CAPRELSA Dailymed

Health Care Provider Letter Section

IMPORTANT PRESCRIBING INFORMATION

Subject: Temporary importation of CAPRELSA® (vandetanib) Tablets to address drug shortage

Dear Healthcare Provider,

As customers were informed on June 17, 2022, Sanofi is currently experiencing global supply disruptions for CAPRELSA® (vandetanib) tablets, 100 mg and 300 mg. We anticipate that supply disruptions will be resolved by September 2022 for the 100mg and October 2022 for the 300 mg. To that end, Sanofi has implemented a mitigation plan to address supply chain issues and as part of that plan, Sanofi is coordinating with the U.S. Food and Drug Administration (FDA) to allow the temporary importation of CAPRELSA 300 mg tablets from the United Kingdom (U.K.) into the U.S. market. The imported tablets are identical in composition and dosing regimen to that of the FDA-approved CAPRELSA 300 mg tablets and will still be available to you through the CAPRELSA REMS Program. Due to current market supply, Sanofi is only able to import the 300 mg.

	NDC Number	PROPRIETARY NAME	ESTABLISHED NAME	STRENGTH	DOSAGE FORM	PACK SIZE
U.K.	NDC 58468-7860-3	CAPRELSA	Vandetanib	300mg	Tablets	3 Bulers of 10 (30 total)

What actions are required of the HCP?

• Advise patients to continue to take CAPRELSA as prescribed
• Educate patients that CAPRELSA from the U.K. product is identical to the U.S. product even though it comes in different packaging
• Refer patients to the Medication Guide. This can be downloaded from: https://www.caprelsa.com/files/caprelsa-medication-guide.pdf
• Ensure you are certified to prescribe CAPRELSA and follow the REMS guidelines

What should you expect?

It is important to note the following differences between the two products:

	CAPRELSA 300 mg Tablets
	U.S.	U.K.
Dosing (Pediatrics)	Not approved	Approved ≥5 years of age
Primary container and carton labeling	Bottle inside a carton	Buler inside a carton

Please note that the U.K. barcode may not register accurately on the U.S. scanning systems. Institutions should manually input the product into their systems to confirm that barcode systems do not provide incorrect information when the product is scanned. Alternative procedures should be followed to assure that the correct drug product is being used and administered to individual patients.

WARNING: QT PROLONGATION, TORSADES DE POINTES, AND SUDDEN DEATH

See full prescribing information for complete boxed warning.

CAPRELSA can prolong the QT interval. Torsades de pointes and sudden death have occurred in patients receiving CAPRELSA. Do not use CAPRELSA in patients with hypocalcemia, hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypocalcemia, hypokalemia and/or hypomagnesemia prior to CAPRELSA administration. Monitor electrolytes periodically. Avoid drugs known to prolong the QT interval. Only prescribers and pharmacies certified with the restricted distribution program are able to prescribe and dispense CAPRELSA (5.1, 5.15).

As a reminder, the following information is taken from the United States Prescribing Information and should continue to be your source of information for CAPRELSA tablets:

Highlights from Section 5: WARNINGS AND PRECAUTIONS

• Prolonged QT interval, torsades de pointes, and sudden death: Monitor electrocardiograms and levels of serum potassium, calcium, magnesium and TSH. Reduce CAPRELSA dose as appropriate.
• Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, some fatal. Discontinue CAPRELSA for severe skin reactions.
• Interstitial lung disease (ILD), including fatalities: investigate unexplained nonspecific respiratory signs and symptoms. Discontinue CAPRELSA for confirmed ILD.
• Ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypertension, and reversible posterior leukoencephalopathy syndrome: Discontinue or interrupt CAPRELSA.
• Risk of impaired wound healing: Withhold for at least 1 month prior to elective surgery. Do not administer CAPRELSA for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment with CAPRELSA after resolution of wound healing complications has not been established.
• Embryo-fetal toxicity: Can cause fetal harm. Advise women of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with CAPRELSA and for 4 months following the last dose.
• REMS: CAPRELSA is available only through a restricted distribution program called the CAPRELSA REMS Program.

Enclosed please find the full U.S. prescribing information for CAPRELSA tablets as well as a more comprehensive table comparing the U.S. and U.K. labels.

Reporting Adverse Events

Healthcare providers and patients are encouraged to report adverse events or quality problems experienced with the use of this product by calling Sanofi Genzyme Customer Service by phone at: 1-800-633-1610.

Adverse events, medication errors, or quality problems experienced with the use of this product may also be reported to FDA’s MedWatch Adverse Reporting Program either online, by regular mail or by fax:

• Complete and submit the report Online: www.fda.gov/medwatch/report.htm
• Regular Mail or Fax: Download form www.fda.gov/MedWatch/getforms.htm or call 1-800-332­1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178 (1-800-332-0178).

Yours sincerely,

George Dickens, Pharm.D.Acting Medical Head U.S. General MedicinesHead, of U.S. Field Base MedicalGeneral Medicine U.S. Business Unit, MedicalGenzyme Corporation, A Sanofi Company

©2022 Genzyme Corporation. All rights reserved.

Highlights of differences and similarities between U.S. and U.K. CAPRELSA tablets

	CAPRELSA 300 mg Tablets
	U.S.	U.K.
Dosing (Adults)	300 mg once daily (starting dose is 200 mg once daily in renal impairment)	Same as the U.S. approved dose
Tablet Description	White, Oval, biconvex, film-coated, and intagliated with 'Z 300' on one side and plain on the reverse side	Same as the U.S. tablet
	Quantity: 30 Tablets	Same as U.S. quantity
Storage Requirements	Store at 25°C (77°F); excursions permitted to (15°C-30°C)	Do not store above 30°C
Information for Patients	Yes, Medication Guide included in all packaging	Yes, Patient Information Leaflet is included in all packaging
Risk Strategy	Yes, Risk Evaluation and Mitigation Strategy (REMS) that requires certification of all prescribing HCPs	Yes, risk minimization materials that include dosing and monitoring guide for HCPs

CAPRELSA (vandetanib) Tablets U.K. and U.S. Prescribing Information Side-by-Side Comparison Table

Sections	U.S. Prescribing Information	U.K. SmPC
INDICATIONS	CAPRELSA is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.Use CAPRELSA in patients with indolent, asymptomatic or slowly progressing disease only after careful consideration of the treatment related risks of CAPRELSA.	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).
DOSAGE	The recommended dose of CAPRELSA is 300 mg taken orally once daily until disease progression or unacceptable toxicity occurs.CAPRELSA may be taken with or without food.Do not take a missed dose within 12 hours of the next dose.Do not crush CAPRELSA tablets. The tablets can be dispersed in 2 ounces of water by stirring for approximately 10 minutes (will not completely dissolve). Do not use other liquids for dispersion. Swallow immediately after dispersion. Mix any remaining residue with 4 additional ounces of water and swallow.The dispersion can also be administered through nasogastric or gastrostomy tubes.	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). Patients treated with Caprelsa must be given the patient alert card and be informed about the risks of Caprelsa (see also package leaflet).Posology in paediatric patients with MTCDosing 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. (make a ref to the U.K. SPC)Special patient populationsPaediatric populationCaprelsa 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.ElderlyNo adjustment in starting dose is required for elderly patients. There is limited clinical data with vandetanib in patients with MTC aged over 75.Renal impairement in adult patients with MTC: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.
CONTRAINDICATIONS	Do not use in patients with congenital long QT syndrome [see Boxed Warning].	Hypersensitivity to the active substance or to any of the excipients uled 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).
WARNINGS & PRECAUTIONS	QT Prolongation and Torsades de Pointes CAPRELSA can prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)]. Torsades de pointes, ventricular tachycardia and sudden deaths have occurred in patients treated with CAPRELSA.Do not start CAPRELSA treatment in patients whose QTcF interval is greater than 450 ms. Do not administer CAPRELSA to patients who have a history of Torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction. Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate to severe renal impairment and monitor QT interval frequently.Obtain an ECG and serum potassium, calcium, magnesium and TSH at baseline, 2 to 4 weeks and 8 to 12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. Monitor electrolytes and ECGs more frequently in patients who experience diarrhea. Following any dose reduction for QT prolongation or any dose interruption greater than 2 weeks, conduct QT assessments as described above. Maintain serum potassium levels of 4 mEq/L or higher (within normal range) and maintain serum magnesium and calcium levels within normal ranges to reduce the risk of QT prolongation.Avoid using CAPRELSA with drugs known to prolong the QT interval [see Warnings and Precautions (5.11) and Drug Interactions (7.4)]. If such drugs are given to patients already receiving CAPRELSA and no alternative therapy exists, perform ECG monitoring of the QT interval more frequently.Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until the QTcF returns to less than 450 ms. Dosing of CAPRELSA can then be resumed at a reduced dose [see Dosage and Administration (2.1)].	In view of the associated risks, it is important to limit treatment with vandetanib to patients who are in real need for treatment, i.e. with a symptomatic aggressive course of the disease. Either symptomatic disease or progressive disease alone is not enough to prompt the need of treatment with vandetanib. Rate of change in biomarker levels such as of calcitonin (CTN) and/or carcinoembryonic antigen (CEA) as well as the rate of change of tumour volume during watchful waiting might help to identify not only patients in need for treatment but also the optimal moment to commence treatment with vandetanib.QTc prolongation and Torsades de Pointes Vandetanib at a dose of 300 mg is associated with a substantial and concentration dependent prolongation in QTc (mean 28 msec, median 35 msec). First QTc prolongations occurred most often in the first 3 months of treatment, but continued to first occur after this time. The half life of vandetanib (19 days) renders this prolongation in QTc interval particularly problematic (see section 4.8). At a dose of 300 mg per day in MTC, ECG QTc prolongation to above 500 msec was observed in a phase III study in 11% of patients. ECG QTc prolongation appears to be dose-dependent. Torsades de pointes and ventricular tachycardia have been uncommonly reported in patients administered vandetanib 300 mg daily. The risk of Torsades may be increased in patients with electrolyte imbalance (see section 4.8).Vandetanib treatment must not be started in patients whose ECG QTc interval is greater than 480 msec. Vandetanib should not be given to patients who have a history of Torsades de pointes. Vandetanib has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.An ECG, and levels of serum potassium, calcium and magnesium and thyroid stimulating hormone (TSH) should be obtained at baseline, at 1, 3, 6 and 12 weeks after starting treatment and every 3 months for at least a year thereafter. This schedule should apply to the period after dose reduction due to QTc prolongation and after dose interruption for more than two weeks. ECGs and blood tests should also be obtained as clinically indicated during this period and afterwards. Frequent ECG monitoring of the QTc interval should be continued.Serum potassium, serum magnesium and serum calcium should be kept within normal range to reduce the risk of ECG QTc prolongation. Additional monitoring of QTc, electrolytes and renal function are required especially in case of diarrhoea, increase in diarrhoea/dehydration, electrolyte imbalance and/or impaired renal function. If QTc increases markedly but stays below 500 msec, cardiologist advice should be sought.The administration of vandetanib with substances known to prolong the ECG QTc interval is contraindicated or not recommended (see section 4.3 and 4.5).The concomitant use of vandetanib with ondansetron is not recommended (see section 4.5)Patients who develop a single value of a QTc interval of ≥500 msec should stop taking vandetanib. Dosing can be resumed at a reduced dose after return of the QTc interval to pretreatment status has been confirmed and correction of possible electrolyte imbalance has been made.
	Severe Skin ReactionsSevere and sometimes fatal skin reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome, have occurred in patients treated with CAPRELSA. Permanently discontinue CAPRELSA for severe skin reactions and refer the patient for urgent medical evaluation. Systemic therapies such as corticosteroids may be required.Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation	Skin reactionsRash 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.
	Interstitial Lung DiseaseInterstitial Lung Disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA. Consider a diagnosis of ILD in patients presenting with non-specific respiratory signs and symptoms.Interrupt CAPRELSA for acute or worsening pulmonary symptoms. Discontinue CAPRELSA if ILD is confirmed.	Interstitial lung diseaseInterstitial 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.
	Ischemic Cerebrovascular EventsIschemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. In the randomized medullary thyroid cancer (MTC) study, ischemic cerebrovascular events occurred more frequently with CAPRELSA compared to placebo (1.3% compared to 0%). The safety of resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied. Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event.	Section not mentioned in U.K. SmPC
	HemorrhageSerious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer CAPRELSA to patients with a recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue CAPRELSA in patients with severe hemorrhage.	HaemorrhageCaution should be used when administering vandetanib to patients with brain metastases, as intracranial haemorrhage has been reported.
	Heart FailureHeart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible upon stopping CAPRELSA.	Heart failureHeart 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.
	DiarrheaDiarrhea of Grade 3 or greater severity occurred in 11% of patients receiving CAPRELSA in the randomized MTC study. If diarrhea occurs, carefully monitor serum electrolytes and ECGs to reduce the risk and enable early detection of QT prolongation resulting from dehydration [see Warnings and Precautions (5.1)]. Interrupt CAPRELSA for severe diarrhea. Upon improvement, resume CAPRELSA at a reduced dose [see Dosage and Administration (2.1)].	DiarrhoeaDiarrhoea is a disease related symptom as well as a known undesirable effect of vandetanib. Roe 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).
	HypothyroidismIn the randomized MTC study in which 90% of the patients enrolled had prior thyroidectomy, increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA-treated patients compared to 17% of placebo-treated patients. Obtain Thyroid-stimulating hormone (TSH) at baseline, at 2 to 4 weeks and 8 to 12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy accordingly.	Section not mentioned in U.K. SmPC
	HypertensionHypertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled, do not resume CAPRELSA [see Dosage and Administration (2.1)].	HypertensionHypertension, 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).
	Reversible Posterior Leukoencephalopathy SyndromeReversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by an MRI of the brain, has occurred in patients treated with CAPRELSA. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had hypertension. Discontinue CAPRELSA treatment in patients with RPLS.	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.
	Drug InteractionsAvoid administration of CAPRELSA with anti-arrhythmic drugs (including but not limited to amiodarone, disopyramide, procainamide, sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited to chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide) [see Drug Interactions (7.4) and Clinical Pharmacology (12.2)].	Medicinal products known to prolong QTc intervalVandetanib 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.
	Renal FailureRenal failure occurred in patients treated with CAPRELSA [see Adverse Reactions (6.1)]. Withhold, reduce the dose or permanently discontinue based on severity [see Dosage and Administration (2.1)].Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in patients with moderate renal impairment and monitor the QT interval closely [see Dosage and Administration (2.1)]. Vandetanib is not recommended for use in patients with severe renal impairment (clearance below 30 mL/min). There is no information available for patients with end-stage renal disease requiring dialysis [see Boxed Warning, Dosage and Administration (2.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].	Patients with renal impairmentVandetanib 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).
	Hepatic ImpairmentCAPRELSA is not recommended for use in patients with moderate and severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration (2.1)].	Patients with hepatic impairmentVandetanib 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).
	Impaired Wound HealingImpaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Impaired wound healing has occurred in patients treated with CAPRELSA.Withhold CAPRELSA for at least 1 month prior to elective surgery. Do not administer CAPRELSA for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment with CAPRELSA after resolution of wound healing complications has not been established.	Section not mentioned in U.K. SmPC
	Embryo-Fetal ToxicityBased on its mechanism of action, CAPRELSA can cause fetal harm when administered to a pregnant woman. In rats, vandetanib was embryotoxic, fetotoxic, and induced fetal malformations at exposures equivalent to or lower than those expected at the 300 mg clinical dose and had adverse effects on female fertility, embryofetal development, and postnatal development of pups.There are no data on the presence of vandetanib or its metabolites in human milk or the effects of vandetanib on the breastfed child or on milk production. Vandetanib was present in the milk of lactating rats. Because of the potential for serious adverse reactions from CAPRELSA in breastfed children, advise women not to breastfeed during treatment with CAPRELSA and for 4 months after the final dose.Verify the pregnancy status of females of reproductive potential prior to initiating treatment with CAPRELSAAdvise women of the potential hazard to a fetus. Advise women of reproductive potential to use effective contraception during treatment with CAPRELSA and for at least 4 months following the last dose [see Use in Specific Populations (8.1), (8.3)].	4.6 Fertility, pregnancy and lactationWomen of childbearing potentialWomen of childbearing potential must use effective contraception during therapy and for at least four months following the last dose.PregnancyThere 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 feedingThere 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.FertilityIn 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.
	CAPRELSA REMS (Risk Evaluation and Mitigation Strategy) ProgramBecause of the risk of QT prolongation, Torsades de pointes, and sudden death, CAPRELSA is available only through a restricted distribution program called the CAPRELSA REMS Program. Only prescribers and pharmacies certified with the program are able to prescribe and dispense CAPRELSA.	Section not mentioned in U.K. SmPC (U.S. specific only). Risk Management Plan is approved in EU annexes
	Section not mentioned in USPI	Rearranged during transfection (RET) statusPatients 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).
	Section not mentioned in USPI	Aneurysms and artery dissectionsThe 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.
	Section not mentioned in USPI	Alanine aminotransferase elevationsAlanine 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.
	Strong CYP3A4 inducers: In a cross-over study in 12 healthy volunteers, a single oral 300 mg dose of CAPRELSA was administered alone on day 1 and on day 10 in combination with daily doses of 600 mg of rifampicin (a strong CYP3A4 inducer) given on days 1 to 31. The coadministration of rifampicin with CAPRELSA decreased the geometric mean AUC0–504h of vandetanib by 40% (90% confidence interval (CI): 56%, 63%) compared to vandetanib alone. No clinically meaningful change in the mean Cmax of vandetanib was observed. The geometric mean AUC0–504h and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively, in the presence of rifampicin compared with vandetanib alone	CYP3A4 inducersThe concomitant use of vandetanib with strong CYP3A4 inducers (such as rifampicin, St John's Wort, carbamazepine, phenobarbital) should be avoided (see section 4.5).
	Section not mentioned in USPI	CTN less than 500 pg/mlThe 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.
	Section not mentioned in USPI	Pediatric populationBased 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.

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 300 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 300 mg of vandetanib.

For a full ul of excipients, see section 6.1.

3. Pharmaceutical Form

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.

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)The starting dose is the dose at which treatment should be initiated	Dose increase (mg)Higher vandetanib doses than 150 mg/m2 have not been used in clinical studies in paediatric patients when tolerated well after 8 weeks at starting dose	Dose reduction (mg) 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
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

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 (* in Table 1), should be recommenced at the reduced dose (^‡ in Table 1).
• Patients who are on the increased dose (^† in Table 1), should be recommenced at the starting dose (* 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 (^‡ 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

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 uled 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 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 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

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 C_max for metformin (OCT2 substrate) were increased by 74% and 50%, respectively and CL_R 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 C_max 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 C_max for vandetanib was decreased by 15% while the AUC_(0-t) for vandetanib was not affected when given together with omeprazole. Neither the C_max 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

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

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 ul 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), uled 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(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))		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 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

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

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 uled below:

United Kingdom Yellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play orApple 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).