Pazopanib

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Votrient (GlaxoSmithKline)
200 mg and 400 mg tablets
Approved indication: metastatic renal cell carcinoma
Australian Medicines Handbook section 14.2.2

Renal cell tumours tend to be very vascular and are insensitive to chemotherapy (Aust Prescr 2006;29:151-3). Pazopanib, previously GW786034, works by inhibiting the formation of new blood vessels and preventing tumour growth. It inhibits tyrosine kinase by binding to several targets including vascular endothelial growth factor receptor (VEGFR)-1, -2, -3, platelet derived factor receptor-α and -β, and the cytokine receptor c-kit.

There are a number of other angiogenesis inhibitors with a similar action to pazopanib. These include sorafenib, sunitinib and bevacizumab (Aust Prescr 2006;29:9-12 and 2006;29:13-5).

The approval of pazopanib is based on a phase III placebo-controlled trial of 435 patients with locally advanced or metastatic renal cell carcinoma. (About half of these people had previously received cytokine-based treatment such as interferon-alfa or interleukin-2.) Patients took pazopanib until their disease progressed or they died, or they could not tolerate treatment. The median duration of treatment was 7.4 months with pazopanib and 3.8 months with placebo. Oral pazopanib 800 mg (once daily) significantly prolonged progression-free survival compared to placebo (median duration of 9.2 months vs 4.2 months). In terms of tumour response, one patient out of 290 had a complete response to pazopanib and almost a third (87) had a partial response. In the placebo group, there were no complete responses and only 3% of patients (5/145) had a partial response.¹ Overall survival was not statistically different between groups at the time of the analysis.

In the pazopanib group, diarrhoea (52%), hypertension (40%), change in hair colour (38%), nausea (26%), anorexia (22%) and vomiting (21%) were the most common adverse events. More patients dropped out because of adverse events in the pazopanib group than in the placebo group (14% vs 3%). Arterial thrombotic events (myocardial infarction or ischaemia, cerebrovascular accident) occurred in 3% of patients and 13% had a haemorrhagic event. Just over half of the patients had elevated liver enzymes (serum transaminases, bilirubin) and some of these people had to discontinue treatment. Serious adverse events (grade 3 or 4) to pazopanib were experienced by 40% of patients.¹Nine of these patients died - reasons included bleeding (4 patients), cardiac event (3), hepatic failure (1) and gastrointestinal perforation (1).

After oral administration, peak concentrations of pazopanib are reached after 2-4 hours. Food increases exposure to this drug so it should be taken on an empty stomach (at least one hour before or two hours after a meal). Tablets should not be crushed as this may affect their rate of absorption. Pazopanib is mainly metabolised by cytochrome P450 3A4, and to a lesser extent by CYP1A2 and CYP2C8. It has a mean half-life of 31 hours and is mainly eliminated in the faeces.

Dose reduction of pazopanib should be considered if strong inhibitors of CYP3A4, such as ketoconazole, ritonavir or clarithromycin, are given concomitantly. Grapefruit juice should be avoided. Inducers of CYP3A4 (rifampicin) may decrease plasma concentrations of pazopanib, and if they cannot be avoided, pazopanib should not be given. Pazopanib use is not recommended with drugs that have a narrow therapeutic window and are metabolised by CYP3A4, CYP1A2 and CYP2C8.

Because of the risk of hepatotoxicity, liver function should be assessed before starting pazopanib and regularly during treatment. Pazopanib may need to be reduced, interrupted or discontinued depending on the results of liver function tests, and specific recommendations are given in the product information. People with moderate hepatic impairment should be given a reduced daily dose and pazopanib is not recommended in patients with severe hepatic impairment.

QT prolongation and torsades de pointes have been reported so pazopanib should be used with caution in patients who have a history of QT prolongation or relevant cardiac disease, or who are taking drugs that prolong the QT interval (see Aust Prescr 2002;25:63-5). In addition, doctors should be cautious when giving pazopanib to patients who have a history or are at increased risk of myocardial infarction, angina, ischaemic stroke and transient ischaemic attack.

As fatal haemorrhage has occurred, pazopanib should not be given to patients with a history of haemoptysis, or cerebral or significant gastrointestinal haemorrhage in the previous six months. Patients with cerebral metastases were excluded from the trials. Fatal gastrointestinal perforation has also been reported and doctors should be vigilant for symptoms.

Hypertension is a common adverse effect of pazopanib and mostly occurs in the first 18 weeks of treatment. Patients should be monitored before starting pazopanib and during treatment. If antihypertensive therapy is not effective, the dose of pazopanib may need to be reduced or discontinued.

Hypothyroidism developed in some patients taking pazopanib so monitoring of thyroid function is recommended. Proteinuria has also occurred - including one serious case - so periodic urinanalysis is advised.

Although pazopanib prolongs median progression-free survival by five months, the risks of adverse effects are considerable. Fatal adverse events - including hepatic toxicity - have occurred with an approximate death rate of 2.2%. Patients should be informed of these risks before deciding whether to start treatment.

It is not known how the efficacy of pazopanib compares to other treatments for renal cell carcinoma but a phase III comparative trial with sunitinib is ongoing.

manufacturer provided the product information

The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.