|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||D (AU) D (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Metabolism||Hepatic (CYP3A4, 1A2 and 2C8-mediated)|
|Excretion||Faeces (primary), urine (<4%)|
|Mol. mass||437.517 g/mol|
|(what is this?)|
Pazopanib (trade name Votrient) is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.
It is approved by numerous regulatory administrations worldwide (including the FDA (19 October 2009), EMA (14 June 2010), MHRA (14 June 2010) and TGA (30 June 2010)) for use as a treatment for advanced/metastatic renal cell carcinoma and advanced soft tissue sarcomas. In Australia it is subsidised under the PBS, under a number of conditions, including:
- The medication is used to treat clear cell variant renal cell carcinoma.
- The treatment phase is continuing treatment beyond 3-months.
- The patient has been issued an authority prescription for pazopanib
- The patient must have stable or responding disease according to the Response Evaluation Criteria In Solid Tumours (RECIST)
- This treatment must be the sole tyrosine kinase inhibitor subsidised for this condition.
It has also demonstrated initial therapeutic properties in patients with ovarian and non-small cell lung cancer, though plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country.
Very common (>10% frequency):
- Reduced appetite
- Taste changes
- High blood pressure[Note 1]
- Abdominal pain
- Hair colour change
- Hand-foot syndrome
- Hair loss
- Increased alanine aminotransferase
- Increased aspartate aminotransferase
- Tumour pain‡
- Myelosuppression‡[Note 2]
- Exfoliative rash‡
- Skin hyperpigmentation‡
- Weight loss‡
Common (1-10% frequency):
- Tumour pain†
- Myelosuppression†[Note 3]
- Underactive thyroid
- Low level of phosphate in the blood
- Peripheral sensory neuropathy
- Blurred vision
- Hot flush
- Venous thromboembolic event
- Nose bleed
- Voice anomalies
- Shortness of breath
- Coughing up blood
- Abdominal distension
- Dry mouth
- Mouth ulceration
- Abnormal liver function
- Skin hypopigmentation
- Dry skin
- Skin depigmentation
- Joint pain
- Muscle aches
- Muscle spasms
- Protein in the urine
- Mucosal inflammation
- Chest pain
- Weight loss†
- Increased blood creatinine
- Lipase increased
- Decreased white blood cell count
- Blood TSH decreased
- Amylase increased
- Gamma-glutamyltransferase increased
- Increased blood pressure
- Increased blood urea
- Abnormal liver function test
- Gingival infection‡
- Peripheral sensory neuropathy
- Heart dysfunction
- Blurred vision
- Low heart rate
- Left ventricular dysfunction
- Bleeding (including haemorrhage)
- High blood sugar
- Low blood sugar
Uncommon (0.1-1% frequency):
- Torsades de pointes
- Heart failure
- Liver failure
- GI perforation (may be fatal)
- Fistula formation
Rare (<0.1% frequency):
- Reversible posterior leucoencephalopathy syndrome
† Denotes side effects seen at the above frequency only in clinical trials performed in people with renal cell carcinoma. ‡ Denotes side effects seen at the above frequency only in clinical trials done in people with soft tissue sarcomas.
- Usually occurs within the first 18 weeks of treatment. 39% of cases develop within the first 9 days of treatment
- This includes leucopenia, thrombocytopenia and neutropenia
- This includes leucopenia, lymphopenia, thrombocytopenia and neutropenia
The most common side effects of pazopanib are nausea, vomiting, diarrhoea (occurs in about half of patients), changes in hair colour, hypertension (which usually occurs during the first few weeks of treatment), appetite loss, hyperglycaemia, hypoglycaemia, electrolyte abnormalities (including hypocalcaemia, hypomagnesemia, hypophosphatemia), lab anomalies (including increased AST, ALT and protein in the urine), oedema, hair loss or discolouration, taste changes, abdominal pain, hypertension, rash, fatigue and myelosuppression (including leucopenia, neutropenia, thrombocytopenia and lymphopenia). It has been associated with a low, but real risk of potentially fatal liver damage.
- Hypertension, including hypertensive crises reported
- QT interval prolongation and torsades de pointes reported.
- Thrombotic microangiopathy reported
- Thrombotic thrombocytopenic purpura reported
- Haemolytic uremic syndrome reported
- Haematologic parameter alterations reported in 31-37% of patients.
- Events of cardiac dysfunction (decreased LVEF and congestive heart failure) have been observed
- Fatal haemorrhage, arterial and venous thrombotic events and GI perforation have been observed in randomized clinical trials.
It has one black box warning by the US FDA, severe hepatotoxicity, including fatalities.
Drug interactions include:
- Coadministration with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, clarithromycin, grapefruit juice) may increase pazopanib serum levels as it is a CYP3A4 substrate.
- CYP3A4 inducers (e.g. rifampin, carbamazepine) decrease pazopanib serum levels
- It is a PGP substrate and hence PGP inhibitors like quinidine.
The treatment for overdose is purely supportive and the symptoms include grade 3 hypertension and fatigue.
Mechanism of action
- "Votrient (pazopanib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 27 January 2014.
- "VOTRIENT (pazopanib hydrochloride) tablet, film coated [GlaxoSmithKline LLC]" (PDF). DailyMed. GlaxoSmithKline LLC. November 2013. Retrieved 27 January 2014.
- "Votrient : EPAR - Product Information" (PDF). European Medicines Agency. Glaxo Group Ltd. 23 January 2014. Retrieved 27 January 2014.
- "Votrient 200 mg and 400 mg film coated tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. GlaxoSmithKline UK. 20 December 2013. Retrieved 27 January 2014.
- "PRODUCT INFORMATION VOTRIENT® TABLETS" (PDF). TGA eBusiness Services. GlaxoSmithKline Australia Pty Ltd. 25 March 2013. Retrieved 27 January 2014.
- "Pharmaceutical Benefits Scheme (PBS) - Pazopanib". Pharmaceutical Benefits Scheme. Australian Government. Retrieved 27 January 2014.
- "Pazopanib shows encouraging activity in several tumour types, including soft tissue sarcoma and ovarian cancer". FierceBiotech. 2008-09-15. Retrieved 2010-08-10.
- "GSK pulls bid to extend use of kidney drug to ovarian cancer". Reuters. 31 March 2014. Retrieved 7 April 2014.
- "Regulatory update: Votrient® (pazopanib) as maintenance therapy for advanced ovarian cancer in the EU". GlaxoSmithKline. 31 March 2014. Retrieved 7 April 2014.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- Zivi, A; Cerbone, L; Recine, F; Sternberg, CN (September 2012). "Safety and tolerability of pazopanib in the treatment of renal cell carcinoma". Expert Opinion on Drug Safety 11 (5): 851–859. doi:10.1517/14740338.2012.712108. PMID 22861374.
- Verweij, J; Sleijfer, S (May 2013). "Pazopanib, a new therapy for metastatic soft tissue sarcoma". Expert Opinion on Pharmacotherapy 14 (7): 929–935. doi:10.1517/14656566.2013.780030. PMID 23488774.
- Schöffski, P (June 2012). "Pazopanib in the treatment of soft tissue sarcoma". Expert Review of Anticancer Therapy 12 (6): 711–723. doi:10.1586/era.12.41. PMID 22716487.
- Pick, AM; Nystrom, KK (March 2012). "Pazopanib for the treatment of metastatic renal cell carcinoma". Clinical Therapeutics 34 (3): 511–520. doi:10.1016/j.clinthera.2012.01.014. PMID 22341567.