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Optimising Care for Patients on SUTENT® (Sunitinib Malate) in Metastatic Renal Cell Carcinoma Pocket guide to managing side effects in first-line SUTENT® treatment of patients with metastatic renal cell carcinoma

Make the Everyday Matter

SUR416 Date of preparation: August 2015 Prescribing information can be found at the end of the document

For more information on the use of Pfizer products in the treatment of advanced RCC, please visit www.renaloncology.comThis site is intended for UK Healthcare Professionals only

April 30

Select a tab to learn more about the prevention, assessment and treatment of each side effect associated with SUTENT®

ContentsStomatitis is an inflammation of the mucous lining of any of the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth3Stomatitis

Hand–foot skin reactions are characterised by red, swollen and painful skin (sometimes with blisters, cracks and/or peeling) and can include palmar–plantar erythema and acral erythema2Hand–foot skin reactions

Cardiovascular side effects during SUTENT® treatment include decreases in left ventricular ejection fraction, heart failure, prolonged QT interval, arrhythmias and hypertension2

Cardiovascular side effects and hypertension

Gastrointestinal side effects associated with SUTENT® therapy include acid indigestion, nausea, bloating, constipation, diarrhoea, sore mouth, vomiting and flatulence1–3

Gastrointestinal side effects

Blood disorders/dyscrasias are characterised by neutropaenia, thrombocytopaenia, anaemia and leukopaenia2Blood disorders/dyscrasias

Fatigue is very common with SUTENT® treatment and can be signalled by changes in patient activities and attention on the phone or in the clinic2. Hypothyroidism can be characterised by symptoms of fatigue, swelling around the eyes, dry skin, shortness of breath and feeling cold2

Fatigue and hypothyroidism

Skin and hair changes include hand–foot skin reactions, rash, dry skin, nail modifications, and skin and hair discolouration/depigmentation2Skin and hair changes

This quick-reference pocket guide has been designed to assist in the therapy management of patients with advanced and/or metastatic renal cell carcinoma (RCC) who are treated with SUTENT®.

Together with patient education, measures to prevent and manage side effects associated with SUTENT® therapy are critical for effective disease management. These measures may reduce the need for dose reductions, delays, interruptions or early treatment discontinuations, and thereby optimise clinical benefit from SUTENT® therapy1.

This guide provides advice to support the treating healthcare professional team for the prevention, identification and treatment of key side effects associated with SUTENT®, with the aim of preventing or reducing their severity and improving treatment tolerability.

Please see the Summary of Product Characteristics for full safety information2.

MANAGING STOMATITIS

Stomatitis

WHAT IS IT?• An inflammation of the mucous lining of any of

the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth3

• Distinct from chemotherapy-related stomatitis; the signs are less obvious, but the symptoms are pronounced and appear to extend through the gastrointestinal tract4

• 2.7% of patients experienced Grade 3/4 stomatitis in SUTENT® clinical trials2

• Typically manifests early, within days/weeks of initiating treatment5

• Often resolves during the 2-week break between cycles, although tends to recur in subsequent cycles5,6

PREVENTION• Before starting SUTENT® therapy, help

patients to minimise risk/severity of stomatitis by encouraging4,6:

– Good oral hygiene, including regular visits to the dentist

– Dietary modifications, such as4–6:

º Avoid hot foods

º Avoid spicy foods

º Avoid acidic foods and alcohol

º Eat little and often

º Drink cool liquids, and keep fluid intake high

SIGNS AND SYMPTOMS• Damage to the mouth area, such as bleeding

gums and mouth ulcers4,5

• General sensitivity in the mouth, which feels sore, or alterations to taste6

• Experiencing pain, particularly when eating or brushing teeth5

ASSESSMENT• Confirm the presence of stomatitis

• Take a full history to check concomitant medications and assess/stabilise co-morbidities7

• Assess the severity of stomatitis and how its impact may differ from patient to patient (see Table 1)8

DOSAGE• Oral changes are reversible and do not

usually require treatment discontinuation (see Table 2)5

• However, progression to Grade 3/4 stomatitis requires dose reduction or treatment interruption4,9

TREATMENT• In addition to preventative measures, encourage

patients to4,6:

– Use baby toothpaste and brushes– Use bicarbonate-based mouthwashes,

e.g. manuka honey or sodium bicarbonate in water (commercial mouthwashes are often too astringent)

– Use lip creams/balms– Eat soft foods that are at room temperature– Consider super-cooled items that may relieve

symptoms, such as frozen pineapple chunks– Eat with a spoon rather than a fork; drink using

a straw• Patients may also need4,6:

– Aspirin mouthwash (mucilage) as local analgesic (do not swallow; contraindicated in patients who are haematologically compromised)

– ‘Magic’ mouthwash containing equal parts of 2% viscous lidocaine, diphenhydramine, and bismuth subsalicylate or aluminum/magnesium hydroxide

– Anti-inflammatories– Nystatin for oral thrush– Artificial saliva for dry mouth

QUESTIONS FOR YOUR PATIENTSDo you get more mouth ulcers than usual?

Inflammation of the oral cavity and mouth ulcers can be an indication of stomatitis or other oral changes

Is your mouth sore or painful?Patients may experience pain, but lack physical signs of functional stomatitis

Does it hurt when you eat certain foods?Encourage your patients to avoid hot, spicy foods and alcohol

Do your gums bleed when you brush your teeth?Encourage your patients to use gentle toothbrushes and sodium bicarbonate-based mouthwashes

TABLE 1: GRADING STOMATITIS8

Grade Characteristics

1Asymptomatic or mild symptoms; intervention not indicated

2Moderate pain; not interfering with oral intake; modified diet indicated

3 Severe pain; interfering with oral intake

4Life-threatening consequences; urgent intervention indicated

TABLE 2: PATIENT MANAGEMENT STRATEGIES FOR STOMATITIS4,9

Grade Strategy

1

Continue at same dose level• Modify diet• Use baby toothbrushes and sodium

bicarbonate mouthwashes• Treatment for mouth ulcers• Anti-inflammatories• Aspirin mucilage• Frozen pineapple chunks

2

Continue at same dose level• Modify diet• Use baby toothbrushes and sodium

bicarbonate mouthwashes• Treatment for mouth ulcers• Anti-inflammatories• Aspirin mucilage• Frozen pineapple chunks

3 Reduce dose or interrupt treatment

4 Reduce dose or interrupt treatment

STOMATITISSTOMATITIS STOMATITISSTOMATITIS

MANAGING HAND–FOOT SKIN REACTIONS

Hand–foot skin reactions

WHAT ARE THEY?• Include palmar–plantar erythema or

acral erythema2,4,6,7

• Very common with SUTENT® therapy, typically occurs early (Cycle 1/2) and is distinct from chemotherapy-related hand–foot skin reactions; lesions are more localised and hyperkeratotic6

• Often mild to moderate, but can be debilitating (7.7% Grade 3/4 in SUTENT® clinical trials)2

• More pronounced on the feet of active people and in hot climates4

• Uncomfortable and can impair daily activities

• Preventable if patients are adequately educated and easily treated if reported early

PREVENTION• Before starting SUTENT® therapy, help patients to

minimise risk/severity of hand–foot skin reactions; encourage them to4,10:

– Take good care of their skin; wash gently with baby soaps and shampoos, and regularly apply moisturising emollients (available from chemists)

– Wear cotton or rubber gloves for housework, washing up, etc

– Keep skin cool– Keep feet bare or wear cotton socks and

comfortable shoes– Visit a chiropodist prior to beginning SUTENT®

therapy for a podiatry review and to remove calluses10

SIGNS AND SYMPTOMS• Hand–foot skin reactions usually occur on the

palms of hands and soles of feet, but may affect other areas

• Typically feet are more affected than hands

• Skin can become red, swollen and painful4,6,10 – sometimes with blisters, cracks and/or peeling4,6

• Hand–foot skin reactions are commonly preceded or accompanied by paraesthesia, tingling or numbness6,10

ASSESSMENT• Confirm the presence of hand–foot skin reactions

• Hand–foot skin reactions often occur in the first 2–4 weeks of SUTENT® therapy6,10

• Take a full history to check concomitant medications and assess/stabilise co-morbidities7

• Assess severity of hand–foot skin reactions; its impact may differ from patient to patient. Use the grading table to assess severity (see Table 3)8

QUESTIONS FOR YOUR PATIENTSHave you felt any tingling sensations?

Skin changes are often preceded by a tingling sensation in the hands and feetCan you hold a cup of tea? Is wearing shoes unbearable? What are your hand–foot skin reactions preventing you from doing?

It is important to assess the severity of hand–foot skin reactions for each individualAre you noticing any skin changes, such as change in colour, feel or sensation?

Encourage your patients to examine their skin regularly and discuss any changes or concerns that they have with you at clinic and by phone in between visits

Do you have any skin changes in other areas?Remember that skin changes may occur in areas of the body that patients may not want to immediately disclose

How does your hand–foot skin reaction affect your everyday life?The severity and impact of hand–foot skin reactions may differ from patient to patient

HAND–FOOT SKIN REACTIONSHAND–FOOT SKIN REACTIONS HAND–FOOT SKIN REACTIONSHAND–FOOT SKIN REACTIONS

TABLE 3: GRADING HAND–FOOT SKIN REACTIONS6

Grade Characteristics

1Minimal skin changes or dermatitis (e.g. erythema, oedema or hyperkeratosis) without pain

2Skin changes (e.g. peeling, blisters, bleeding, oedema or hyperkeratosis) with pain; limiting instrumental activities of daily living

3Severe skin changes (e.g. peeling, blisters, bleeding, oedema or hyperkeratosis) with pain; limiting self care activities of daily living

TREATMENT• Provide supporting advice to patients if they suffer

hand–foot skin reactions. Reinforce preventative advice (see prevention) and further encourage patients to4,6,10:

– Avoid/reduce activities that put a lot of pressure on the affected areas

– Wear loose, comfortable clothes and shoes, and use gel/soft insoles

– Avoid strong sunlight or extreme heat (including very hot baths)

– Protect tender areas, pressure points with padding, foam absorbents and shock absorbers10

• Relief from symptoms can be found using:

– Topical morphine combined with a petroleum jelly-based ointment for patients experiencing severe pain6

– Moisturising emollient creams and urea-based creams, especially for the feet

– Topical skin adhesives (medical superglue) applied to cracks and painful areas6

– Daily foots soak in lukewarm water with Epsom salts for 20–30 minutes10

CONTINUE

MANAGING CARDIOVASCULAR SIDE EFFECTS AND HYPERTENSION

DOSAGE• SUTENT® dose interruptions/reductions from the recommended 50 mg

daily dosing can be avoided or minimised using therapy management, helping patients to gain optimal benefit7

• Some patients may require a SUTENT® dose adjustment or treatment break based on severity of hand–foot skin reactions (see Table 4)4

– The severity of hand–foot skin reactions needs to be weighed up against the benefits of maintaining the recommended SUTENT® dosing schedule

• Once hand–foot skin reactions have resolved, consider re-initiating or re-establishing SUTENT® treatment at 50 mg daily7

• If a patient believed to have hand–foot skin reactions does not respond to dose interruption or dose reduction, then other diagnoses must be considered6

TABLE 4: MANAGEMENT STRATEGIES FOR HAND–FOOT SKIN REACTIONS11

Grade Strategy

1Continue at same dose levelTreat with emollient creams and encourage measures to avoid skin irritation

2Treat with emollient creams and encourage measures to avoid skin irritationConsider a SUTENT® dose reduction

3Consider a SUTENT® dose reduction or treatment break until Grade ≤1Resume treatment at reduced dose

HAND–FOOT SKIN REACTIONSHAND–FOOT SKIN REACTIONS

Cardiovascular side effects and

hypertension

CARDIOVASCULAR SIDE EFFECTS AND HYPERTENSIONCARDIOVASCULAR SIDE EFFECTS AND HYPERTENSION CARDIOVASCULAR SIDE EFFECTS AND HYPERTENSIONCARDIOVASCULAR SIDE EFFECTS AND HYPERTENSION

WHAT ARE THEY?CARDIOVASCULAR SIDE EFFECTS

• Decreases in left ventricular ejection fraction (LVEF) of greater than or equal to 20% and below the lower limit of normal – 2.1% of patients at all grades2

• Heart failure has been reported in mRCC clinical trials and in post-marketing experience2

• SUTENT® has the potential to prolong the QT interval2

• Arrhythmias – incidence <1% (e.g. bradycardia and Torsades de Pointes)2,5

• Cardiovascular side effects associated with SUTENT® are generally reversible on stopping treatment

HYPERTENSION

• Associated with SUTENT®, typically manifests early (within days/weeks of initiating treatment) and is usually mild to moderate (Grade 2/3)4

• Occurred in 28% of patients at all grades, in 7.1% of patients at Grade 3 and 0.2% of patients at Grade 4 in clinical trials with SUTENT®2

• Exact aetiology unknown when caused by SUTENT® treatment5,12

PREVENTION• Normalise pre-existing hypertension prior to

starting SUTENT® therapy2,13

• Close monitoring is recommended for patients with cardiac risk factors and/or history of coronary artery disease2

• Encourage patients to keep a diary of their blood pressure and report any signs of hypertension to staff13

• Before starting SUTENT® treatment, help patients to minimise risk/severity of cardiovascular side effects/hypertension – encourage them to:

– Exercise regularly12,13

– Control their weight12,13

– Consider a Mediterranean diet– Moderate their alcohol consumption12,13

– Reduce their salt intake to less than 2 g/day12

QUESTIONS FOR YOUR PATIENTSHave you taken your blood pressure this week?

Encourage your patients to monitor their blood pressure and keep a diary of their blood pressure readingsHave you felt short of breath, very tired or any swelling of the hands and feet since taking SUTENT®?

These symptoms may indicate a cardiovascular side effect and will require urgent attentionHave you had a persistent headache or felt any dizziness since taking SUTENT®?

These symptoms may indicate a cardiovascular side effect and will require urgent attention

SIGNS AND SYMPTOMSCARDIOVASCULAR SIDE EFFECTS

• Shortness of breath

• Extreme fatigue

• Swelling of the hands or feet

HYPERTENSION

• Persistent headache

• Dizziness

• Usually asymptomatic

Advise your patients to report any of the above signs and symptoms to you immediately. They should ring the clinic and not wait for their next hospital appointment.

ASSESSMENT• Conduct a full cardiovascular assessment, including baseline ECG and LVEF evaluation, and monitor

throughout treatment1,2,7,8,14,15

• Screen for hypertension, stabilise blood pressure and monitor throughout treatment1,7,14

• Blood pressure should be monitored weekly for the first 4 weeks and monthly thereafter, ideally by patients themselves or in primary care4

• Perform risk:benefit analysis based on cardiovascular risk factors/coronary artery disease history2

• Take a full history to check concomitant medications and assess or stabilise co-morbidities7

• Assess severity of hypertension – its impact may differ from patient to patient8 (see Table 5 for the grading criteria for hypertension)

TABLE 5: GRADING HYPERTENSION8

Grade Characteristics

1 Prehypertension (systolic BP 120–139 mmHg or diastolic BP 80–89 mmHg)

2Stage 1 hypertension (systolic BP 140–159 mmHg or diastolic BP 90–99 mmHg); medical intervention indicated; recurrent or persistent (≥24 hours); symptomatic increase by >20 mmHg (diastolic) or to >140/90 mmHg if previously within normal limit; monotherapy indicated

3Stage 2 hypertension (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg); medical intervention indicated; more than one drug or more intensive therapy than previously used/indicated

4Life-threatening consequences (e.g. malignant hypertension, transient or permanent neurologic deficit, hypertensive crisis); urgent intervention indicated

BP=blood pressure; ULN=upper limit of normalCONTINUE

TREATMENT• Reinforce preventative advice and further encourage patients to consider

non-pharmacological measures in the first instance (see prevention)12

• SUTENT® dose interruptions/reductions from the recommended 50 mg daily dosing can be avoided or minimised through careful SUTENT® therapy management thereby helping patients to gain optimal benefit7

• Some patients may require SUTENT® dose adjustment or treatment break based on severity of their cardiovascular side effects/hypertension (see Table 6)2,5,14

• The severity of the cardiovascular side effects/hypertension needs to be weighed up against the benefits of maintaining the recommended SUTENT® dosing schedule

CARDIOVASCULAR SIDE EFFECTS

• Interrupt/reduce SUTENT® dose in patients with clinical evidence of chronic heart failure if LVEF <50% and >20% below baseline1,2

HYPERTENSION

• Temporarily suspend SUTENT® in patients with severe uncontrolled hypertension that is not controlled with medical management; treatment may resume once hypertension is controlled2,7

• If prescribed, antihypertensive treatment may need to be reduced during off-treatment periods and stopped altogether when not taking SUTENT®, to prevent postural hypotension4

TABLE 6: MANAGEMENT STRATEGIES FOR CARDIAC TOXICITY5

Grade Strategy

1 Continue at same dose level

2

Continue at same dose level, except in the event of:• Asymptomatic decrease in LVEF by an absolute value of 20% and below lower limit of normalOR• Non-urgent ventricular paroxysmal dysrhythmia requiring intervention interrupt SUTENT® therapy until

Grade ≤1 THEN resume at –1 dose level

3Interrupt SUTENT® therapy until Grade ≤1 or return to baseline Resume at –1 dose level

4 Discontinue

MANAGING GASTROINTESTINAL SIDE EFFECTS

CARDIOVASCULAR SIDE EFFECTS AND HYPERTENSIONCARDIOVASCULAR SIDE EFFECTS AND HYPERTENSION

Gastrointestinal side effects

GASTROINTESTINAL SIDE EFFECTSGASTROINTESTINAL SIDE EFFECTS GASTROINTESTINAL SIDE EFFECTSGASTROINTESTINAL SIDE EFFECTS

WHAT ARE THEY?• Gastrointestinal side effects include2,4,6,12: – Acid indigestion – Bloating – Constipation – Diarrhoea – Nausea – Sore mouth – Vomiting – Flatulence – Anal/rectal discomfort – Haemorrhoids – Swallowing difficulties – Bleeding of the mouth and rectum DIARRHOEA• Occurred in 52.4% of patients in SUTENT®

clinical trials2

– Grade 3 was observed in 6.0% of cases and Grade 4 was observed in 0.2% of cases2

• Occurs irregularly and is distinct from chemotherapy-related diarrhoea (which is usually continuous)6

• Usually resolves quickly in the 2-week break between cycles6

NAUSEA AND VOMITING2

• 34.0% of patients experience vomiting at all Grades, 4% experience Grade 3; 0.2% experience Grade 4

• 42.7% of patients experience nausea at all Grades, 3.5% experience Grade 3; 0.1% experience Grade 4

OTHER GASTROINTESTINAL DISORDERS2

• Any grade oral mucositis/stomatitis and painful tongue sensation (glossodynia) occurred in 28.3% and 6.0% of patients, respectively

• Any grade dyspepsia, abdominal pain and constipation occurred in 22.0, 30.4 and 23.2% of patients, respectively

PREVENTION• Before starting SUTENT® therapy, help patients to

minimise the risk and severity of gastrointestinal side effects by encouraging them to:

– Adjust their diet – bananas, rice, grated apple and toast can increase stool consistency12,13

– Anti-emetics can be given prophylactically before administration of SUTENT® to limit treatment-related nausea and vomiting6

– Follow advice from a dietician about calorie intake before and while taking SUTENT®7

• Avoid grapefruit or its juice since these will increase plasma concentrations of SUTENT®2

SIGNS AND SYMPTOMS• Loss of appetite, generally caused by altered

taste, tender mouth or indigestion is very common4

– Symptoms generally resolves after a week off treatment4

• Weight loss has been reported in 9.9% of patients taking SUTENT®2 and can be treatment-limiting4

QUESTIONS FOR YOUR PATIENTSHave you suffered from a loss of appetite since starting treatment?

This may be due to a variety of reasons, such as nausea, taste changes and pain while eating

Have you experienced any increase in indigestion, diarrhoea, constipation or flatulence since starting treatment?

Changes in bowel movements are very common with SUTENT®, but symptoms are usually mild to moderate

Have you felt nauseous or been sick since starting treatment?Discuss other possible reasons for nausea or vomiting, as well as a side effect of SUTENT® therapy

ASSESSMENT• Confirm the presence of gastrointestinal symptoms

• Take a full history to check concomitant medications and assess/stabilise co-morbidities7

• Assess severity of gastrointestinal symptoms since their impact may differ from patient to patient (see Table 7)

TREATMENT• Patients should be made aware that both diarrhoea and

constipation are associated with SUTENT®

• Patient education regarding nutrition and consultation with a dietician is recommended6

• SUTENT® dose interruptions/reductions from the recommended 50 mg daily dosing can be avoided or minimised using therapy management, helping patients to gain optimal benefit (see Table 8 for advice on diarrhoea)6

• Provide supporting advice to patients if they suffer gastrointestinal side effects and reinforce preventative advice

NAUSEA AND VOMITING4,6

• Encourage patients to:

– Use common anti-emetics to relieve nausea and vomiting

– Eat small, more frequent meals if nauseated• Lack of appetite because of altered taste, tender mouth

(avoid hot or cold temperatures; drinks preferably at room temperature for sore mouth) or indigestion is very common, but generally resolves after a week off treatment

• Nausea is not usually experienced after the first few treatment cycles

TABLE 7: GRADING DIARRHOEA, NAUSEA AND VOMITING8

Grade Diarrhoea Nausea Vomiting

1Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline

Loss of appetite without alteration in eating habits

1–2 episodes (separated by 5 minutes) in 24 hours

2

Increase of 4–6 stools per day over baseline; moderate increase in ostomy output compared to baseline

Oral intake decreased without significant weight loss, dehydration or malnutrition

3–5 episodes (separated by 5 minutes) in 24 hours

3

Increase of ≥7 stools per day over baseline; incontinence; hospitalisation indicated; severe increase in ostomy output compared to baseline; limiting self care activities of daily living

Inadequate oral caloric or fluid intake; tube feeding, total parenteral nutrition or hospitalisation indicated

≥6 episodes (separated by 5 minutes) in 24 hours; tube feeding, total parenteral nutrition or hospitalisation indicated

4Life-threatening consequences; urgent intervention indicated

- Life-threatening consequences; urgent intervention indicated

CONTINUE

DIARRHOEA4,6

• Encourage patients to:– Temporarily discontinue the use of stool softeners or fibre supplements,

as required – Eat and drink often in small amounts– Drink plenty of liquids (approx. 2–2.5 L/day, in small amounts at a time)

and avoid drinking fluids with meals and for 1 hour after meals– Avoid spicy, high-fibre and fatty foods, and caffeine– Use anti-diarrhoeal treatments (e.g. loperamide), as required– Eat live yoghurt and other acidophilus products– Keep a diary to help monitor their bowel movements and highlight any

factors that may make symptoms worse– Apply barrier creams (e.g. Sudocrem, Drapolene, Vaseline, aloe vera)– Use local analgesia (e.g. lignocaine gel)

• Resolves quickly in the 2-week treatment break

OTHER GASTROINTESTINAL DISORDER• Oral mucositis/stomatitis and burning tongue sensation:

– Take plenty of fluids; use children’s or cheap toothpaste with no additives; and avoid salty, spicy, too hot or too cold foods and drink4,6 (see section on stomatitis for more information)

• Dyspepsia:

– Peppermint and antacids, according to local prescribing policy

• Abdominal pain:

– Analgesia and antispasmodics

• Constipation:

– Fluids, diet, exercise and mild laxatives

TABLE 8: MANAGEMENT STRATEGIES FOR DIARRHOEA6

Grade Strategy

1*Continue at same dose levelOral hydration in small amounts at a time + anti-diarrhoeal medications

2*Continue at same dose level Oral hydration in small amounts at a time + anti-diarrhoeal medications

3Interrupt SUTENT® therapy until Grade ≤1Resume SUTENT® dose at –1 dose level (12.5 mg) in subsequent cycles in cases of Grade 3 or 4 diarrhoea5

4Interrupt SUTENT® therapy until Grade ≤1Resume SUTENT® dose at –1 dose level (12.5 mg) in subsequent cycles in cases of Grade 3 or 4 diarrhoea5

MANAGING BLOOD DISORDERS/DYSCRASIAS

GASTROINTESTINAL SIDE EFFECTSGASTROINTESTINAL SIDE EFFECTS

* Dose reductions are rarely necessary for Grade 1 and 2 toxicity2

Blood disorders/dyscrasias

BLOOD DISORDERS/DYSCRASIASBLOOD DISORDERS/DYSCRASIAS BLOOD DISORDERS/DYSCRASIASBLOOD DISORDERS/DYSCRASIAS

WHAT ARE THEY?• Blood disorders/dyscrasias such as neutropaenia,

thrombocytopaenia, anaemia and leukopaenia have been associated with SUTENT® treatment2

NEUTROPAENIA AND THROMBOCYTOPAENIA

• Occurred at all grades in 17.2% (neutropaenia) and 22.0% (thrombocytopaenia) of patients receiving in SUTENT® clinical trials2

– Grade 4 neutropaenia and thrombocytopaenia occurred in 0.6 and 1.6% of patients, respectively

• Typically manifest early, during the first treatment cycle, without progression during later cycles7,16

• SUTENT®-induced neutropaenia and thrombocytopaenia usually resolve during the 2-week treatment break5,7,16

ANAEMIA

• Anaemia occurred at all grades in 23.9% of patients receiving SUTENT® in clinical trials2

– Grade 4 anaemia occurred in 1.4% of patients

LEUKOPAENIA

• Leukopaenia occurred at all grades in 10.2% of patients receiving SUTENT® in clinical trials2

– Grade 4 leukopaenia was seen in 0.1% of patients

PREVENTION• Before starting SUTENT®, advise patients on:

– The importance of good hygiene and diet7

– Basic guidelines to minimise the risk of infection (e.g. washing hands)5

SIGNS AND SYMPTOMS• Signs of infection/elevated temperature

• Bruising (thrombocytopaenia)

• Fatigue, pale skin (anaemia)

ASSESSMENT• Carry out a complete blood count to assess for blood

disorders and abnormal blood counts2,16

– This should be performed before initiating SUTENT® and at the start of each treatment cycle2,16

• Full blood count monitoring is recommended every 3 weeks, work with GP to carry out blood counts locally

• Take a full history to check concomitant medications (such as NSAIDs that may increase bleeding risk) and assess or stabilise co-morbidities7

• Assess severity of blood disorders – the impact may differ from patient to patient (see Table 9 and 10 for grading and management recommendations)

TREATMENT• Provide supporting advice to patients with blood disorders

NEUTROPAENIA

• Typically, the neutropaenia associated with SUTENT® treatment requires no intervention – blood counts tend to recover during the 2-week treatment break between cycles5,6

ANAEMIA

• Grade 3/4 anaemia usually does not require dose modification6

• Anaemia can be treated with iron supplementation or blood transfusions if severe or life threatening5, however, erythropoietin-stimulating agents should be used with caution owing to potential risks and toxicities associated with these drugs6

QUESTIONS FOR YOUR PATIENTSHave you felt ill or had a temperature recently?

Any incidence of temperature over 38°C and other signs of infection may indicate underlying neutropaenia

Are you bruising more easily or having more nosebleeds than normal?This may indicate thrombocytopaenia

Have you been very tired recently, any breathlessness, faster heart rate than normal, rushing sounds in the ears, feeling faint, headaches or pallor?

These symptoms may indicate anaemia

How do the blood disorders affect your everyday life?The severity of symptoms and the impact may differ from patient to patient

TABLE 9: GRADING NEUTROPAENIA AND ANAEMIA

Grade Neutropaenia17 Anaemia8

1 ANC ≥1.5 to <2 x 109/L Hb <LLN 10.0 g/dLHb <LLN 6.2 mmol/LHb <LLN 100 g/L

2 ANC ≥1.0 to <1.5 x 109/L Hb <10.0–8.0 g/dLHb <6.2–4.9 mmol/LHb <100–80 g/L

3 ANC ≥0.5 to <1.0 x 109/L Hb <8.0 g/dLHb <4.9 mmol/LHb <80 g/L

4 ANC <0.5 x 109/LLife-threatening consequences;urgent intervention indicated

TABLE 10: MANAGEMENT STRATEGIES FOR BLOOD DISORDERS/DYSCRASIAS5,6

Grade Strategy

1 Continue at same dose level

2 Continue at same dose level

3Withhold dose When Grade ≤2, resume treatment at original dose*

4Withhold dose When Grade ≤2, resume treatment at –1 dose level*

ANC=absolute neutrophil count; Hb=haemoglobin; LLN=lower limit of normal

*Recurring Grade 3/4 neutropaenia or thrombocytopaenia persisting for at least 5 days and/or neutropaenic fever/bleeding signs may require dose/schedule changes6

MANAGING FATIGUE AND HYPOTHYROIDISM

Fatigue and hypothyroidism

FATIGUE AND HYPOTHYROIDISMFATIGUE AND HYPOTHYROIDISM FATIGUE AND HYPOTHYROIDISMFATIGUE AND HYPOTHYROIDISM

WHAT ARE THEY?FATIGUE

• Is very common with SUTENT® treatment, affecting 66.7% of patients in SUTENT® clinical trials2

• Is usually not troublesome to patients, but it can reduce their quality of life12,16

• 18.2% Grade 3/4 treatment-related fatigue in SUTENT® clinical trials2

• Typically manifests early, within days or weeks of SUTENT® treatment initiation16

• May be transient, resolving as the patient responds to treatment12

• Is often related to both the disease and psychosomatic factors related to disease, as well as SUTENT®4,16

• Can be a treatment effect since SUTENT® can cause hypothyroidism or anaemia2, which results in fatigue18

HYPOTHYROIDISM

• Is also very common with SUTENT® treatment (12.5% incidence; all Grades)2 and may be the underlying cause of the fatigue18

• Is often under-diagnosed4

• Typically takes time to manifest (usually months), although occasionally the time to onset can be within weeks of SUTENT® treatment initiation4,6

• Is generally manageable4

SIGNS AND SYMPTOMSFATIGUE

• Changes in your patients’ activities and attention on the phone or in the clinic4

• Check for underlying factors that may affect the level of fatigue; for example, hypothyroidism, anaemia, depression, dehydration, poor diet, lack of exercise, pain, insomnia, chronic illness and appetite4,16

HYPOTHYROIDISM

• Symptoms of hypothyroidism include4:

– Fatigue– Swelling around the eyes– Dry skin– Shortness of breath– Feeling cold

• Several of these symptoms can also be independent side effects of SUTENT® therapy

ASSESSMENT• Confirm the presence of fatigue and/or hypothyroidism

• Take a full history to check concomitant medications and assess/stabilise co-morbidities7

• In Cycles 1–3, monitor for impact of fatigue on quality of life16

• Every 2–3 cycles check for anaemia, depression and hypothyroidism; treat as appropriate16

• Encourage patients to rate their fatigue on a numeric scale, where 0=‘no fatigue’ and 10=‘worst fatigue imaginable’

• Thyroid profile should be measured at baseline on Day 1 of each cycle, for 4 cycles, and every 3 months thereafter (see Figure)6

PREVENTION• Identify and resolve underlying factors that may

affect the level of fatigue4:– Haemoglobin levels– Thyroid function– Pain control

• Assess baseline thyroid function/manage before treatment initiation2

• Advise patients that they may feel tired once SUTENT® therapy begins4

• In order to minimise the impact of fatigue, advice on lifestyle modification can help; patients should4,6: – Take short naps or breaks when necessary– Try not to do too much, particularly between treatment cycles– Accept help from others– Take regular light exercise– Try to maintain a normal sleep pattern– Use relaxation techniques; read a book or listen to music– Make use of treatment breaks

QUESTIONS FOR YOUR PATIENTSHave you been feeling more tired than usual since you started taking SUTENT®?

It is important to have educated your patient to tell you as soon as a side effect, like fatigue, becomes troublesome so that the most appropriate supportive care can be promptly provided

Do you do any exercise?Light physical exercise may reduce fatigue levels and help your patient get a better night’s sleep

At what time of the day do you take SUTENT®?Some patients cope better if they take SUTENT® in the evening, while others have difficulty sleeping after a

night-time dose. There is no ‘correct’ time, but once a pattern has been established, medication should be taken at roughly the same time every day

How does your fatigue and/or hypothyroidism affect your everyday life?The severity and impact of fatigue/hypothyroidism may differ from patient to patient

FIGURE: RECOMMENDATIONS FOR THYROID DYSFUNCTION MANAGEMENT6

Measure thyroid profile at baseline. During treatment measure thyroid profile on Day 1 of each cycle for 4 cycles. After Cycle 4, measure every 3 months

TSH with no symptoms

TSH with symptoms

Observe; no treatment Low T4 (overt symptomatic

hypothyroidism) Low T4

Fatigue only

Thyroid hormone replacement

Trial of thyroid hormone replacement; continue if beneficial. SUTENT® dose

modifications are rarely, if ever, required

TSH=thyroid-stimulating hormone; T4=thyroxineCONTINUE

TREATMENT• SUTENT® dose interruptions/reductions from the recommended 50 mg daily

dosing can be avoided or minimised using therapy management, helping patients to gain optimal benefit7

• Patients may require SUTENT® dose adjustment or treatment break based on severity of fatigue/hypothyroidism (see Table 116)

• Severity of the symptoms need to be weighed up against the benefits of maintaining the recommended SUTENT® dosing schedule

FATIGUE

• Determine if fatigue is disease- or drug-related6

• Alternative causes for fatigue should be ruled out; fatigue may be exacerbated by dehydration, hypercalcaemia, anaemia or depression6

• Reinforce preventative advice (see prevention for more tips) and further encourage patients to:

– Maintain normal work and social schedules, but to take breaks where necessary12,13

– Carry out light physical exercise in order to reduce fatigue levels and help to get to sleep4,12

• Identify and treat all fatigue-inducible factors to optimise quality of life (daily activities, comfort, associated pain, emotional distress, depression, and nutrition disorders)5,12

• Treat anaemia with iron supplementation5 or blood transfusions if severe or life threatening6; use of erythropoietin-stimulating agents is cautioned due to potential risks and side effects6

• Incidence of fatigue has been shown to reduce following subsequent treatment cycles6

HYPOTHYROIDISM

• Thyroid-stimulating hormone levels tends to improve during the 2-week treatment break

• Hypothyroidism can be managed with thyroid hormone replacement therapy4,5

TABLE 11: MANAGEMENT STRATEGIES FOR FATIGUE AND HYPOTHYROIDISM6

Grade Strategy

1 Continue at same dose level

2 Continue at same dose level

3Interrupt SUTENT® therapy until Grade ≤1 or return to baselineResume at same or –1 dose level

4Interrupt SUTENT® therapy until Grade ≤1 or return to baselineResume at same or –1 dose level or discontinue

MANAGING SKIN AND HAIR CHANGES

FATIGUE AND HYPOTHYROIDISMFATIGUE AND HYPOTHYROIDISM

Skin and hair changes

SKIN AND HAIR CHANGESSKIN AND HAIR CHANGES SKIN AND HAIR CHANGESSKIN AND HAIR CHANGES

WHAT ARE THEY?• Have been commonly reported in patients

receiving SUTENT®2

• Are reversible and generally mild or moderate in severity2; however, they can also have a physical and psychological impact on patients

• Include the following conditions2,6 (see Table 12 for more side effects and incidence)

– Hand–foot skin reactions (the most clinically significant)

– Rash

– Dry skin

– Nail modifications

– Skin and hair discolouration depigmentation

• Often occur within the first 6 weeks of treatment (typically in Weeks 3 and 4)6

• Are not physically harmful – the benefits of maintaining the optimal SUTENT® dosing schedule generally outweigh the inconvenience of these side effects

PREVENTION• Inform patients of the potential for reversible

depigmentation of the hair and skin

• Patients should avoid hot showers, use sun protection and wear loose-fitting cotton clothes6

• Before starting SUTENT® therapy, help patients to minimise risk/severity of skin and hair changes – encourage them to:

– Reduce pressure on skin areas7

– Take good care of their skin – wash gently with baby soaps and shampoos, and regularly apply moisturising emollients (available from chemists)

– Use anti-itch and anti-dandruff shampoos6, hydrocolloidal bandages, thick-soled shoes, local corticoid cream, vitamin A and urea creams7

SIGNS AND SYMPTOMS• Skin colour changes – a yellowish,

reversible discolouration2,6

• Hair depigmentation – growing hair may become grey or white during the course of treatment6,19

• Genital dermatitis – an erythematous, desquamative rash that can become erosive20

• Small subungual haemorrhages – small linear brown or black lines located under the distal portion of the nails19

ASSESSMENT• Take a full history to check concomitant

medications and assess/stabilise co-morbidities7

• Assess severity of the skin and hair changes since their impact may differ from patient to patient

• A bilirubin level may be required to distinguish between SUTENT®-induced skin discolouration and jaundice due to liver disease or biliary obstruction6

• Use a grading table to assess and make management recommendations – see Table 13 for grading rash8

TABLE 12: KEY TREATMENT-RELATED DERMATOLOGICAL ADVERSE EVENTS WITH SUTENT® IN CLINICAL TRIALS2

Adverse event All grades, % Grade 3, % Grade 4, %

Hand–foot skin reactions 27.9 7.7 0

Skin discolouration 24.8 0.2 0

Rash 22.4 1 0

Hair colour changes 12.1 0.1 0

Dry skin 11.3 0.1 0

Alopecia 7.9 0 0

Erythema 6.9 0.2 0

Pruritus 6.5 0 0

Skin exfoliation 5.2 0.2 0

Periorbital oedema 4.7 0 0

Dermatitis 3.6 0.5 0

Skin lesion 2.7 0.2 0

Skin reaction 2.5 0.2 0

Nail disorder 2.5 0 0

TABLE 13: GRADING FOR RASH8

Grade Characteristics

1Macules/papules covering <10% body surface area with or without symptoms (e.g. pruritus, burning, tightness)

2Macules/papules covering 10–30% body surface area with or without symptoms (e.g. pruritus, burning, tightness); limiting instrumental active daily living

3Macules/papules covering >30% body surface area with or without associated symptoms; limiting self care active daily living

QUESTIONS FOR YOUR PATIENTSHave you felt any tingling sensations?

Skin changes are often preceded by a tingling sensation in the hands and feetAre you noticing any skin or hair changes, such as change in colour, feel or sensation?Encourage your patients to examine their skin and hair regularly, and discuss any changes

or concerns that they have with you at clinic and by telephone in between visitsHow are you managing your skin and hair changes? Do they affect your everyday life?

The severity of the symptoms, and their physical and psychological impact may differ from patient to patientCONTINUE

TREATMENT• There are no known treatments for hair or skin discolouration and no

treatment is known or needed for subungual haemorrhages

• Provide supporting advice to patients if they suffer from skin and hair changes

• Patients with dry skin/rash4,6,12:

– Can benefit from moisturising creams and ointments, which are usually sufficient to alleviate skin dryness

– Should change to an odour-free soap or liquid shower gel

– Should reduce friction from clothes by wearing loose-fitting clothing

– If it worsens, prescription-strength emollients may be needed

– If affecting the scalp, should use an anti-dandruff shampoo to help relieve discomfort

• Patients with severe genital rash should be referred to a dermatologist who can prescribe an appropriate treatment after ruling out a yeast or bacterial infection

• The severity of the skin and hair changes need to be weighed up against the benefits of maintaining the recommended SUTENT® dosing schedule

SKIN AND HAIR CHANGESSKIN AND HAIR CHANGES

REFERENCES

1. Ravaud A. Ann Oncol 2009;20:i7–i12.

2. Pfizer Ltd. SUTENT®. Summary of Product Characteristics. Available at: www.medicines.org.uk/emc/

3. In a page. Signs and symptoms. Second edition. Eds. Kahan S, Miller R and Smith EG. Lippincott Williams and Wilkins. Philadelphia, PA.

4. Pyle L, et al. Cancer Nursing Pract 2008;7:42–47.

5. Kollmannsberger C, et al. Can Urol Assoc J 2007;1(2Suppl):S41–S54.

6. Kollmannsberger C, et al. Oncologist 2011;16:543–553.

7. Roigas J. Eur Urol Suppl 2008;7:593–600.

8. Common Terminology Criteria for Adverse events v4.03 (CTCAE). June 14, 2010. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. (Last accessed March 2013).

9. Guevremont C, et al. Curr Opin Support Palliat Care 2009;3:170–179.

10. Wood LS, et al. Commun Oncol 2010;7:23–29.

11. Lacouture ME, et al. Oncologist 2008;13:1001–1011.

12. Wood LS. Commun Oncol 2006;3:558–562.

13. Grünwald V, et al. World J Urol 2010;28:343–351.

14. Schmidinger M, et al. Cancer Invest 2010;28:856–864.

15. Ravaud A. Oncologist 2011;16(Suppl 2):32–44.

16. Négrier S, Ravaud A. Eur J Cancer Suppl 2007;5:S12–S19.

17. Crawford J, et al. Cancer 2004;100:228–237.

18. Torino F, et al. Nat Rev Clin Oncol 2009;6:219–228.

19. Robert C, et al. Lancet Oncol 2005;6:491–500.

20. Billemont B, et al. N Engl J Med 2008;359:975–976.

SUTENT® Capsules (sunitinib malate) - GIST, MRCC, PNETPRESCRIBING INFORMATION UKPlease refer to the Summary of Product Characteristics (SmPC) beforeprescribing SUTENT 12.5 mg, 25 mg or 50 mg.

Presentation: Hard gelatin capsules containing sunitinib malate equivalent to 12.5 mg, 25 mg and 50 mg sunitinib. Indications: For the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) in adults after failure of imatinib treatment due to resistance or intolerance; advanced and/or metastatic renal cell carcinoma (MRCC) in adults; unresectable or metastatic, well differentiated pancreatic neuroendocrine tumours (pNET) with disease progression in adults. Dosage: Therapy should be initiated by a physician experienced in the administration of anti-cancer agents. The recommended dose for GIST and MRCC is 50 mg taken orally, once daily, with or without food, for 4 consecutive weeks, followed by a 2-week rest period, to comprise a complete cycle of 6 weeks (4/2 schedule). For pNET: 37.5 mg taken orally once daily without a scheduled rest period. Dose modifications in 12.5 mg steps may be applied based on individual safety and tolerability. Dose interruption may be required based on individual safety and tolerability. Daily dose should not exceed 75 mg nor be decreased below 25 mg for GIST or MRCC, the maximum daily dose administered during the Phase 3 pNET study was 50 mg. The use of sunitinib in the paediatric population is not recommended. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: Co-administration of potent CYP3A4 inhibitors or inducers should be avoided if possible, or the dose of sunitinib altered, based on careful monitoring of tolerability. Skin discolouration, depigmentation of the hair or skin and rash affecting the palms of hands and soles of feet, may occur during treatment. Pyoderma gangrenosum, generally reversible after drug discontinuation, has been reported. Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM) and cases suggestive of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of SJS, TEN, or EM are present, sunitinib should be discontinued. If SJS or TEN is confirmed, treatment must not be restarted. Haemorrhagic events, most common being epistaxis, and some of which were fatal, have been reported. Serious, sometimes fatal gastrointestinal complications have occurred in patients with intra-abdominal malignancies. Hypertension was a very common adverse reaction reported in clinical trials. Patients should be screened for hypertension and this should be controlled as appropriate. Temporary suspension is recommended in patients with severe hypertension that is not controlled with medical management. Decreased absolute neutrophil and platelet counts occurred during clinical trials and complete blood counts should be performed at the beginning of each treatment cycle. Cardiovascular events, including CHF, cardiomyopathy and myocardial ischaemia and myocardial infarction, some of which were fatal, have been reported. Use with caution in patients who are at risk for, or have a history of such events. Closely monitor for clinical signs and symptoms of CHF and consider baseline and periodic evaluations of LVEF especially in patients with cardiac risk factors and/or history of coronary artery disease. If clinical manifestations of CHF present, discontinuation of sunitinib is recommended. The administration of sunitinib should be interrupted and/or dose reduced in patients without clinical evidence of CHF but who have a LVEF <50% and >20% below baseline. Sunitinib should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antiarrhythmics, or medicinal products that can prolong QT intervals, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Treatment-related venous thromboembolic events (VTE) have been reported. Arterial thromboembolic events

(ATE), sometimes fatal, have been reported including cerebrovascular accident, transient ischaemic attack, and cerebral infarction. Thrombotic microangiopathy (TMA), including thrombotic thrombocytopaenic purpura (TTP) and haemolytic uraemic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, has been reported with sunitinib as monotherapy and in combination with bevacizumab. Sunitinib therapy should be discontinued in patients who develop TMA and prompt treatment is required. Respiratory events have been reported. Baseline lab measurements and 3 monthly routine monitoring of thyroid function during treatment are required, including monitoring for signs and symptoms suggestive of thyroid dysfunction and patients treated as per standard medical practice. Cases of thyroiditis and hyperthyroidism, some followed by hypothyroidism have been uncommonly reported. Pancreatitis and serious pancreatic events, some with fatal outcome have been reported. Hepatotoxicity has been observed in patients treated with sunitinib. Monitor liver function tests at baseline during each cycle of treatment, and as clinically indicated. If symptoms of pancreatitis or hepatic failure are present, treatment with sunitinib should be discontinued and the patient provided with appropriate supportive care. Sunitinib treatment may be associated with cholecystitis, including acalculous and emphysematous cholecystitis. Some cases with fatal outcome have been reported. Cases of renal impairment, renal failure and/or acute renal failure, in some cases with fatal outcome, have been reported. Baseline urinalysis is recommended. Patients should be monitored for the development or worsening of proteinuria. Sunitinib should be discontinued in patients with nephrotic syndrome. If fistula formation occurs, treatment with sunitinib should be interrupted. Cases of impaired wound healing have been reported during sunitinib therapy and the decision to resume sunitinib therapy following a major surgical intervention should be based upon clinical judgement of recovery from surgery. Osteonecrosis of the jaw (ONJ) has been reported, the majority of cases occurred in patients who had received prior or concomitant treatment with IV bisphosphonates. Caution should therefore be exercised when sunitinib and IV bisphosphonates are used either simultaneously or sequentially. Prior to treatment with sunitinib either along with or subsequent to IV bisphosphonates, a dental examination and appropriate preventative dentistry should be considered. Invasive dental procedures are also an identified risk factor and should be avoided if possible. In case of angioedema due to hypersensitivity, treatment with sunitinib should be interrupted and medical care provided. Seizures with or without radiological evidence of brain metastases have been reported, including a few reports (<1%), some fatal, of seizures with radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS should be controlled with medical management, including control of hypertension as above and temporary suspension of sunitinib is recommended. Cases of Tumour Lysis Syndrome, some fatal, have been reported. Patients should be monitored closely and treated as indicated clinically and prophylactic hydration should be considered. Serious infections most commonly respiratory, urinary tract, skin infections and sepsis, with or without neutropaenia, including some with a fatal outcome, have been reported. Rare cases of necrotising fasciitis, including of the perineum, sometimes fatal, have been reported. Sunitinib therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated. During sunitinib treatment, decreases in blood glucose leading to loss of consciousness have been reported. In case of symptomatic hypoglycaemia, sunitinib should be temporarily interrupted. Blood glucose levels in diabetic patients should be checked regularly in order to assess if anti-diabetic drug dosage needs to be adjusted to minimize the risk of hypoglycaemia. Other interactions: None. Fertility, pregnancy and lactation: Sunitinib should be used during pregnancy only if the potential benefit to the mother justifies the potential

risk to the foetus and is not recommended during breast-feeding. Male and female fertility may be compromised during treatment with sunitinib. Driving and operating machinery: Patients should be advised that they may experience dizziness during treatment with sunitinib. Undesirable effects: The most important treatment-related serious adverse reactions associated with sunitinib, some fatal, are renal failure, heart failure, pulmonary embolism, gastrointestinal perforation and haemorrhages (e.g. respiratory tract, gastrointestinal, tumour, urinary tract, and brain haemorrhages). Very common adverse events are neutropaenia, thrombocytopaenia, anaemia, leukopenia, hypothyroidism, decreased appetite, insomnia, dizziness, headache, taste disturbance, hypertension, dyspnoea, epistaxis, cough, stomatitis, abdominal pain, vomiting, diarrhoea, dyspepsia, nausea, constipation, skin discolouration, palmar-plantar erythrodysaesthesia syndrome, rash, hair colour changes, dry skin, pain in extremity, arthralgia, back pain, mucosal inflammation, fatigue, oedema, pyrexia. Commonly reported adverse events are viral infections, respiratory infections, abscess, fungal infections, urinary tract infection, skin infections, sepsis, lymphopaenia, dehydration, hypoglycaemia, depression, neuropathy peripheral, paraesthesia, hypoaesthesia, hyperaesthesia, periorbital oedema, eyelid oedema, lacrimation increased, myocardial ischaemia, ejection fraction decreased, deep vein thrombosis, hot flush, flushing, pulmonary embolism, pleural effusion, haemoptysis, dyspnoea exertional, oropharyngeal pain, nasal congestion, nasal dryness, gastro-oesophageal reflux disease, dysphagia, gastrointestinal haemorrhage, oesophagitis, abdominal distension, abdominal discomfort, rectal haemorrhage, gingival bleeding, mouth ulceration, proctalgia, cheilitis, haemorrhoids, glossodynia, oral pain, dry mouth, flatulence, oral discomfort, eructation, skin exfoliation, skin reaction, eczema, blister, erythema, alopecia, acne, pruritus, skin hyperpigmentation, skin lesion, hyperkeratosis, dermatitis, nail disorder, myalgia, musculoskeletal pain, muscle spasms, muscular weakness, renal failure, renal failure acute, chromaturia, proteinuria, chest pain, pain, influenza like illness, chills, weight decreased, white blood cell count decreased, lipase increased, platelet count decreased, haemoglobin decreased, amylase increased, aspartate aminotransferase increased, alanine aminotransferase increased, blood creatinine increased, blood pressure increased, blood uric acid increased. Refer to SmPC for information on other adverse effects. Legal Category: POM. Basic NHS cost: Pack of 28, 12.5  mg capsules [EU/1/06/347/004] £784.70, Pack of 28, 25  mg capsules [EU/1/06/347/005] £1,569.40, Pack of 28, 50  mg capsules [EU/1/06/347/006] £3,138.80. Marketing Authorisation Holder: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom. Further Information is available on request from: Medical Information at Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS, UK. Tel +44 (0) 1304 616161

Last revised: June 2015Ref: ST 24_0

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Pfizer Medical

Information on 01304616161

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