Vandetanib

Vandetanib is a potent inhibitor of several receptor tyrosine kinases involved in tumour growth and blood vessel formation: vascular endothelial growth factor receptor-2 (VEGFR-2, also known as KDR), epidermal growth factor receptor (EGFR) and RET. It is also a sub-micromolar inhibitor of VEGFR-3. The precise mechanism of action in locally advanced or metastatic medullary thyroid cancer (MTC) is unknown.

Mechanism of Action

• VEGFR inhibition: in in vitro models of angiogenesis, vandetanib inhibits VEGF-stimulated endothelial cell migration, proliferation, survival and new blood vessel formation.
• EGFR inhibition: it blocks EGF-stimulated EGF receptor tyrosine kinase in tumour cells and endothelial cells, and inhibits EGFR-dependent cell proliferation and survival in vitro.
• RET inhibition: it inhibits wild-type RET and the majority of mutated, activated forms of RET, and significantly inhibits the proliferation of MTC cell lines in vitro.
• In vivo: in mouse xenograft models it reduced tumour-induced angiogenesis, tumour vessel permeability and tumour microvessel density, and inhibited tumour growth, including that of MTC xenografts.
• Cardiac electrophysiology: vandetanib causes a concentration-dependent prolongation of the QTc interval (see Special Instructions).

Pharmacokinetics

• Absorption: slow; peak plasma concentrations are reached at a median of 6 hours (range 4–10 hours). Vandetanib accumulates about 8-fold on repeated dosing, with steady state reached after approximately 2 months. Food does not affect exposure.
• Distribution: binds to human serum albumin and alpha-1-acid glycoprotein; protein binding is about 90% in vitro (mean 93.7% in plasma samples from patients at steady state). The volume of distribution is about 7,450 L.
• Metabolism: unchanged vandetanib and the metabolites vandetanib N-oxide and N-desmethyl vandetanib are found in plasma, urine and faeces; a glucuronide conjugate is a minor metabolite in excreta only. N-desmethyl-vandetanib is made mainly by CYP3A4 and the N-oxide by flavin-containing monooxygenases (FMO1 and FMO3). They circulate at about 11% and 1.4% of the vandetanib concentration.
• Elimination: clearance is about 13.2 L/h and plasma half-life about 19 days. In 21 days after a single radiolabelled dose, about 69% was recovered: 44% in faeces and 25% in urine. Excretion is slow.
• Special populations: in volunteers, exposure was increased up to 1.5-, 1.6- and 2-fold in mild, moderate and severe renal impairment. Hepatic impairment did not affect exposure after a single dose, but data in patients with serum bilirubin above 1.5 times the upper limit of normal are limited.

• Medullary thyroid cancer: aggressive and symptomatic RET (Rearranged during Transfection) mutant medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease.
• Authorised in adults, children and adolescents aged 5 years and older.
• The presence of a RET mutation should be determined by a validated test before treatment, because activity is considered insufficient in patients with no identified RET mutation.

• Hypersensitivity to the active substance or to any of the excipients.
• Congenital long QTc syndrome.
• QTc interval over 480 msec.
• Concomitant use with medicines known to also prolong the QTc interval and/or induce Torsades de pointes: arsenic, cisapride, erythromycin intravenous (IV), toremifene, mizolastine, moxifloxacin, and Class IA and III antiarrhythmics.
• Breastfeeding.

The most commonly reported reactions are diarrhoea, rash, nausea, hypertension and headache. The frequencies below come from clinical studies in patients with MTC and from post-marketing reports.

Very common (≥1/10): nasopharyngitis, bronchitis, upper respiratory tract infections, urinary tract infections, decreased appetite, hypocalcaemia, insomnia, depression, headache, paraesthesia, dysaesthesia, dizziness, blurred vision, structural corneal change (including corneal deposits and corneal opacity), ECG QTc prolongation, hypertension, abdominal pain, diarrhoea, nausea, vomiting, dyspepsia, photosensitivity reactions, rash and other skin reactions (including acne, dry skin, dermatitis and pruritus), nail disorders, proteinuria, nephrolithiasis, asthenia, fatigue, pain, oedema.

Common (≥1/100 to <1/10): pneumonia, sepsis, influenza, cystitis, sinusitis, laryngitis, folliculitis, furuncle, fungal infection, pyelonephritis, hypothyroidism, hypokalaemia, hypercalcaemia, hyperglycaemia, dehydration, hyponatraemia, anxiety, tremor, lethargy, loss of consciousness, balance disorders, dysgeusia, visual impairment, halo vision, photopsia, glaucoma, conjunctivitis, dry eye, keratopathy, hypertensive crisis, ischaemic cerebrovascular conditions, epistaxis, haemoptysis, pneumonitis, colitis, dry mouth, stomatitis, dysphagia, constipation, gastritis, gastrointestinal haemorrhage, cholelithiasis, palmar-plantar erythrodysaesthesia syndrome, alopecia, dysuria, haematuria, renal failure, pollakiuria, micturition urgency, pyrexia, increased ALT and AST, weight decrease, increased blood creatinine.

Uncommon (≥1/1,000 to <1/100): appendicitis, staphylococcal infection, diverticulitis, cellulitis, abdominal wall abscess, malnutrition, convulsion, clonus, brain oedema, cataract, accommodation disorders, heart failure, acute heart failure, heart rate and rhythm disorders, cardiac conduction disorders, ventricular arrhythmia and cardiac arrest, respiratory failure, aspiration pneumonia, pancreatitis, peritonitis, ileus, intestinal perforation, faecal incontinence, bullous dermatitis, chromaturia, anuria, impaired wound healing, increased haemoglobin, increased serum amylase.

Not known: arterial aneurysms and dissections, Stevens-Johnson syndrome or toxic epidermal necrolysis, erythema multiforme, osteonecrosis (including osteonecrosis of the jaw).

QTc prolongation is the key serious reaction: at 300 mg daily, a QTc above 500 msec was seen in 11% of patients in a phase III study, and Torsades de pointes and ventricular tachycardia have been reported uncommonly. Other serious reactions include heart failure, severe cutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), interstitial lung disease, intracranial haemorrhage, hypertensive crisis, renal failure and osteonecrosis.

• Medicines that prolong the QTc interval: vandetanib prolongs the QTc interval, so combining it with other QTc-prolonging medicines is either contraindicated or not recommended. Contraindicated: cisapride, erythromycin intravenous, toremifene, mizolastine, moxifloxacin, arsenic, and Class IA and III antiarrhythmics. Not recommended: methadone, haloperidol, amisulpride, chlorpromazine, sulpiride, zuclopenthixol, halofantrine, pentamidine and lumefantrine. If there is no suitable alternative, a not-recommended combination may be used with additional ECG monitoring of the QTc interval, evaluation of electrolytes and further checks at the onset or worsening of diarrhoea.
• Ondansetron: with vandetanib it had little effect on vandetanib levels but a small additive effect of about 10 ms on QTc prolongation. The combination is not recommended; if ondansetron is given, serum electrolytes and ECGs need closer monitoring and any abnormality aggressive management.
• Metformin (OCT2 substrate): vandetanib inhibits OCT2. Metformin exposure (AUC) rose by 74% and its peak level by 50%, and its renal clearance fell by 52%. Clinical and/or laboratory monitoring is recommended, and a lower metformin dose may be needed.
• Digoxin (P-gp substrate): digoxin AUC rose by 23% and peak level by 29%. Digoxin’s bradycardic effect may also increase the risk of QTc prolongation and Torsades de pointes. Clinical (for example ECG) and/or laboratory monitoring is recommended, and a lower digoxin dose may be needed.
• Other P-gp substrates: clinical monitoring is recommended with medicines such as dabigatran.
• Strong CYP3A4 inducers: rifampicin reduced vandetanib exposure by 40%. Strong CYP3A4 inducers (such as rifampicin, St John’s wort, carbamazepine and phenobarbital) should be avoided.
• CYP3A4 inhibitors and acid-reducing medicines: the potent CYP3A4 inhibitor itraconazole had no clinically significant effect on vandetanib exposure. Omeprazole lowered the peak level by 15% without changing AUC, and ranitidine had no effect, so no dose change is needed with either.
• Vitamin K antagonists: because of the high variability of the anticoagulant response in cancer patients, more frequent INR monitoring is recommended if a vitamin K antagonist is used.
• Food: vandetanib can be taken with or without food. Grapefruit juice inhibits CYP3A4 and is sometimes advised against, but in the SmPC study the strong CYP3A4 inhibitor itraconazole had no clinically significant effect on vandetanib exposure.

Treatment should be started and supervised by a physician experienced in the treatment of MTC and in the use of anticancer medicinal products, and experienced in the assessment of the electrocardiogram (ECG). The presence of a RET mutation should be determined by a validated test before treatment starts; where possible, tissue samples should be taken at the start of treatment rather than at diagnosis. Vandetanib is taken by mouth.

Recommended Dose in Adults

• 300 mg once a day, with or without food, at about the same time each day. Treatment may continue until disease progression or until the benefits no longer outweigh the risks, considering the severity of adverse events against the degree of clinical stabilisation of the tumour.
• Dose adjustments: assess the QTc interval carefully before starting. For CTCAE grade 3 or higher toxicity or QTc prolongation, stop vandetanib at least temporarily and restart at a reduced dose once the toxicity has resolved or improved to CTCAE grade 1. The 300 mg dose can be reduced to 200 mg (two 100 mg tablets) and then to 100 mg if necessary. Because of the 19-day half-life, adverse reactions including a prolonged QTc interval may not resolve quickly, so the patient must be monitored appropriately.

Children and Adolescents (5 to 18 Years)

Dosing is based on body surface area (BSA). Patients and caregivers must be given the dosing guide and be told the correct dose with the first prescription and after each dose adjustment. The SmPC dosing table (BSA, starting dose, increase after 8 weeks if well tolerated, and reduction) is:

• BSA 0.7 to below 0.9 m²: start 100 mg every other day; increase to 100 mg daily; no lower step is given.
• BSA 0.9 to below 1.2 m²: start 100 mg daily; increase to the 7-day schedule of 100, 200, 100, 200, 100, 200 and 100 mg; reduce to 100 mg every other day.
• BSA 1.2 to below 1.6 m²: start with the 7-day schedule (100-200-100-200-100-200-100 mg); increase to 200 mg daily; reduce to 100 mg daily.
• BSA 1.6 m² or more: start 200 mg daily; increase to 300 mg daily; reduce to the 7-day schedule (100-200-100-200-100-200-100 mg).
• Doses above 150 mg/m² have not been used in paediatric studies. A patient needing a dose reduction should stop vandetanib for at least a week, then restart at the reduced dose when fully recovered.
• For CTCAE grade 3 or higher toxicity or QTc prolongation, stop at least temporarily and restart at the reduced dose when toxicity has resolved or improved to grade 1. A patient on an increased dose restarts at the starting dose. If another such event occurs, stop temporarily and restart at the reduced dose; if a further event occurs, stop permanently.
• Vandetanib should not be given to children below 5 years of age. There is no experience in children with hereditary MTC below 9 years of age.

Special Populations

• Elderly: no adjustment of the starting dose; clinical data are limited in patients aged over 75.
• Renal impairment (adults): no change in starting dose in mild impairment. In moderate impairment (creatinine clearance 30 to below 50 mL/min) the starting dose should be reduced to 200 mg, although safety and efficacy have not been established at 200 mg; the QT interval should be monitored closely. Not recommended in severe impairment (clearance below 30 mL/min). Children: no experience; no change in mild impairment, the reduced dose in the paediatric table for moderate impairment, and not recommended in severe impairment.
• Hepatic impairment: not recommended in adults and children, because data are limited and safety and efficacy have not been established. The SmPC defines this by serum bilirubin above 1.5 times the upper limit of the reference range (not applied in Gilbert’s disease) and by ALT, AST or ALP above 2.5 times that limit, or above 5.0 times if the physician judges it related to liver metastases. Pharmacokinetic data from volunteers suggest no change in starting dose in mild, moderate or severe hepatic impairment.

Missed Dose

Take it as soon as the patient remembers. If it is less than 12 hours to the next dose, do not take the missed dose. Never take a double dose to make up for a forgotten one.

Patients Who Cannot Swallow Tablets

Vandetanib tablets may be dispersed in half a glass of non-carbonated drinking water; no other liquid should be used. Drop the tablet into the water without crushing it, stir until dispersed (about 10 minutes) and swallow the dispersion immediately. Mix any residue in the glass with half a glass of water and swallow that too. The liquid can also be given through a nasogastric or gastrostomy tube.

Patient Selection

Because of the risks, treatment should be limited to patients in real need, that is, with a symptomatic and aggressive course of disease. Symptomatic disease alone, or progressive disease alone, is not enough. Changes in calcitonin (CTN) and carcinoembryonic antigen (CEA) levels, and in tumour volume, during watchful waiting may help to identify the optimal moment to start. The benefit in patients with CTN below 500 pg/mL has not been determined, so use in these patients should be carefully considered.

QTc Prolongation and Torsades de Pointes

• Size of the effect: vandetanib 300 mg is associated with a substantial, concentration-dependent prolongation of the QTc (mean 28 msec, median 35 msec). First prolongations occurred most often in the first 3 months but continued to appear later, and the 19-day half-life makes this particularly problematic. QTc prolongation to above 500 msec was seen in 11% of patients in a phase III study and appears to be dose-dependent. Torsades de pointes and ventricular tachycardia have been uncommonly reported at 300 mg daily; the risk may be higher with electrolyte imbalance.
• When not to start: treatment must not be started in patients whose ECG QTc interval is greater than 480 msec, and vandetanib should not be given to patients with a history of Torsades de pointes. It has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
• Monitoring schedule: an ECG and serum potassium, calcium, magnesium and thyroid stimulating hormone (TSH) should be obtained at baseline, at 1, 3, 6 and 12 weeks after starting, and every 3 months for at least a year thereafter. The same schedule applies after a dose reduction for QTc prolongation and after a dose interruption of more than two weeks. ECGs and blood tests should also be obtained as clinically indicated, and frequent ECG monitoring of the QTc interval should be continued.
• Electrolytes: serum potassium, magnesium and calcium should be kept within the normal range. Additional monitoring of the QTc, electrolytes and renal function is needed especially with diarrhoea, increased diarrhoea or dehydration, electrolyte imbalance and/or impaired renal function.
• If the QTc rises: if the QTc increases markedly but stays below 500 msec, cardiologist advice should be sought. A patient with a single QTc value of 500 msec or more should stop taking vandetanib. Dosing can be resumed at a reduced dose once the QTc has been confirmed to be back to its pretreatment status and any electrolyte imbalance has been corrected.
• Other QTc-prolonging medicines: see Drug Interactions; their use is either contraindicated or not recommended.

Physician Guidelines and 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.

Other Warnings

• Posterior reversible encephalopathy syndrome (PRES): observed infrequently with vandetanib combined with chemotherapy and also with vandetanib alone. Consider it in any patient with seizures, headache, visual disturbances, confusion or altered mental function; brain MRI should be done in anyone with seizures, confusion or altered mental status.
• Severe skin reactions: toxic epidermal necrolysis and Stevens-Johnson syndrome, which can be life-threatening or fatal, have been reported. Patients should be told the signs and symptoms at prescription and monitored closely. If either is suspected, withhold vandetanib and refer the patient to a specialised unit; if confirmed, stop permanently and consider alternative treatment. Photosensitivity reactions occur: wear protective clothing and/or sunscreen in the sun. Mild to moderate skin reactions can be managed symptomatically or by dose reduction or interruption.
• Diarrhoea: routine antidiarrhoeal medicines are recommended; monitor QTc and electrolytes more often. For severe (CTCAE grade 3 or 4) diarrhoea, stop vandetanib until it improves, then resume at a reduced dose.
• Haemorrhage: use caution in patients with brain metastases, because intracranial haemorrhage has been reported.
• Heart failure: has been observed, some cases fatal, and it may not be reversible on stopping. Temporary or permanent discontinuation may be necessary.
• Hypertension: including hypertensive crisis. Monitor blood pressure; if it cannot be controlled with medical management, do not restart until it is controlled. A dose reduction may be necessary.
• Wound healing: impaired wound healing can occur with drugs that inhibit VEGF signalling. Consider interrupting vandetanib for at least 4 weeks before elective surgery; the decision to resume after major surgery should rest on clinical judgement of adequate wound healing.
• Osteonecrosis: cases, including osteonecrosis of the jaw, have been reported, some in patients who had received antiresorptive bone therapy. An oral examination should be done before starting and periodically; patients should be advised on oral hygiene. If possible, hold vandetanib at least 4 weeks before scheduled dental surgery or invasive dental procedures, especially with agents such as bisphosphonates, and consider stopping it if osteonecrosis occurs.
• Aneurysms and artery dissections: VEGF pathway inhibitors may promote these, with or without hypertension. Consider the risk carefully before starting in patients with risk factors such as hypertension or a history of aneurysm.
• Renal failure: has been reported; dose interruptions, adjustments or discontinuation may be necessary. Exposure is increased in renal impairment (see Special Populations). There is no information in end-stage renal disease requiring dialysis.
• Alanine aminotransferase: elevations are common. Most resolve during continued treatment and others after a 1–2 week interruption; periodic monitoring is recommended.
• Interstitial lung disease: some cases have been fatal. If dyspnoea, cough and fever occur, interrupt vandetanib and investigate promptly; stop permanently if interstitial lung disease is confirmed.
• CYP3A4 inducers: avoid strong inducers (such as rifampicin, St John’s wort, carbamazepine and phenobarbital).
• Children: all children and adolescents in a paediatric study showed linear growth while on vandetanib, but long-term safety data in children are not available.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential and fertile men must use effective contraception during treatment and for at least four months after the last dose.
• Pregnancy: data are limited. Vandetanib had significant effects on all stages of female reproduction in rats. A woman who is treated during pregnancy, or who becomes pregnant on treatment, should be told of the potential for foetal abnormalities or loss of the pregnancy. Treatment should continue in a pregnant woman only if the potential benefit to the mother outweighs the risk to the foetus.
• Breastfeeding: contraindicated. There are no data in breastfeeding women, but vandetanib and/or its metabolites pass into the milk of rats.
• Fertility: there are no human data. Animal studies indicate that vandetanib can impair male and female fertility. Effects on reproduction in paediatric patients are not known.

Effect on Driving

No studies of the effect on the ability to drive and use machines have been done. Fatigue and blurred vision have been reported, and patients who have these symptoms should take care when driving or using machines.

Do not store Caprelsa tablets above 30 °C. They are supplied in PVC/PVDC/aluminium blisters sealed with aluminium foil, each pack holding 30 film-coated tablets.

4 years.

Prescription only (Rx). Treatment is initiated and supervised by a physician experienced in the treatment of MTC and in the use of anticancer medicinal products, and experienced in ECG assessment. Vandetanib tablets are taken at home, so they are supplied to the patient or the treating clinic on prescription. The patient is given the Patient Alert Card with each prescription, and paediatric patients and their caregivers are given the dosing guide.