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Pazopanib oral

Presentation

Tablets containing pazopanib

Drugs List

  • pazopanib 200mg tablets
  • pazopanib 400mg tablets
  • VOTRIENT 200mg tablets
  • VOTRIENT 400mg tablets
  • Therapeutic Indications

    Uses

    Advanced renal cell carcinoma
    Sarcoma - soft tissue

    First line treatment of advanced Renal Cell Carcinoma and for patients who have received prior cytokine therapy for advanced disease.

    Treatment of selective subtypes of advanced Soft Tissue Sarcoma (STS) who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo) adjuvant therapy.

    Dosage

    Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

    Adults

    The recommended dose is 800 mg pazopanib once a day.

    Dose modification should be done in 200 mg steps based on individual tolerability in order to manage adverse reactions. Dose should not exceed 800 mg.

    Patients with Renal Impairment

    Caution is advised in patients with creatinine clearance below 30 ml/minute.

    Patients with Hepatic Impairment

    Normal bilirubin and any degree of raised alanine transferase (ALT): 800 mg pazopanib once daily.

    Elevation of bilirubin (greater than 35% direct) up to 1.5 times upper limit of normal (ULN) regardless of ALT values: 800 mg pazopanib once daily.

    Elevation of bilirubin greater than 1.5 times to 3 times ULN regardless of ALT values: 200 mg pazopanib once daily.

    Additional Dosage Information

    Dose modifications for drug induced hepatotoxicity
    Transaminase elevation between 3 and 8 times upper limit of normal (ULN)
    Continue treatment monitoring liver function weekly until transaminases return to grade 1 or baseline.
    Transaminase elevation greater than 8 times ULN
    Interrupt treatment until transaminases return to grade 1 or baseline. If the benefit of reinitiating pazopanib outweighs the risk of hepatotoxicity, reintroduce pazopanib at 400 mg once a day. Monitor liver function weekly for 8 weeks. If transaminase elevations are greater than 3 times ULN after reintroduction then permanently discontinue treatment.
    Transaminase elevation greater than 3 times ULN with bilirubin elevations greater than 2 times ULN
    Permanently discontinue treatment. Monitor patients until levels return to grade 1 or baseline.

    Patients with only a mild indirect hyperbilirubinaemia, known or suspected Gilbert's syndrome and transaminase elevation greater than 3 times ULN should be managed as outlined for isolated transaminase elevations.

    Contraindications

    Children under 18 years
    Within 6 months of haemoptysis
    Breastfeeding
    Pregnancy
    Serum bilirubin above 3 times upper limit of normal
    Within 6 months of cerebrovascular haemorrhage
    Within 6 months of severe gastrointestinal haemorrhage

    Precautions and Warnings

    Family history of long QT syndrome
    History of treatment with anthracyclines
    Predisposition to gastrointestinal perforation
    Predisposition to venous thromboembolism
    Risk factors for cardiovascular disorder
    Risk of cerebrovascular accident
    Risk of haemorrhage
    Tobacco smoking
    Behcet's disease
    Cardiac disorder
    Cerebrovascular disorder
    Dehydration
    Diabetes mellitus
    Gastrointestinal fistula
    Giant cell arteritis
    History of aneurysm
    History of torsade de pointes
    Hyperlipidaemia
    Hypertension
    Hypocalcaemia
    Hypokalaemia
    Hypomagnesaemia
    Ischaemic heart disease
    Long QT syndrome
    Marfan syndrome
    Mild hepatic impairment
    Occlusive peripheral arterial disease
    Renal impairment - creatinine clearance below 30 ml/minute
    Serum bilirubin between 1.5 and 3 times upper limit of normal
    Takayasu arteritis
    Vascular Ehlers-Danlos syndrome

    Dose adjustment may be necessary in patients with hepatic impairment
    Advise ability to drive/operate machinery may be affected by side effects
    Consider premedication with hypouricaemic agent
    Ensure hypertension is controlled prior to treatment
    Maintain adequate hydration of patient prior / during treatment
    Treatment to be prescribed under the supervision of a specialist
    Consult local policy on the safe use of oral anti-cancer drugs
    Staff: Not to be handled by pregnant staff
    Measurement of LV ejection fraction recommended before and during treatment
    Monitor hepatic function at months 3 and 4, and periodically thereafter
    Monitor hepatic function on weeks 3, 5, 7, and 9
    Monitor hepatic function prior to treatment
    Monitor liver function weekly if isolated transaminase elevation up to 8ULN
    Monitor blood pressure regularly
    Monitor ECG in patients at risk of QT prolongation
    Monitor for signs and symptoms of interstitial lung disease
    Monitor for signs and symptoms of pneumonitis
    Monitor for signs/symptoms of pneumothorax
    Monitor patients for signs and symptoms of cardiac failure
    Monitor patients for signs of tumour lysis syndrome
    Monitor serum electrolytes
    Monitor thyroid function regularly
    Perform regular urinalysis
    Advise patient to report any new or worsening respiratory symptoms
    Advise patient to report headaches, seizures, confusion, visual disturbance
    Reduce dose if hypertension cannot be controlled
    Discontinue at least 7 days prior to scheduled surgery
    Discontinue at first signs of thrombotic microangiopathy
    Discontinue if AST or ALT level > 3x ULN and bilirubin > 2x ULN
    Discontinue if evidence of interstitial lung disease
    Discontinue if Grade 4 proteinuria occurs (Nephrotic syndrome)
    Discontinue if persistent hypertension unresponsive to therapy occurs
    Discontinue if posterior reversible encephalopathy syndrome (PRES) develops
    Discontinue if treatment related pneumonitis is diagnosed
    Discontinue in patients with wound dehiscence
    Interrupt treatment if hepatic transaminases > 8 times ULN
    Advise patient not to take St John's wort concurrently
    Advise patient grapefruit products may increase plasma level
    Female: Contraception required during and for 2 weeks after treatment
    Male: Use of condoms required during and for 2 weeks after treatment
    Advise patient on giving up smoking

    If persistent hypertension occurs despite treatment, pazopanib dose should be reduced. Suspension of pazopanib is recommended in patients with persistently elevated blood pressure values (greater than 140/90 mmHg) or persistent severe arterial hypertension despite anti-hypertensive treatment and dose reduction of pazopanib.

    Posterior reversible encephalopathy syndrome (PRES) has been reported in some patients treated with this agent. If patients present with symptoms indicating PRES such as headache, altered mental state, seizures and visual disturbances, an MRI should be performed. If PRES is diagnosed, treatment should be discontinued and adequate blood pressure and seizure control administration is advisable. The safety of reinstating treatment in patients previously experiencing PRES is unknown.

    Neutropenia, thrombocytopenia and palmar-plantar erythrodysesthesia syndrome were observed more frequently in patients of east Asian descent.

    Risk factors for aneurysm and artery dissection
    Use of systemic VEGF inhibitors may promote the formation of aneurysms or artery dissections, mainly in relation to aortic aneurysm rupture and aortic dissection. It is therefore important to consider the risk of aneurysm and artery dissection in patients with risk factors such as hypertension, history of aneurysm, smoking, diabetes, coronary, cerebrovascular or peripheral arterial disease, and hyperlipidaemia. Other risk factors include Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, and the use of fluoroquinolones. In patients receiving VEGF inhibitors, any modifiable risk factors such as smoking and hypertension should be reduced as far as possible.

    Pregnancy and Lactation

    Pregnancy

    Use in pregnancy is contraindicated.

    Studies in rats and rabbits have shown pazopanib to be embryotoxic and teratogenic but the risk to humans is unknown. However as renal carcinoma is a fatal condition, treatment should not be withheld due to pregnancy as long as informed consent is obtained.

    The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

    Lactation

    Breastfeeding is contraindicated during treatment with pazopanib.

    There is limited data on the excretion of pazopanib in human or animal milk therefore a risk to the nursing infant cannot be excluded. 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 (greater than 99%) might limit the amount (Brigs 2011).

    Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
    Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

    Counselling

    To be taken orally and the tablets must be swallowed whole with water at least 1 hour before or 2 hours after a meal.

    Advise patients to avoid grapefruit products whilst on pazopanib.

    Advise patients against taking concurrent St John's Wort.

    Advise patients to report headache, seizures, confusion and visual disturbances promptly.

    Advise women of child bearing potential to use adequate contraception during and for 2 weeks after treatment.

    Advise patients that side effect such as dizziness, tiredness or weakness may affect their ability to drive or operate machinery.

    Side Effects

    Abdominal distension
    Alopecia
    Aneurysm
    Artery dissection
    Asthenia
    Blood urea increased
    Bradycardia
    Cardiac disorders
    Cerebrovascular accident
    Changes in hair colour
    Chest pain
    Decreased appetite
    Decreased blood glucose
    Dizziness
    Dry skin
    Dysgeusia
    Dysphonia
    Elevated amylase levels
    Elevated serum lipase
    Epistaxis
    Erythema
    Eyelash changes
    Fatigue
    Flushing
    Gamma glutamyl transferase (GGT) increased
    Gastro-intestinal disturbances
    Gastro-intestinal fistulae
    Gastro-intestinal haemorrhage
    Gastro-intestinal perforation
    Haematemesis
    Haematochezia
    Haemoptysis
    Haemorrhage
    Haemorrhoidal bleeding
    Headache
    Hepatic failure
    Hepatic impairment
    Hepatotoxicity
    Hot flushes
    Hyperbilirubinaemia
    Hyperhidrosis
    Hypertension
    Hypertensive crisis
    Hypoaesthesia
    Hypomagnesaemia
    Hypophosphataemia
    Hypopigmentation
    Hypothyroidism
    Increase in serum ALT/AST
    Infections
    Interstitial lung disease
    Ischaemic stroke
    Jaundice
    Lethargy
    Leukopenia
    Melaena
    Menorrhagia
    Metrorrhagia
    Mouth ulcers
    Mucous membrane disorder
    Muscle spasm
    Myalgia
    Myocardial infarction
    Myocardial ischaemia
    Neutropenia
    Oedema
    Oesophageal haemorrhage
    Palmar-Plantar Erythrodysaesthesia syndrome
    Pancreatitis
    Papules
    Paraesthesia
    Peripheral neuropathy
    Photosensitivity
    Pneumonitis
    Polycythaemia
    Possible alteration of thyroid function tests
    Posterior reversible encephalopathy syndrome (PRES)
    Prolongation of QT interval
    Proteinuria
    Pruritus
    Pulmonary embolism
    Pulmonary haemorrhage
    Rash
    Rectal haemorrhage
    Retinal detachment
    Retinal tear
    Serum bilirubin increased
    Serum creatinine increased
    Skin depigmentation
    Skin exfoliation
    Stomatitis
    Thrombocytopenia
    Thrombotic microangiopathy
    Transient ischaemic attack
    Tumour lysis syndrome
    Tumour pain
    Urinary tract bleeding
    Vaginal haemorrhage
    Vesiculation
    Weight loss

    Overdosage

    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

    Further Information

    Last Full Review Date: November 2013

    Reference Sources

    Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

    Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press. Accessed on 18 June 2015.

    MHRA Drug Safety Update July 2020
    Available at: https://www.gov.uk/drug-safety-update/systemically-administered-vegf-pathway-inhibitors-risk-of-aneurysm-and-artery-dissection
    Last accessed: 10 November 2020

    Summary of Product Characteristics: Votrient 200 mg and 400 mg film coated tablets. Novartis UK Ltd. Revised July 2020.

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