Pazopanib

Registered South African indications:

• Renal cell carcinoma

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Severe hepatic impairment

Cautions

• Severe renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Males and females of reproductive potential
• Children
• Pre-existing cardiac dysfunction
• Congestive cardiac failure
• Decreased left ventricular ejection fraction
• Hypertension 
• History of QT interval prolongation
• Risk factors for or previous history of thrombotic events
• Risk factors for haemorrhage
• Haemoptysis
• Cerebral haemorrhage
• Clinically significant gastrointestinal haemorrhage
• Risk factors for gastrointestinal perforation or fistula
• Hypothyroidism
• Wound dehiscence  
• Patients under wound care therapy  
• History of aneurysm and/or artery dissections  
• Proteinuria
• Recent/repeated history of pneumothorax

Forms avail. in SA and covered in this monograph: tab

Used for the treatment of

Advanced or metastatic renal cell carcinoma

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Consult specialist for dosages and regimens

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Soft-tissue sarcoma 

- In 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

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Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Contraindicated
• There is no adequate data from the use of pazopanib in pregnant women
• Studies in animals have shown reproductive toxicity
• The potential risk for humans is unknown
• Pazopanib should not be used during pregnancy unless the clinical condition of the woman requires treatment with pazopanib
• If pazopanib is used during pregnancy, or if the patient becomes pregnant while receiving pazopanib, the potential hazard to the foetus should be explained to the patient
• Women of childbearing potential should be advised to use adequate contraception during treatment and for at least 2 weeks after the last dose of pazopanib and to avoid becoming pregnant while receiving treatment with pazopanib
• Male patients (including those who have had vasectomies) should use condoms during sexual intercourse while taking pazopanib and for at least 2 weeks after the last dose of pazopanib to avoid potential exposure to the medicinal product for pregnant partners and female partners of reproductive potential

Breastfeeding

• Contraindicated 
• The safe use of pazopanib during breastfeeding has not been established
• It is not known whether pazopanib or its metabolites are excreted in human milk
• There is no animal data on the excretion of pazopanib in animal milk
• A risk to the breastfed child cannot be excluded. Breastfeeding should be discontinued during treatment with pazopanib
• The molecular weight (about 438 for the free base) and long elimination half-life (about 31 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (>99%) might limit the amount
• In adults, adverse reactions occurring in >10% of patients were diarrhoea, hypertension, hair colour changes, nausea and vomiting, anorexia, fatigue,, asthenia, abdominal pain, and headache. Other serious toxicities, such as hepatotoxicity, were also observed. Because the potential for severe toxicity in a nursing infant is a concern, women receiving pazopanib should not breastfeed

Fertility

• Animal studies indicate that male and female fertility may be affected by treatment with pazopanib

Renal Impairment

• Mild to moderate (CrCl > 30ml/min): No dose adjustment recommended
• Severe (CrCl < 30ml/min): Caution; no information available

Hepatic Impairment

• Mild to moderate (Child-Pugh Classes A & B): Caution; dose adjustment recommended
  - initiate with 25% of recommended dose increments in a stepwise fashion based on individual tolerability and LFT results in order. The total daily dose should not exceed 800mg
  - if an increase in ALT and/or bilirubin >X1.5 and <X3 ULN, only administer 25% of the dose per day
  - Discontinue therapy when the increase in ALT and/or bilirubin levels is/are progressive >X3 ULN, with clinical hepatic decompensation
• Severe (Child-Pugh Class C): Contraindicated
  Use is not recommended

Elderly            

• Caution; no dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Insomnia
• Headache
• Lethargy
• Dizziness
• Paraesthesia
• Peripheral sensory neuropathy
• Hypoaesthesia
• Transient ischaemic attack
• Somnolence
• Cerebrovascular accident
• Ischaemic stroke
• Posterior reversible encephalopathy
• Reversible posterior leukoencephalopathy syndrome
• Fatigue

Cardiovascular Disorders

• Bradycardia
• Myocardial infarction
• Cardiac dysfunction
  - Cardiac failure
  - Left ventricular dysfunction
  - Restrictive cardiomyopathy
• Myocardial ischaemia
• Hypertension
• Hot flush
• Venous thromboembolic event
  - Deep vein thrombosis
  - Pulmonary embolism
• Hypertensive crisis
• Haemorrhage
• Aneurysms and artery dissections
• Chest pain
• Increased diastolic blood pressure
• Increased systolic blood pressure
• Prolonged QT interval
• Thrombotic microangiopathy

Respiratory Disorders

• Epistaxis
• Dysphonia
• Dyspnoea
• Haemoptysis
• Rhinorrhoea
• Pulmonary haemorrhage
• Pneumothorax
• Interstitial lung disease
• Pneumonitis

Gastrointestinal Disorders

• Gingival infection
• Infectious peritonitis
• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Stomatitis
• Dyspepsia
• Flatulence
• Abdominal distension
• Mouth ulceration
• Dry mouth
• Pancreatitis
• Rectal haemorrhage
• Haematochezia
• Gastrointestinal haemorrhage
• Melaena
• Frequent bowel movements
• Anal haemorrhage
• Large intestine perforation
• Mouth haemorrhage
• Upper gastrointestinal haemorrhage
• Enterocutaneous fistula
• Haematemesis
• Haemorrhoidal haemorrhage
• Ileal perforation
• Oesophageal haemorrhage
• Retroperitoneal haemorrhage

Hepatobiliary Disorders

• Hyperbilirubinaemia
• Abnormal hepatic function
• Hepatotoxicity
• Jaundice
• Drug induced liver injury
• Hepatic failure
• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased amylase
• Increased gamma-glutamyltransferase
• Increased hepatic enzymes
• Increased transaminase
• Increased blood bilirubin
• Increased lipase

Genitourinary Disorders

• Proteinuria
• Urinary tract haemorrhage
• Menorrhagia
• Vaginal haemorrhage
• Metrorrhagia
• Increased blood urea
• Increased creatinine

Endocrine and Metabolic Disorders

• Hypothyroidism
• Decreased appetite
• Hypophosphataemia
• Dehydration
• Hypomagnesaemia
• Abnormal thyroid function test
• Increased blood thyroid stimulating hormone
• Decreased blood glucose
• Decreased weight

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Muscle spasms
• Musculoskeletal pain

Skin and Subcutaneous Tissue Disorders

• Hair colour change
• Palmar-plantar erythrodysaesthesia syndrome
• Alopecia
• Rash
• Skin hypopigmentation
• Dry skin
• Pruritus
• Erythema
• Skin depigmentation
• Hyperhidrosis
• Nail disorders
• Skin exfoliation
• Photosensitivity reaction
• Rash erythematous
• Skin disorder
• Rash macular
• Rash pruritic
• Rash vesicular
• Papular rash
• Plantar erythema
• Pruritis
• Flushing

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Neutropenia
• Leukopenia
• Polycythaemia
• Thrombotic microangiopathy
• Thrombotic thrombocytopenic purpura
• Haemolytic uraemic syndrome
• Infections 
• Tumour pain
• Decreased white blood cell count
• Chills
• Infections (with or without neutropenia)
• Oedema
• Mucosal inflammation

Sensory Disorders

• Dysgeusia
• Blurred vision
• Retinal detachment
• Retinal tear

Other

• Mucous membrane disorder

• CYP3A4 inhibitors
• Itraconazole
• Clarithromycin
• Atazanavir
• Indinavir
• Nefazodone
• Nelfinavir
• Ritonavir
• Saquinavir
• Telithromycin
• Voriconazole
• CYP3A4 inducers
• Rifampicin
• P-glycoprotein inhibitors and substrates
• Breast cancer resistance protein inhibitors
• Ketoconazole 
• Uridine diphosphate glucuronosyl transferase 1A1 substrates
• Irinotecan
• Simvastatin
• Atorvastatin
• Fluvastatin
• Pravastatin
• Rosuvastatin
• Pemetrexed
• Lapatinib
• Midazolam
• Dextromethorphan
• Paclitaxel
• Proton-pump inhibitors
• H2-receptor anatagonists
• Esomeprazole
• Grapefruit juice 

• Hepatic function
• Blood pressure
• ECG
• Echocardiogram
• Electrolytes
• Urinanalysis 
• 24 hour urine protein
• Thyroid function

Specific cases may require

• Pregnancy test
• Left ventricular ejection faction

Tyrosine kinase inhibitors (TKI) and cerebrovascular adverse events safety concern

• TKI containing medicines may have different kinase inhibition profiles and/or off target binding profiles, with some TKIs approved for very similar indications and others approved for different indications
• Although many adverse events/side effects/toxicities could not be explained by a class related adverse event or a related off-target kinase inhibition effect, there is some evidence that the TKIs share to a variable degree, class related cerebrovascular adverse events
• The abovementioned cerebrovascular adverse events may occur in patients on treatment with TKI containing medicines with or without risk factors for these events and may occur at any time during treatment with TKIs
• Patients on treatment with TKI containing medicine should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events
• Treatment with TKI containing medicines should be discontinued, and alternative treatment options be considered in patients who develop these class related cerebrovascular adverse events

Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) and limits tumor growth via inhibition of angiogeneisis by inhibiting surface vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, platelet-derived growth factor (PDGFR) -α and –β, and stem cell factor receptor (c-KIT), interleukin-2 receptor inducible T-cell kinase, lymphocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms)

Tablet 200mg

• Votrient fct (Novartis) originator

Tablet 400mg

• Votrient fct (Novartis) originator