Vandetanib

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.

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

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 σ in patients with mild, moderate (creatinine clearance ≥30 to <50 ml/min) and severe (clearance below 30 ml/min) renal impairment at baseline. Clinical data suggest that no change in starting dose is required in patients with mild renal impairment. There is limited data with 300 mg in patients with moderate renal impairment: the dose needed to be lowered to 200 mg in 5 out of 6 patients due to an adverse reaction of QT prolongation. The starting dose should be reduced to 200 mg in patients with moderate renal impairment; safety and efficacy have however not been established with 200 mg. Vandetanib is not recommended for use in patients with severe renal impairment since there is limited data in patients with severe renal impairment, and safety and efficacy have not been established.

Renal impairment in paediatric patients with MTC

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

• No change in starting dose is recommended in paediatric patients with mild renal impairment
• The reduced dose as specified in Table 1 should be used in paediatric patients with moderate renal impairment. Individual patient management will be required by the physician, especially in paediatric patients with low BSA.
• Vandetanib is not recommended in paediatric patients with severe renal impairment.

Table 1. Dosing nomogram for paediatric patients with MTC:

^a The starting dose is the dose at which treatment should be initiated.
^b Higher vandetanib doses than 150 mg/m² have not been used in clinical studies in paediatric patients.
^c Patients with an adverse reaction requiring a dose reduction should stop taking vandetanib for at least a week. Dosing can be resumed at a reduced dose thereafter when fully recovered from adverse reactions.

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.

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

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.

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.

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 CLR of metformin was decreased by 52% when given together with vandetanib. Appropriate clinical and/or laboratory monitoring is recommended for patients receiving concomitant metformin and vandetanib, and such patients may require a lower dose of metformin.

Wound healing complications

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

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.

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

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.

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.

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.

Breast-feeding is contraindicated while receiving vandetanib therapy.

Women of childbearing potential

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

Fertility

In rats, vandetanib had no effect on male fertility but impaired female fertility.

Effects on reproduction in paediatric patients treated with vandetanib are not known.

No studies to establish the effects of vandetanib on ability to drive and use machines have 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.

Summary of the safety profile

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

Tabulated list of adverse reactions

The following adverse reactions have been identified in clinical studies with patients receiving vandetanib as treatment for MTC and in post-marketing setting. Their frequency is presented in the table below, adverse reactions using Council for International Organizations of Medical Sciences (CIOMS III), listed by MedDRA System Organ Class (SOC) and at the preferred term level and then by frequency classification. Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Adverse reactions and system organ class:

^* 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)

Description of selected adverse reactions

Events such as Torsades de pointes, interstitial lung disease (sometimes fatal) and PRES (RPLS) have occurred in patients treated with vandetanib monotherapy. It is expected that these would be uncommon adverse reactions in patients receiving vandetanib for MTC.

Ocular events such as blurred vision are common in patients who received vandetanib for MTC. Scheduled slit lamp examinations have revealed corneal opacities (vortex keratopathies) in treated patients; however, routine slit lamp examinations are not required for patients receiving vandetanib.

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

Paediatric population

Paediatric clinical trial data with vandetanib in MTC 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.