Description of selected adverse reactions

Events such as Torsades de pointes, 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

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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).