What to Look For:

Hypertension is defined as:^7,8

• Systolic BP >140 mmHg and
• Diastolic BP >90 mmHg

Hypertension of all grades (as defined by NCI-CTCAE version 3.015) was reported in 40% of patients on INLYTA® in the Phase III AXIS study²

• Hypertension of Grade 3 or above was reported in 16% of patients²

Hypertension that develops while receiving INLYTA® has been proposed as a biomarker for the anti-tumour effects of INLYTA®⁶

The median onset time for hypertension was within the first month of initiating INLYTA® therapy¹

• BP elevations were observed as early as 4 days after starting INLYTA®.¹

Prevention:

Measure baseline BP before initiating treatment.⁹ BP should be well-controlled before starting INLYTA®^1,6,10

• Actively treat towards a target BP of ≤140/90 mmHg using standard antihypertensive medications¹⁰
• Consider different BP goals in some patients (e.g. those who have pre-existing cardiovascular risk factors)^6,10,11 or via their GP or community HCP

Advise patients that BP levels may increase following the start of INLYTA®. Encourage patients and family members/ caregiver to measure BP at home^6,10,11

If monitoring at home:

• Show patients how to measure BP correctly, including the proper fitting of the cuff⁶
• Provide individualised thresholds for contacting their clinician⁶

• Weight control
• Regular exercise
• Moderate alcohol consumption
• Change in diet, including reduced salt and fat intake, and increased fruit and vegetable consumption

• Persistent headache
• Dizziness
• Pallor

• Screen for hypertension and stabilise BP before starting INLYTA®^1,11
• Assess severity of hypertension as its impact may differ from patient to patient (see Table 1 for grading)^7,8

• Have you checked your BP this week?

• Have you had a persistent headache or felt any dizziness since taking INLYTA®?

• Non-dihydropyridine calcium channel blockers (e.g. verapamil and diltiazem) are CYP3A4/5 inhibitors and may increase INLYTA® plasma levels. Selection of alternative antihypertensive medicines with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be co-administered, a dose decreases of INLYTA® to approximately half the dose is recommended¹

What to Look For:

Disorders of the voice, characterised by altered vocal quality, pitch, loudness or
vocal effort that impairs communication¹³

Dysphonia of Grade 1/2 was reported in 31% of patients on INLYTA® in the Phase III
AXIS study²

• No dysphonia of Grade 3 or above was reported

Prevention:

Encourage patients to keep hydrated and avoid irritants, such as smoking¹³

Advise patients that they may experience hoarseness once INLYTA therapy begins but that it is usually mild and reversible.

Signs and Symptoms: 

• Persisting sensation of a lump in throat¹³
• Difficulty or pain with swallowing¹³
• Sore throat¹³
• Chronic throat clearing and coughing¹³
• Weak, hoarse, rough or harsh voice⁶

Assessment:

Confirm the presence of dysphonia through voice-specific questions and physical examination¹³

Voice-specific questions include:¹³

• Does it take more effort to use your voice?
• What is different about the sound of your voice?
• Do you have a difficult time getting loud or projecting?
• Have you noticed changes in your pitch or range?

Assess severity of dysphonia as its impact may differ from patient to patient¹³

Questions for your patients

• Have you experienced a sore throat or hoarseness since you started taking INLYTA®?

• Has your hoarseness persisted for three months or longer?

Patients should be referred to an ear, nose and throat specialist if their hoarseness persists or if a serious underlying cause for their dysphonia is suspected

• How are the symptoms of dysphonia affecting your everyday life?

The severity and impact of dysphonia may differ from patient to patient

Management

Dysphonia is intermittent with INLYTA® treatment⁶, and usually resolves rapidly following a 1–2-day treatment interruption

• Physical examination of the head and neck is recommended if hoarseness persists¹³

Encourage patients to:

• Drink ample water¹³
• Avoid irritants, such as tobacco smoke¹³
• Limit voice strain¹³
• Use lozenges⁶

Consider a dose reduction if dysphonia is severe for the patient¹⁰

Grading Dysphonia¹⁴
Assessment of the patient's voice - can be done through a simple scale:​​​

What to look for

Hand-foot skin reactions (palmar-plantar erythrodysesthesia) are characterised by redness and swelling of the palms of the hands or soles of the feet¹⁵

• They are distinct from chemotherapy-related hand-foot skin reactions¹⁵

Hand-foot skin reactions of all grades were reported in 27% of patients on INLYTA® in the Phase III AXIS study²

• Hand-foot skin reactions of Grade 3 or above were reported in 5% of patients²

Although often mild-to-moderate in severity, they can be uncomfortable and may impair daily activities¹⁵

Hand-foot skin reactions associated with INLYTA® may be reduced if patients are adequately educated and follow preventative advice and easily treated if reported early.

Prevention

Before starting INLYTA® therapy, help patients to minimise the risk and severity of hand-foot skin reactions by encouraging them to:

• Visit a podiatrist to remove existing hyperkeratotic areas and calluses^6,11
• Reduce exposure of hands and feet to hot water¹¹
• Avoid constrictive clothing and footwear¹¹
• Avoid vigorous exercise that may result in excessive rubbing and friction on the skin¹¹
• Wear open shoes with padded soles and gloves^6,11
• Apply alcohol-free moisturising creams after bathing and regularly use moisturising creams (e.g. urea- containing creams)^10,11

Educate patients to look for the visible signs of hand-foot skin reactions and the 3C approach for managing the condition:^11,15

• Control calluses
• Comfort with cushions
• Cover with creams

• Hand-foot skin reactions usually occur on the palms of the hands or soles of the feet but may affect other areas¹⁵
• Skin can become red, swollen and painful – sometimes with blisters, cracks and/or peeling¹⁵
• Hand-foot skin reactions are often preceded or accompanied by tingling or numbness¹⁵

• Confirm the presence of hand-foot skin reactions
• Assess severity of hand-foot skin reactions as their impact may differ from patient to patient (see Table 8 for grading)¹²

• Have you felt any tingling sensations?

• Can you hold a cup of tea? Is wearing shoes unbearable? What is your hand-foot skin reaction preventing you from doing?

• Are you noticing any skin changes, such as a change in colour, feel or sensation?

• Do you have any skin changes in other areas?

• Avoid/reduce activities that put a lot of pressure on the affected areas¹¹
• Wear loose, comfortable clothes and shoes, and use cushioned insoles^6,11 - Avoid exposure to hot water¹¹
• Protect tender areas, pressure points with padding, foam absorbents and shock absorbers^11,15

• Moisturising emollient creams and urea-based creams, especially for the feet¹¹
• Daily foot soaks in lukewarm water with Epsom salts for 20–30 minutes¹⁵

What to look for

Fatigue of all grades was reported in 39% of patients on INLYTA® in the Phase III AXIS study²

• Fatigue of Grade 3 or above was reported in 11% of patients²

Several factors may contribute to fatigue in patients with RCC, including anaemia, hypothyroidism, depression and other co-morbidities^6,10,11,16

Fatigue may be related to both the disease and psychosomatic factors related to the disease^11,16

Prevention

Identify and resolve underlying factors that may affect the level of fatigue:¹¹

• Anaemia
• Thyroid function
• Pain control

Review concomitant medications and comorbidities that may cause fatigue^10,11

Advise patients that they may feel tired once INLYTA® therapy begins.
Advise patients of lifestyle modifications to minimise the impact of fatigue, including:

• Conserve energy^6,11
• Accept help from others⁶
• Reschedule activities to periods of peak energy¹¹
• Stay active^11,16
• Try to maintain a normal sleep pattern¹⁸
• Use relaxation techniques to alleviate stress^11,16
• Modify diet^6,11

Signs and symptoms

Look out for changes in patient activities and attention on the telephone or in the clinic.

Check for underlying factors that may affect the level of fatigue; for example, hypothyroidism, anaemia and dehydration^6,10,11

Assessment

• Confirm the presence of fatigue
• Take a full history to check concomitant medicines and comorbidities before initiating treatment^6,10
• Encourage patients to rate their fatigue on a numeric scale, where 0= 'no fatigue' and 10=' worst fatigue imaginable.'
• Assess severity of fatigue as its impact may differ from patient to patient¹²

Questions for your Patients

• Have you been feeling more tired than usual since you started taking INLYTA®?

It is important to have educated your patient to tell you that as soon as a side effect, like fatigue, becomes troublesome, 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.

• How does your fatigue affect your everyday life?

The severity and impact of fatigue may differ from patient to patient

Management

• Treatment of fatigue is supportive in nature – reinforce preventative advice (see Prevention for more details)
• Encourage patient to pace themselves and schedule activities to times of peak energy^6,11
• Baseline and ongoing monitoring of thyroid function⁶
• Identify and treat all fatigue-inducible factors to optimise quality of life (daily activities, comfort, associated pain, emotional distress, depression and nutrition disorders)^{6, 10,11}
• Grade 3 or 4 fatigue may require treatment interruption or dose adjustment (see Table 7 for management recommendation)^10,11

Grading Fatigue¹²

Grading Management Strategies for Fatigue¹⁰

What to look for

Diarrhoea of all grades was reported in 55% of patients on INLYTA® in the Phase III AXIS study²

• Diarrhoea of Grade 3 or above was reported in 11% of patients²

Diarrhoea can lead to dose interruption or reduction of INLYTA®¹⁰ and requires early and ongoing evaluation and intervention.⁶

Diarrhoea associated with anti-cancer therapy can lead to aversions to some foods, with subsequent weight loss and reduced quality of life, and be potentially life-threatening if not managed appropriately¹¹

• Weight loss of all grades was reported in 25% of patients on INLYTA® in the Phase III AXIS study²
• Decreased appetite of all grades was reported in 34% of patients on INLYTA® in the Phase III AXIS study²

Prevention

Before starting INLYTA® therapy, help minimise the risk and severity of diarrhoea in patients by:

• Assessing baseline bowel habits, including frequency and consistency of stools and the use of laxative or stool softener⁶
• Reviewing concomitant medicines, such as opioids⁶
• Consulting with a dietician, if necessary or appropriate¹¹

Encourage patients to modify their diet:

• Bananas, rice, apple and toast can slow gastrointestinal motility and increase stool consistency^11,16
• Reduce intake or try to avoid diarrhoea-enhancing foods and drink, for example, high-fibre foods, caffeine, alcohol and dairy products^6,10,11,16

Patients should avoid grapefruit or juice throughout their treatment with INLYTA® since these may increase plasma concentrations of INLYTA® and the risk of side effects.¹

Advise patients that diarrhoea is associated with INLYTA® therapy and the importance of reporting diarrhoea to the healthcare team early as it can be life-threatening if not managed before.

Signs and symptoms¹⁷

Common signs of diarrhoea include:

• Increased frequency of stools
• Loose, watery stools
• Incontinence
• Abdominal pain

Assessment

• Confirm the presence of diarrhoea
• Take a full history to check concomitant medications and co-morbidities^6,10
• Evaluate the severity of diarrhoea as its impact may differ from patient to patient (see Table 3 and 4 for grading and management recommendations)¹²

Questions for your Patients 

• Have you experienced an increase in diarrhoea, indigestion or flatulence since starting INLYTA®?

Changes in bowel movements are widespread with INLYTA®, but symptoms are usually mild to moderate

• How does your diarrhoea affect your everyday life?

The severity and impact of diarrhoea may differ from patient to patient

• What is your diet like?

Eating foods that slow gastrointestinal motility and increase stool consistency, and reducing intake or trying to avoid diarrhoea-enhancing foods and drink can help reduce the frequency and severity of diarrhoea

Management

Patient education regarding diet and hydration is recommended¹⁰

• Consultation with a dietician should be considered¹¹

Encourage patients to:

• Avoid the use of stool softeners or fibre supplements¹¹
• Avoid spicy, high-fibre and fatty foods and caffeine^6,10,11,16
• Eat and drink often in small amounts¹⁶
• Use anti-diarrhoeal treatments (e.g. loperamide), and dehydration management^6,10,11,16
• Keep a diary to help monitor their bowel movements and highlight any factors that may make symptoms worse¹¹
• Consider dose reduction or interruption as necessary and then re-escalate¹

What to look for 

Hypothyroidism of all grades was reported in 19% of patients on INLYTA® in the Phase III AXIS study²

• Hypothyroidism of Grade 3 or above was reported in <1% of patients²

Prevention 

• Monitor thyroid function before initiation of INLYTA® treatment^1,6
• Treat any existing hypothyroidism before starting INLYTA® therapy using standard medical practice to achieve and maintain a euthyroid state¹
• Advise patients that hypothyroidism may develop with INLYTA®

Signs and symptoms

Symptoms of hypothyroidism include:¹⁸

• Fatigue
• Swelling around the eyes
• Dry skin
• Shortness of breath
• Feeling cold
• Anorexia¹⁹
• Fluid retention¹⁹
• Skin and hair alterations¹⁹

Several of these symptoms can also be independent side effects of INLYTA® therapy¹

Typical symptoms are consistent with declining metabolic functions, including:¹⁹

• Fatigue
• Changes in mental function and memory
• Lethargy
• Weight gain
• Cold intolerance 

Assessment 

Confirm the presence of hypothyroidism

• Take a patients full medical history to check concomitant medications and comorbidities before initiating treatment^6,10
• Thyroid function should be monitored before initiation of INLYTA® and periodically after that during treatment^1,6,19
• Consider assessing levels of thyroid-stimulating hormone, triiodothyronine and thyroxine/free thyroxine index at baseline and every 10–12 weeks.⁶ Assess severity of hypothyroidism as its impact may differ from patient to patient¹²

Questions for your Patients

• Have you been feeling more tired than usual since you started taking INLYTA®?

It is important to have educated your patient about potential side effects and to tell you as soon as any become troublesome so that the most appropriate supportive care can be promptly provided

• Have you experienced fatigue, swelling around the eyes or feeling cold since you started taking INLYTA®?

These symptoms may be indicative of hypothyroidism and will require assessment and possible treatment

• How do the symptoms of hypothyroidism affect your everyday life?

The severity and impact of hypothyroidism may differ from patient to patient

Management 

Monitor patient for signs and symptoms of hypothyroidism. Hypothyroidism can be managed with thyroid hormone replacement therapy^6,19

• Initiate levothyroxine treatment if required, based on laboratory results to maintain euthyroid state^6,19

Grading Hypothyroidism¹²

Management strategies for Hypothyroidism¹⁰