CAPRELSA: Package Insert and Label Information

CAPRELSA- vandetanib tablet, film coated
Genzyme Corporation

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 NumberPROPRIETARY NAMEESTABLISHED NAMESTRENGTHDOSAGE FORMPACK SIZE
U.K.NDC 58468-7860-3CAPRELSAVandetanib300mgTablets3 Blisters 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 approvedApproved ≥5 years of age
Primary container and carton labeling Bottle inside a cartonBlister inside a carton
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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.

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:

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).

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 Medicines
Head, of U.S. Field Base Medical
General 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 sideSame as the U.S. tablet
Quantity: 30 TabletsSame 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 packagingYes, Patient Information Leaflet is included in all packaging
Risk Strategy Yes, Risk Evaluation and Mitigation Strategy (REMS) that requires certification of all prescribing HCPsYes, 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
SectionsU.S. Prescribing InformationU.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 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).
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 discontinuationSkin 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 USPIRearranged 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 USPIAneurysms 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 USPIAlanine 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 aloneCYP3A4 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 USPICTN 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 USPIPediatric 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.

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