Safety Considerations and Side Effect Management with Tyverb (Lapatinib)

Transcription

1 Safety Considerations and Side Effect Management with Tyverb (Lapatinib) Prescribing information can be found at the end of the presentation Date of prep: 19-Sep-2011 UK/LPD/0226a/11

2 HER2 (ErbB2)-positive Breast Cancer Breast Cancer is the most common malignancy in women in UK - Approximately 48,000 new cases and 12,000 deaths in UK in Approximately 15-30% of patients have tumours that overexpress HER2 2,3 HER2-postive disease tends to be more aggressive, less responsive to chemotherapy and has a poorer prognosis Average survival time, with treatment, from diagnosis of advanced or metastatic disease is months; reduced by up to 50% if HER Cancer Research UK. UK breast cancer incidence and mortality statistics. Accessed: 20/05/ Penault-Llorca et al. JCO NICE. Technology Appraisal Guidance No. 34. London: NICE, 2002.

3 Introduction Small molecule, works intracellularly Targets both the EGFR (ErbB1) and HER2 (ErbB2) receptors Once-daily oral treatment Treatment option for HER2 patients with metastatic disease - in combination with capecitabine for patients with advanced or metastatic disease with progression following prior therapy, which must have included anthracyclines and taxanes, and therapy with trastuzumab in the metastatic setting - in combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy. The patients in the registration study were not previously treated with trastuzumab or an aromatase inhibitor Tyverb Summary of Product Characteristics May 2011

4 Practical Considerations: Lapatinib/Capecitabine Combination Practical Considerations Lapatinib Capecitabine Dosage/administration 1250mg ONCE daily 1000mg/m 2 TWICE daily Food interaction Taken continuously 250mg tablets (5 tablets/day) > 1 hour pre- or post food (standardised) 14 day cycle with 7 day rest 150mg/ 500mg tablets (3-7 tablets twice daily) Within 30 minutes after food Do not crush, take whole one at a time with a glass of water Grapefruit juice Drug interaction Avoid concomitant treatment with inducers or inhibitors of CYP3A4 Refer to SmPC for further details Please refer to Tyverb and Xeloda Summary of Product Characteristics for full details

5 Practical Considerations: Lapatinib/Aromatase Inhibitor Combination Practical Considerations Lapatinib Aromatase Inhibitor Dosage/administration 1500mg ONCE daily ONCE daily Food interaction 250mg tablets (6 tablets/day) > 1 hour pre- or post food (standardised) Do not crush, take whole one at a time with a glass of water Grapefruit juice Taken continuously Letrozole: 2.5mg (1 tablet/day) Anastrozole: 1mg (1 tablet/day) Exemestane: 25mg (1 tablet/day) Refer to respective SmPC for full details Drug interaction Avoid concomitant treatment with inducers or inhibitors of CYP3A4 Please refer to the Summaries of Product Characteristics for full details

6 Introduction to the Guiding your patient through Tyverb treatment material

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10 Tyverb Information for patients and healthcare professionals Practical advice on administration/dosage

11 Questions your patient may ask... What should I do if I forget to take my Tyverb? Answers: - If it is still the same day, take your Tyverb tablets as soon as you remember. Do NOT double the dose the next day - Remember to inform the cancer unit What if I missed a whole day? Answers: - Take the usual dose of Tyverb on the day after the missed day at the usual time(s) - Remember to inform the cancer unit

12 Questions your patient may ask... What if I am sick after taking Tyverb? Answers: - Do not take a second dose to make up for the vomited dose - Take the next dose as normal when due - If vomiting continues, contact the cancer unit Can I crush, split or dissolve the tablets? Answers: - Tyverb tablets should be swallowed whole with a drink of water - Crushing, splitting, chewing and dissolving the tablets are not recommended - Talk to the breast cancer/chemotherapy nurse if experiencing difficulty taking tablets

13 Management of Tyverb-associated side effects

14 Common Side Effects Safety of Tyverb evaluated as monotherapy or in combination with other chemotherapies for various cancers in more than 11,000 patients including: patients who received Tyverb in combination with capecitabine (EGF100151) patients who received Tyverb in combination with letrozole (EGF30008) Most common AEs (>25%) during therapy with Tyverb were gastrointestinal events (such as diarrhoea, nausea, and vomiting) and rash. Tyverb Summary of Product Characteristics May 2011

15 EGF most common adverse events (all grades) Cameron D, et al. Breast Can Res Treat 2008;112:

16 EGF most common adverse events (all grades) Diarrhoea Johnston S et al. J Clin Oncol ;

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18 Management of Diarrhoea associated with Tyverb

19 Diarrhoea events across several Tyverb studies The incidence and characteristics of diarrhoea associated with Tyverb treatment have been reviewed across several clinical trials Grade Diarrhoea events were mainly grade 1 and grade 2 (mild to moderate) Grade 3 and 4 events occurred in 9% and <1% of patients, respectively Onset and duration 42% of patients who experienced diarrhoea developed it within the first 6 days of treatment Each episode lasted a median of 5 days Few patients had events worsen from grade 1 or 2 Management and resolution Vast majority (92%) of diarrhoea events resolved. Most (85%) events required no interruption, dose adjustment or discontinuation of treatment Diarrhoea infrequently led to withdrawal of Tyverb (2%) Patients who required intervention responded to standard anti-diarrhoeal medications (e.g. loperamide). In more severe cases, management included hydration and use of antibiotics Crown JP et al. Breast Cancer Res Treat 2008

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21 5 steps for managing diarrhoea 1. TELL SOMEONE 2. DRINK PLENTY OF CLEAR FLUIDS 3. LOPERAMIDE

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24 5 steps for managing diarrhoea 1. TELL SOMEONE 2. DRINK PLENTY OF CLEAR FLUIDS 3. LOPERAMIDE 4. EAT THE RIGHT THINGS

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27 5 steps for managing diarrhoea 1. TELL SOMEONE 2. DRINK PLENTY OF CLEAR FLUIDS 3. LOPERAMIDE 4. EAT THE RIGHT THINGS 5. ASSESS YOUR DIARRHOEA

28 Questions your patient may ask What should I do if I get diarrhoea whilst taking Tyverb? Answers: If diarrhoea occurs it usually happens during the first week or so but can happen at any time during treatment It is usually mild or moderate, but can be severe in some cases Most people with diarrhoea should be able to continue their treatment with Tyverb with appropriate management If experiencing diarrhoea or a change in your normal bowel pattern, inform the cancer unit

29 Management of Skin Rash associated with Tyverb

30 Pooled analysis of skin events associated with Tyverb... Among Tyverb-treated patients across nine clinical trials (n= 1417): Skin events were reported in 70% with Tyverb + capecitabine The majority of events were of low-grade severity (Grade 1 or 2) No Grade 4 events Events tend to present early in the course of treatment Days 1 14 are usually self-limiting (median duration 29 days) Presentation of rash is variable Dermatitis is the predominant event Pruritus / urticaria (3%), hair disorder (3%) and nail disorders/infection (< 1%) are infrequent Distribution of events is mostly on the trunk ; however facial rash may occur Majority (88%) did not require Tyverb dose adjustment or treatment interruption 1% discontinued therapy Lacouture ME et al. Breast Cancer Res Treat 2008

31 Examples of skin events associated with Tyverb Grade 1 Grade 3 Grade 2 Lacouture ME et al. Breast Cancer Res Treat 2008

32 Management of rash... There are no clear evidence-based treatment options for skin rashes or other skin reactions associated with Tyverb 1 Mild to moderate skin events are most often seen in first 14 days of Tyverb treatment, usually self-limiting, lasting on average 29 days 2 The most commonly seen rash is a acneiform rash on the upper body, which may include the face and/or scalp 2 Patients should receive a skin examination prior to starting Tyverb treatment and at regular intervals thereafter 1. Moy B & Goss PE. The Oncologist Lacouture ME et al. Breast Cancer Res Treat 2008

33 Management of rash Patients experiencing skin events should: - Avoid sunlight - Apply a suncream (SPF 30) - Have full body examinations until one month after resolution Interruption of Tyverb treatment should be considered for skin events with associated pruritus, desquamation or vesicular eruption in addition to macular/papular eruption or erythema Pharmacological intervention is at the clinician s discretion (e.g., oral or topical antibiotics, topical corticosteroids) In severe cases, referral to a dermatologist is recommended Moy B & Goss PE. The Oncologist 2007

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35 Questions your patient may ask What should I do if I get a rash while taking Tyverb? Answers: Rash is a very common side-effect of taking Tyverb It usually develops within the first 2 weeks of treatment The rash will usually improve or disappear after a few weeks Most people who develop a rash are able to continue their treatment with Tyverb If a rash develops, or if your skin feels dry, itchy or painful, inform your doctor or nurse

36 Tyverb cardiac side-effect profile

37 Decreased Left Ventricular Ejection Fraction (LVEF)... Across all clinical studies, LVEF decreases have been reported in approximately 1% of patients receiving Tyverb and were asymptomatic in more than 90% of cases Symptomatic LVEF decreases have been observed in approximately 0.2% of patients who received Tyverb as monotherapy or in combination with other anti-cancer agents Observed symptoms have included dyspnoea, cardiac failure and palpitations. Overall 58% of symptomatic subjects recovered Tyverb Summary of Product Characteristics May 2011

38 Decreased LVEF In the pivotal trial of Tyverb in combination with capecitabine versus capecitabine alone, LVEF decreases were reported in 2.5% of patients who received Tyverb in combination with capecitabine, compared to 1.0% with capecitabine alone In the pivotal trial of Tyverb in combination with letrozole versus letrozole alone, LVEF decreases were reported in 3.1% of patients in the Tyverb plus letrozole group, compared to 1.3% in patients receiving letrozole alone Tyverb Summary of Product Characteristics May 2011

39 LVEF monitoring LVEF should be assessed by an echocardiogram (ECHO) or multigated acquistion (MUGA) scan in all patients before starting Tyverb treatment to check that their baseline LVEF is within institutional limits of normal 1 LVEF should also be monitored during treatment to ensure that it does not fall to an unacceptable level 1 Subsequent cardiac examinations should be performed using the same method as the baseline examination There is no specific recommendation as to how frequently LVEF should be assessed, but every few months would seem prudent 2 1. Tyverb Summary of Product Characteristics May Moy B & Goss PE. The Oncologist 2007

40 Recommendations for management of decreased LVEF Interrupt Tyverb if symptoms associated with decreased LVEF are NCI CTCAE > Grade 3 and/or if LVEF drops below LLN Restart Tyverb at a reduced dose (1000mg/day) after > 2 weeks if LVEF recovers to normal and symptoms resolve Monitor LVEF regularly after re-challenge If symptoms recur, discontinue treatment permanently LLN = Institution s Lower Limit of Normal Tyverb Summary of Product Characteristics May 2011

41 Hepatobiliary Events

42 Hepatobiliary events associated with Tyverb treatment Hepatobiliary events are a recognised class effect of tyrosine kinase inhibitors e.g. erlotinib, imatinib 1,2 Adverse liver events also reported with capecitabine treatment 3 Hepatobiliary events have been observed during Tyverb treatment 4 Mainly elevated liver enzymes and/or bilirubin levels Commonly reported with Tyverb plus capecitabine ( 1/100 to < 1/10) 4 Generally returned to normal on stopping treatment 1. Tarceva Summary of Product Characteristics; 2. Glivec Summary of Product Characteristics; 3. Xeloda Summary of Product Characteristics; 4. Tyverb Summary of Product Characteristics May 2011

43 Management of hepatobiliary events associated with Tyverb Liver function should be monitored AST/ALT, alkaline phosphatase, bilirubin Before initiation of treatment Monthly thereafter, or as clinically indicated Discontinue Tyverb if changes in liver function are severe and do not re-treat Use Tyverb with caution in patients with moderate or severe hepatic impairment Insufficient data to provide a dose adjustment recommendation Tyverb Summary of Product Characteristics May 2011

44 Other useful information in A step-by-step guide to your treatment 8 week treatment guide pg 24 Fridge magnet and food lists pg 34 Recipe cards/shopping lists pg 40

45 Summary Lapatinib, an oral targeted therapy, in combination with: - capecitabine or - an aromatase inhibitor has a predictable and manageable side effect profile Diarrhoea and rash are amongst the most frequent adverse events Prompt diagnosis and management of side effects is important Patient education plays a major role in the prevention and early detection of side effects To have clear guidelines in place is critical

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48 Diarrhoea Associated with Lapatinib Treatment Management Guidelines EVALUATION Obtain history of onset and duration of diarrhoea Describe number of stool as composition (e.g. watery, contain blood) Assess for fever, dizziness, abdominal cramping to rule out risk for sepsis, bowel obstruction and dehydration Dietary profile Uncomplicated grade 1-2, MANAGEMENT Dietary modifications (stop all lactose-containing products; eat small meals) Hydration (drink 8-10 large glasses of clear liquids [Gatorade, broth] per day For grade 2 diarrhoea: Consider withholding lapatinib and other cytotoxic treatment Consider lapatinib dose reduction TREATMENT Administer standard loperamide dosing (especially in high-risk patients) 4 mg initially, then 2 mg every 4 h or after every unformed stool Re-assess 24 hrs later Symptoms persist Complicated grade 3-4 or grade 1-2 with complicating features (cramping, nausea/ vomiting grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding and/or dehydration) MANAGEMENT Hospitalisation for patients at risk for life-threatening complications (i.e. with GI syndrome) Patient must call physician immediately for any complicated, severe diarrhoea event Discontinue lapatinib and other cytotoxic treatment Hydration (intravenous fluids as needed); for severe dehydration administer octreotide TREATMENT Initiate loperamide immediately 4 mg initially, then 2 mg every 2 h or after every unformed stool Administer antibiotics as needed (especially if there is fever or grade 3-4 neutropenia or symptoms persist >24 hrs) DIARRHOEA RESOLVING Continue instruction for dietary modification Gradually add solid foods to diet Discontinue loperamide treatment after 12-hr diarrhoea-free interval DIARRHOEA UNRESOLVED Administer loperamide 2 mg every 2 hrs plus oral antibiotics Re-assess 24 hrs later DIARRHOEA UNRESOLVED Start second-line agents* (octreotide, budesonide or tincture of opium) DIARRHOEA-FREE FOR 24 HRS Discontinue intervention Consider re-introducing lapatinib (and other cytotoxic therapy) at reduced dose) Guidelines developed by GSK based on Benson et al. J Clin Oncol 2004; 22: *unlicensed agents for this indication

49 NCI CTC grading: Rash Grade Rash 1 Macular or papular eruption or erythema without associated symptoms 2 Macular or papular eruption or erythema + itching / other associated symptoms. Local desquamation. Covering <50% BSA 3 Severe. Confluent lesions, or vesicular eruption; desquamation covering >50% BSA 4 Generalised rash, deep ulcerations, exfoliative or bullous dermatitis 5 Death National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0,