Pazopanib

Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor. It acts on receptors of the angiogenesis pathway, through which tumours form new blood vessels, and on the stem cell factor receptor c-KIT.

Mechanism of Action

• Targets: pazopanib inhibits VEGFR-1, -2 and -3, PDGFR-α and -β and c-KIT, with IC50 values of 10, 30, 47, 71, 84 and 74 nM respectively.
• Receptor inhibition: in cells it dose-dependently blocked ligand-induced auto-phosphorylation of VEGFR-2, c-Kit and PDGFR. In mice it inhibited VEGF-induced VEGFR-2 phosphorylation in the lung, angiogenesis in several animal models and the growth of multiple human tumour xenografts.
• Effects in patients: reduced tumour blood flow, increased tumour-cell apoptosis, slower tumour growth and lower interstitial fluid pressure have been observed at the concentrations reached with treatment.
• Pharmacogenomics: in a meta-analysis of 31 clinical studies, ALT above 5 times the upper limit of normal (grade 3) occurred in 19% of carriers of the HLA-B*57:01 allele and in 10% of non-carriers; 133 of 2,235 patients (6%) were carriers.

Pharmacokinetics

• Absorption: slow and incomplete; absolute bioavailability of an 800 mg tablet is about 21% in cancer patients. After a single 800 mg dose, the peak concentration (about 19 ± 13 µg/mL) was reached after a median of 3.5 hours (range 1.0–11.9) and AUC0–∞ was about 650 ± 500 µg·h/mL. Daily dosing raises AUC 1.23- to 4-fold, and doses above 800 mg gave no consistent further increase. A high-fat or low-fat meal roughly doubles AUC and peak concentration, so pazopanib is taken at least 2 hours after or 1 hour before food. A crushed 400 mg tablet raised AUC(0–72) by 46% and the peak about 2-fold.
• Distribution: more than 99% bound to plasma proteins, independent of concentration over 10–100 µg/mL. Pazopanib is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP).
• Metabolism: mainly CYP3A4, with minor contributions from CYP1A2 and CYP2C8. The four principal metabolites make up only 6% of plasma exposure; one is about as potent as pazopanib in vitro and the others are 10- to 20-fold less active, so activity depends mainly on the parent compound.
• Elimination: slow, with a mean half-life of 30.9 hours after 800 mg. Elimination is mainly in the faeces; less than 4% of a dose is excreted in the urine as pazopanib and metabolites.
• Special populations: renal impairment is unlikely to have a clinically relevant effect on exposure. In severe hepatic impairment, exposure at a 200 mg dose is markedly reduced and highly variable.

• Renal cell carcinoma (RCC): in adults, for the first-line treatment of advanced renal cell carcinoma and for patients who have received prior cytokine therapy for advanced disease.
• Soft-tissue sarcoma (STS): in adult patients with selective subtypes of advanced soft-tissue sarcoma who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo)adjuvant therapy. Efficacy and safety have been established only in certain histological subtypes of soft-tissue sarcoma (see section 5.1 of the SmPC).

• Hypersensitivity to the active substance or to any of the excipients.

The safety data come from pooled studies in renal cell carcinoma (1,149 patients) and soft-tissue sarcoma (382 patients) and from post-marketing reports. The most common reactions (at least 10% of patients, any grade) were diarrhoea, hair colour change, skin hypopigmentation, exfoliative rash, hypertension, nausea, headache, fatigue, anorexia, vomiting, dysgeusia, stomatitis, weight decreased, pain, and increased ALT and AST. The groups below follow the renal cell carcinoma table; differences in the sarcoma table are noted at the end.

Very common (≥1/10): decreased appetite; dysgeusia, headache; hypertension; diarrhoea, nausea, vomiting, abdominal pain; hair colour change, palmar-plantar erythrodysaesthesia syndrome, alopecia, rash; proteinuria; fatigue; increased ALT and AST.

Common (≥1/100 to <1/10): infections (with or without neutropenia); thrombocytopenia, neutropenia, leukopenia; hypothyroidism; hypophosphataemia, dehydration; insomnia; dizziness, lethargy, paraesthesia, peripheral sensory neuropathy; blurred vision; hot flush, flushing, venous thromboembolic events; epistaxis, dysphonia, dyspnoea, haemoptysis; stomatitis, dyspepsia, flatulence, abdominal distension, mouth ulceration, dry mouth; hyperbilirubinaemia, abnormal hepatic function, hepatotoxicity; skin hypopigmentation, dry skin, pruritus, erythema, skin depigmentation, hyperhidrosis; arthralgia, myalgia, muscle spasms; mucosal inflammation, asthenia, oedema, chest pain; weight decreased and increases in blood bilirubin, creatinine, lipase, amylase, gamma-glutamyltransferase, thyroid-stimulating hormone, blood pressure and blood urea, with decreased white blood cell count and abnormal liver function tests.

Uncommon (≥1/1,000 to <1/100): gingival infection, infectious peritonitis; tumour pain; polycythaemia; hypomagnesaemia; hypoaesthesia, transient ischaemic attack, somnolence, cerebrovascular accident, ischaemic stroke; retinal detachment, retinal tear, eyelash discolouration; bradycardia, myocardial infarction, cardiac dysfunction, myocardial ischaemia; hypertensive crisis, haemorrhage; rhinorrhoea, pulmonary haemorrhage, pneumothorax; pancreatitis, rectal, anal, oral, upper gastrointestinal, oesophageal, haemorrhoidal and retroperitoneal haemorrhage, haematochezia, melaena, haematemesis, large intestine and ileal perforation, enterocutaneous fistula, frequent bowel movements; jaundice, drug-induced liver injury, hepatic failure; nail disorders, skin exfoliation, photosensitivity reaction and several other types of rash; musculoskeletal pain; urinary tract haemorrhage; menorrhagia, vaginal haemorrhage, metrorrhagia; chills, mucous membrane disorder; increased hepatic enzymes and transaminases, decreased blood glucose, QT prolongation on the ECG, abnormal thyroid function tests, increased systolic or diastolic blood pressure.

Rare (≥1/10,000 to <1/1,000): thrombotic microangiopathy (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome); posterior reversible encephalopathy syndrome / reversible posterior leukoencephalopathy syndrome; aneurysms and artery dissections; interstitial lung disease / pneumonitis.

Not known: tumour lysis syndrome.

Soft-tissue sarcoma studies: some categories differ. Tumour pain, leukopenia, thrombocytopenia, neutropenia, hypoalbuminaemia, stomatitis, skin hypopigmentation, exfoliative rash and weight decreased were very common, and cardiac dysfunction, left ventricular dysfunction, bradycardia, pneumothorax, pulmonary haemorrhage and cough were common. Neutropenia, thrombocytopenia and palmar-plantar erythrodysaesthesia syndrome were seen more often in patients of East Asian descent. The safety profile in the 101 paediatric patients studied was similar to that in adults.

Important serious reactions: the most important serious reactions in the studies, each in under 1% of patients, were transient ischaemic attack, ischaemic stroke, myocardial ischaemia and infarction, cerebral infarction, cardiac dysfunction, gastrointestinal perforation and fistula, QT prolongation, torsade de pointes, and pulmonary, gastrointestinal and cerebral haemorrhage. In sarcoma studies venous thromboembolic events, left ventricular dysfunction and pneumothorax were also important. Fatal events considered possibly related to pazopanib included gastrointestinal haemorrhage, pulmonary haemorrhage or haemoptysis, abnormal hepatic function, intestinal perforation and ischaemic stroke.

Pazopanib is metabolised mainly by CYP3A4 and is a substrate of P-glycoprotein and BCRP, so inhibitors and inducers of these pathways change its exposure.

• Strong CYP3A4, P-gp or BCRP inhibitors (for example ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole): ketoconazole raised pazopanib AUC(0–24) by 66% and the peak by 45%. The SmPC advises avoiding these combinations and choosing alternative medicines with no or minimal inhibitory potential. In the interaction study, 400 mg once daily with ketoconazole gave exposure similar to 800 mg alone in most patients, although some patients had higher exposure. Hyperglycaemia has been seen with concomitant ketoconazole.
• CYP3A4 inducers: avoid, because exposure to pazopanib may fall. St John’s Wort lowers pazopanib concentrations.
• Grapefruit juice: contains a CYP3A4 inhibitor and may raise plasma concentrations; avoid it during treatment.
• Simvastatin: increases the risk of ALT elevations; use with caution and close monitoring.
• UGT1A1 substrates (for example irinotecan): use with caution, because pazopanib inhibits UGT1A1.
• Antiarrhythmics and other QT-prolonging medicines: use pazopanib with caution; see Special Instructions.
• Other anti-cancer therapies: studies combining pazopanib with pemetrexed, lapatinib or pembrolizumab were stopped early because of increased toxicity and/or mortality, and no safe and effective combination dose has been established.
• Food and antacids: food roughly doubles exposure, so pazopanib is taken without food. Antacids should be separated from pazopanib by several hours.

Treatment should be started only by a physician experienced in the use of anti-cancer medicinal products. Pazopanib is taken by mouth without food, at least one hour before or two hours after a meal. The tablets are swallowed whole with water and are not broken or crushed.

Recommended Dose

• 800 mg once daily for both renal cell carcinoma and soft-tissue sarcoma.

Dose Modifications

• The dose can be decreased or increased in steps of 200 mg, according to individual tolerability, to manage adverse reactions. It should not exceed 800 mg.
• Dose changes for drug-induced hepatotoxicity are set out under Special Instructions.

Special Populations

• Elderly: data in patients aged 65 and over are limited. In the renal cell carcinoma studies there were no clinically significant differences in safety between patients aged 65 or over and younger patients, but greater sensitivity in some older patients cannot be ruled out.
• Renal impairment: no dose adjustment is needed if creatinine clearance is above 30 mL/min. Caution is advised below 30 mL/min because there is no experience.
• Hepatic impairment: liver function tests are done in all patients before and during treatment. With mild or moderate impairment, pazopanib is used with caution and close monitoring of tolerability. The dose stays 800 mg once daily in mild abnormalities of serum liver tests (normal bilirubin with any degree of ALT elevation, or bilirubin above normal and up to 1.5 times the upper limit of normal regardless of ALT). In moderate impairment (bilirubin above 1.5 to 3 times the upper limit of normal, regardless of ALT) the recommended dose is 200 mg once daily. Pazopanib is not recommended in severe impairment (total bilirubin above 3 times the upper limit of normal, regardless of ALT).
• Children and adolescents: pazopanib must not be used under 2 years of age because of safety concerns for organ growth and maturation. Safety and efficacy at 2 to 18 years have not been established, and no dose recommendation can be made.

Liver Function and Hepatotoxicity

• Hepatic failure: cases of hepatic failure, including fatalities, have been reported. In the studies, serum transaminases (ALT, AST) and bilirubin rose; in most cases only ALT and AST rose, without a rise in alkaline phosphatase or bilirubin. Patients over 60 years may be at greater risk of mild (above 3 times the upper limit of normal) to severe (above 8 times) ALT elevation, and carriers of the HLA-B*57:01 allele have a higher risk of pazopanib-associated ALT elevations. Liver function should be monitored in all patients, regardless of genotype or age.
• Monitoring schedule: serum liver tests before starting, at weeks 3, 5, 7 and 9, then at months 3 and 4, with extra tests as clinically indicated. Periodic testing should then continue after month 4.
• Dose modification for drug-induced hepatotoxicity (SmPC Table 1, which applies to patients with the baseline bilirubin and transaminase values stated there):
  • Transaminases between 3 and 8 times the upper limit of normal: continue pazopanib with weekly liver monitoring until transaminases return to grade 1 or baseline.
  • Transaminases above 8 times the upper limit of normal: interrupt pazopanib until they return to grade 1 or baseline. If the potential benefit of restarting is judged to outweigh the risk of hepatotoxicity, restart at a reduced dose of 400 mg daily with weekly serum liver tests for 8 weeks. If transaminases above 3 times the upper limit of normal recur, stop pazopanib permanently.
  • Transaminases above 3 times the upper limit of normal together with bilirubin above 2 times: stop pazopanib permanently, and monitor the patient until values return to grade 1 or baseline.
• Gilbert’s syndrome: pazopanib inhibits UGT1A1, so mild indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert’s syndrome. If only mild indirect hyperbilirubinaemia is present, in known or suspected Gilbert’s syndrome, together with ALT above 3 times the upper limit of normal, manage as for isolated ALT elevations.
• Simvastatin: using it with pazopanib increases the risk of ALT elevations.

Cardiovascular and Bleeding Risks

• Hypertension: hypertension, including hypertensive crisis, occurred. Blood pressure should be well controlled before starting, checked within a week of starting and frequently afterwards (about 40% of cases occurred by day 9 and about 90% in the first 18 weeks), and managed with antihypertensive therapy and dose modification. Pazopanib is stopped for hypertensive crisis or for severe hypertension that persists despite treatment and dose reduction.
• Cardiac dysfunction and heart failure: benefit and risk should be weighed in patients with pre-existing cardiac dysfunction; use in moderate to severe heart failure or low left ventricular ejection fraction has not been studied. Baseline and periodic LVEF assessment is recommended in patients at risk. Interruption and/or dose reduction, together with treatment of hypertension, is advised for significant LVEF falls.
• QT prolongation and torsade de pointes: caution in patients with a history of QT prolongation, taking antiarrhythmics or other QT-prolonging medicines, or with relevant cardiac disease. Baseline and periodic ECGs are recommended, with calcium, magnesium and potassium kept in the normal range.
• Arterial and venous thrombotic events: myocardial infarction, myocardial ischaemia, ischaemic stroke and transient ischaemic attack, some fatal, have occurred; caution in patients at increased risk or with a history, and pazopanib has not been studied after an event in the previous 6 months. Venous thromboembolism, including fatal pulmonary embolism, was more frequent in soft-tissue sarcoma (5%) than in renal cell carcinoma (2%).
• Thrombotic microangiopathy: pazopanib is stopped permanently; effects reversed after discontinuation.
• Haemorrhage: fatal haemorrhagic events have occurred. Pazopanib has not been studied after haemoptysis, cerebral haemorrhage or clinically significant gastrointestinal haemorrhage in the past 6 months; use with caution when the bleeding risk is significant.
• Aneurysms and artery dissections: VEGF pathway inhibitors may promote these, so the risk is weighed before starting, especially with hypertension or a history of aneurysms.

Other Warnings

• PRES/RPLS: posterior reversible encephalopathy syndrome can present with headache, hypertension, seizure, lethargy, confusion, blindness and other visual or neurological disturbances, and can be fatal; stop pazopanib permanently.
• Interstitial lung disease and pneumonitis: can be fatal; patients are monitored for pulmonary symptoms and pazopanib is stopped.
• Gastrointestinal perforation and fistula: fatal perforations have occurred; use with caution in patients at risk.
• Wound healing: VEGF inhibitors may impair it, so pazopanib is stopped at least 7 days before scheduled surgery, restarted when wound healing is judged adequate, and stopped in wound dehiscence.
• Hypothyroidism and proteinuria: thyroid function is measured at baseline and periodically; urinalysis is done at baseline and periodically, and pazopanib is stopped in nephrotic syndrome.
• Tumour lysis syndrome: including fatal cases; risk is higher with rapidly growing tumours, high tumour burden, renal dysfunction or dehydration, and preventive measures such as treating high uric acid and intravenous hydration should be considered before starting.
• Pneumothorax and infections: pneumothorax occurred in sarcoma studies. Serious infections, with or without neutropenia and sometimes fatal, have been reported.
• Children: not to be given to children under 2 years of age.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate data, and animal studies show reproductive toxicity. Pazopanib should not be used in pregnancy unless the woman’s condition requires it, and the potential hazard to the foetus should then be explained.
• Contraception: women of childbearing potential should use adequate contraception during treatment and for at least 2 weeks after the last dose. Male patients, including those who have had vasectomies, should use condoms during treatment and for at least 2 weeks after the last dose.
• Breastfeeding: safe use has not been established and a risk to the child cannot be excluded; breastfeeding should be discontinued during treatment.
• Fertility: animal studies indicate that male and female fertility may be affected.

Sodium

Each film-coated tablet contains less than 1 mmol (23 mg) of sodium, that is essentially sodium-free.

Effect on Driving

Pazopanib has no or negligible influence on the ability to drive and use machines. Patients should avoid driving or using machines if they feel dizzy, tired or weak.

Votrient does not require any special storage conditions. The tablets are supplied in HDPE bottles with child-resistant polypropylene closures: 200 mg in bottles of 30 or 90 tablets, 400 mg in bottles of 30 or 60 tablets (not all pack sizes may be marketed).

3 years.

Prescription only (Rx), subject to restricted medical prescription (Annex II B of the marketing authorisation). Treatment must be started by a physician experienced in the use of anti-cancer medicinal products. The tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.