Pazopanib in Renal cell carcinoma

Transcription

1 REGIMEN TITLE: Pazopanib in Renal cell carcinoma Page 1 of 5 Indication: Notes: First line treatment option in advanced renal cell carcinoma Patients who have not received prior cytokine therapy Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Patient able to tolerate and comply with oral dosage forms Do not administer pazopanib to patients with hemoptysis, cerebral, or serious gastrointestinal hemorrhage in the previous 6 months. Use with caution if history of arterial thrombotic events (eg myocardial infarction, angina, ischemic stroke or transient ischemic attack) in the previous 6 months. Pazopanib should not be used in patients with severe hepatic impairment (see Hepatic impairment section below). Withhold treatment at least 7 days prior to elective surgery. Regimen details: Pazopanib 800mg PO Daily as a single daily dose Continuous therapy. Dose may be modified in 200mg steps based on individual safety and tolerability. Initial dose adjustment should be 400 mg with additional dose adjustments in 200 mg increments based on tolerability (dosing range 200mg-800mg). Administration: Frequency: Anti-emetics: Supportive medication: Available as 200mg and 400mg film-coated tablets (30 tablet packs) Take tablets without food, at least one hour before or two hours after a meal. Swallow whole. Prescribed in 4 week cycles - continued until disease progression or unacceptable toxicity Mildly emetogenic Diarrhoea can be managed with loperamide 2mg PRN (max. 16mg/day). Mouthwashes according to local mouth care guidance if needed. Regular investigations: LFTs (incl. AST,ALT) FBC,Hb U&Es Blood pressure MUGA/ECHO Baseline in pre-existing cardiac disease, repeat if cardiac toxicity suspicion ECG Baseline and periodic monitoring Thyroid function Alternate cycles, monitor for symptoms/ signs of thyroid dysfunction. Urinalysis (proteinuria) Baseline & periodically when required * Mid-cycle assessment is recommended during the first cycle

2 Comments: To be supplied to the patient for oral self-administration. Ensure that the patient has an information pack and the treatment plan. Adequate contraception methods to be applied during the therapy. Page 2 of 5 Toxicities: hepatic failure and increased transaminases, hypertension, risk of QT prolongation, cardiac impairment, arterial thrombotic events (stroke, MI, TIA), myelosuppression, haemorrhage, GI perforation/ fistula, stomatitis, diarrhoea, impaired wound healing, hypothyroidism, proteinuria, hair colour change, nausea, fatigue, anorexia, dysgeusia, PPE, rash Precautions and Dose Modifications Haematological toxicity Discuss any haematological toxicity and dosing reductions with consultant Thrombocytopenia: Investigate and document underlying cause Grade 1 or 2 (Platelets 50 x 10 9 /L) Grade 3 lasting 5 days or Grade 4. (Platelets < 49 x 10 9 /L) Recurrent Grade 3/4 event after initial dose reduction Neutropenia Grade 1 or 2 (Neut 1.0 x 10 9 /L) Grade 3 lasting 5 days (Neut < 0.9 x 10 9 /L) Grade 4 (Neut < 0.5 x 10 9 /L) Recurrent Grade 3/4 event after initial dose reduction Continue treatment at same dose; monitor as clinically indicated. Step 2. Restart treatment with lower dose. Step 2. Restart treatment with lowest dose (200mg/day) Continue treatment at same dose; monitor as clinically indicated. Step 2. Restart treatment same dose. Step 2. Restart treatment with lower dose Step 2. Restart treatment with lowest dose (200mg/day) Non-Haematological Toxicity Hypertension Blood pressure should be well controlled prior to initiating pazopanib. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite anti-hypertensive therapy, the pazopanib dose may be reduced in 200mg increments. Pazopanib should be discontinued if there is evidence of persistently elevated values of blood pressure (140/90 mm Hg) or if

3 Page 3 of 5 arterial hypertension is severe and persists despite anti-hypertensive therapy and pazopanib dose reduction. Cardiotoxicity QT prolongation and Torsades de Pointes have been reported. Pazopanib should be used with caution in patients with any relevant cardiac history, or those taking anti-arrhythmics or other medicines that may prolong the QT interval. Ensure electrolytes are maintained within normal range. Proteinuria Hand-feet symptoms Renal Impairment Discontinue in Grade 4 proteinuria. See appendix 1. for some management suggestions. Encourage regular use of moisturizers to hand and feet regularly. Advise minimizing activities that put pressure on feet or hands, as usually the pressure point areas are affected. Keeping skin cool is beneficial, avoiding extreme heat (such as strong sunlight or hot baths). Support use of non-deodorant, non-fragrance products. Consider products with anti-itch additions in pruritus, and exfoliating urea containing products in hyperkeratosis. Anti-dandruff shampoo may help in management of itchy scalp. Non-steroidal antiinflammatory creams and analgesia may help but a 1-2 week dose interruption may be necessary for painful symptoms. See appendix 1. for some management suggestions. Studies have excluded patients with calculated CrCl <30ml/min. Discuss the management of the treatment for such patients with the consultant. Hepatic Impairment Pazopanib should be used with caution in patients with mild/moderate hepatic impairment. Reduced dose of 200mg daily of Pazopanib is recommended in moderate hepatic impairment (Bilirubin x ULN). *Discuss dose reductions with consultant. Dose re-escalation is not permitted following re-challenge for liver toxicity. Pazopanib is contra-indicated in severe hepatic impairment. Transaminases & Bilirubin Pazopanib dose Subsequent cycles Transaminases 8xULN and/or Bilirubin 1.5 x ULN *Transaminases > 8xULN *Transaminases > 3xULN and Bilirubin > 2xULN * Discuss dose reductions with consultant Continue full dose with weekly monitoring, until returned to Grade1 or baseline Interrupt until returned to Grade1 or baseline Reduce dose and monitor weekly for 8 weeks. If transaminases > 3xULN, discontinue treatment. Perform Bilirubin fractionation. If direct (conjugated) bilirubin > 35% of total bilirubin, Discontinue treatment

4 Drug interactions: Page 4 of 5 Caution with a history of QT interval prolongation or relevant pre-existing cardiac disease, and concurrent antiarrhythmics or other medicines that may prolong the QT interval. Concurrent use of CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin, barbiturates, dexamethasone, St John s Wort) can decrease pazopanib plasma concentration and reduce efficacy. Concurrent use of CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin, grape fruit juice) can increase pazopanib plasma concentration and increase toxicity. References: NICE TA215, Feb 2011 Sternberg C.N. (2010);JCO 28(6): Study protocol VEG108844, Phase III, May 2008 consultations with GlaxoSmithKline, March 2011

5 Appendix 1. Page 5 of 5 Table 1. Suggested Dose Modification/Discontinuation Algorithms for Potential Treatment-Related Adverse Events Proteinuria UPC <3 Continue treatment at the current dose; monitor as clinically indicated UPC 3 Step 1. Interrupt treatment. Step 2. Weekly monitoring with UPC or 24-hr urine protein until UPC is <3 Or 24-hr urine protein is <3g/L Then restart treatment with dose-reduced by 200 mg. Step 3. If UPC or 24-hr urine protein level recurs to 3 or 3g/L, respectively, repeat steps 1 and 2 Step 4. If UPC 3 or 24-hr urine protein 3 (or 3g/L) recurs and dose of the treatment can no longer be reduced, discontinue. Hand-foot Syndrome Grades 1 and 2 Continue treatment at same dose; monitor as clinically indicated Grade 3 Grade 1. Step 2. Restart treatment at same or lower dose. Discuss with consultant. Grade 4 Grade 2 Step 2. Restart treatment at lower dose or discontinue. Discuss with consultant.