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For Healthcare Professionals

GIOTRIF®

Side effects and safety

Side effects:

GIOTRIF® (afatinib) has a well-characterised side effects profile1-5

The most frequent adverse reactions associated with GIOTRIF® (afatinib) are diarrhoea, skin related adverse events, stomatitis and paronychia1

  • Overall tolerability-guided dose reductions have led to a lower frequency of common adverse reactions

Summary of ADRs per frequency category from all NSCLC trials and post marketing experience with daily GIOTRIF® (afatinib) doses of 40 mg or 50 mg as monotherapy1

summary1

Adapted from GIOTRIF® (afatinib), Summary of Product Characteristics, 2020.1


In a real-world setting, GIOTRIF® (afatinib) dose modification reduced the incidence and severity of ADRs without compromising effectiveness.6

aIncludes paronychia, nail infection, nail bed infection.

bIncludes stomatitis, aphthous stomatitis, mucosal inflammation, mouth   ulceration, oral mucosa erosion,mucosal erosion, mucosal ulceration. 

cIncludes group of rash preferred terms.

dIncludes acne, acne pustular, dermatitis acneiform. 

eIncludes pruritus, pruritus generalised.

fIncludes dry skin, skin chapped.

gIncludes nail disorder, onycholysis, nail toxicity, onychoclasis, ingrowing nail, nail pitting, onychomadesis, nail discoloration, nail dystrophy, nail ridging, and onychogryphosis.

hBased on post-marketing experience.

AE management:

summary2

Monitoring

For early identification and management of AEs, a series of follow-up appointments are recommended. Below is a table displaying the recommended follow-up schedule for patients receiving GIOTRIF® (afatinib) treatment:

aBy an oncologist or an oncology nurse on the basis of the hospital/centre   organisation.

Adapted from Arriola E, et al. 2015.7

Typical time to onset

Diarrhoea typically has the earliest onset of all common AEs (2-3 days)7

summary3

AE management

Common AEs associated with GIOTRIF® (afatinib) treatment are generally well managed with supportive care,2-5 and many of the most common AEs can potentially be managed by dose modification, without compromising efficacy.6,9,10

Adverse event management: decreased appetite

Management recommendations1,11

If possible, the first step in treating decreased appetite is to address the underlying cause:

  • Addressing symptoms of nausea may help improve appetite
  • Treatment for any conditions such as mouth sores, dry mouth, pain or depression may help to improve appetite
  • Additional treatments for appetite loss and associated weight loss may include medications that increase appetite, medications that help food move through the intestine and nutritional supplements

Grade 1–2:

  • Continue GIOTRIF® (afatinib) treatment at current dose

Grade ≥3 or intolerable Grade 2:

  • Interrupt GIOTRIF® (afatinib), resuming treatment at a reduced dose (10 mg lower) if patient recovers to grade ≤1. Permanent discontinuation should be considered in patients who cannot tolerate 20 mg/day of GIOTRIF® (afatinib) treatment

Advice for patients11

  • Eat 5–6 small meals a day and snack when hungry
  • Identify the times of day when usually hungry − eat at those times and do not limit the amount eaten
  • Eat nutritious snacks that are high in calories and protein, such as dried fruits, nuts, yogurt, cheeses, eggs, milkshakes, ice cream, cereal and muesli bars
  • Drink fluids between meals, instead of with meals, to avoid filling up too quickly
  • When too tired to shop/cook, ask family members or friends for help; consider buying pre-cooked meals
  • If the smell or taste of food brings on nausea, eat cold/room temperature food to decrease odour and reduce taste
  • Meet with a dietitian for additional advice on meal planning

Grading12

summary4

Adapted from CTCAE version 3.12

Adverse event management: diarrhoea

Management recommendations1,13

Approach to management depends on which grade is identified in each patient. A breakdown of the management guidelines is displayed below.

Grade 1–2:

  • GIOTRIF® (afatinib) treatment is continued at the same dose
  • Patients should be followed closely to avoid dehydration
  • Patients should stop taking laxatives and drink 8–10 glasses of water or clear fluids per day
  • Patients should make dietary changes, as described in the “Advice for Patients” subsection below
  • Start immediately on loperamide. Initially with a dose of 4 mg, then 2 mg after each episode of diarrhoea
  • (up to 20 mg/day) until bowel movements cease for 12 hours

If Grade 2 diarrhoea persists longer than 48 hours or is intolerable:

  • Continue loperamide treatment
  • Interrupt GIOTRIF® (afatinib) treatment, restarting once diarrhoea symptoms have resolved to Grade ≤1 at a dose reduced by 10 mg to a minimum of 20 mg/day
  • Assess patients for dehydration and electrolyte imbalance and consider intravenous fluids and electrolyte replacement

Grade 3-4:

  • Continue loperamide treatment
  • Interrupt GIOTRIF® (afatinib) treatment, restarting once diarrhoea symptoms have resolved to Grade ≤1 at a dose reduced by 10 mg to a minimum of 20 mg/day
  • Admit patient to hospital to monitor progress and to take stool specimen for microbiologic examination
  • Initiate intravenous fluid replacement for ≥24 hours, noting that substantial fluid loss may have occurred
  • Consider prophylactic antibiotics if the patient is neutropenic

If diarrhoea symptoms do not resolve to grade ≤1 within 14 days, despite optimal supportive care and treatment interruption:

  • Permanently discontinue GIOTRIF® (afatinib) treatment

Advice for patients13

  • Drink ≥2 L of clear fluids daily to avoid dehydration; some fluids should contain sugar or salt to avoid electrolyte loss
  • Incorporate bananas, rice, apple sauce and toast into their diet (BRAT diet)
  • Avoid food that exacerbates symptoms (e.g. greasy, spicy and fried foods) are difficult to digest or contain lactose/caffeine

Grading12

The diarrhea grade can be used to guide the management strategy.

summary8_0_11zon.jpg

Adapted from CTCAE version 3.12

Adverse event management: paronychia

Adverse event management: paronychia

Management recommendations14

Grade 1:

  • Continue GIOTRIF® (afatinib) treatment at current dose
  • Topical antibiotics or antiseptics*, vinegar soaks† and topical ultrapotent steroids should be considered

Grade 2:

  • Continue GIOTRIF® (afatinib) treatment at current dose
  • Topical antibiotic*, vinegar soaks† and topical ultrapotent steroids
  • Weekly application of silver nitrate

Grade ≥3 or intolerable Grade 2:

  • Refer to a dermatologist
  • Interrupt GIOTRIF® (afatinib), resuming treatment at a reduced dose (10 mg lower) if patient recovers to grade ≤1. Permanent discontinuation should be considered in patients who cannot tolerate 20 mg/day of GIOTRIF® (afatinib) treatment
  • Topical antibiotics* and vinegar soaks†
  • Weekly application of silver nitrate
  • Nail avulsion and systemic antibiotics should be considered

Advice for patients8

Avoid biting nails, overly aggressive manicures/pedicures and nail trauma

Avoid contact with irritating substances and prolonged exposure to water

When it is necessary to wear vinyl gloves, cotton gloves should be worn underneath

High risk patients should take extra care to ensure their nails are kept dry and clean. These include:

  • Patients repeatedly exposed to moist environments, e.g. housekeepers, swimmers
  • Diabetic and immunosuppressed patients who may be more prone to infections

Grading12

summary9_0_11zon.jpg

The paronychia grading system can be used to steer management strategy.

aInstrumental ADL=preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.

bSelf-care ADL=bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 

Adapted from CTCAE version 3.12

Adverse event management: pruritus & dry skin

Management recommendation14

Pruritus

Grade 1:

  • Continue GIOTRIF® (afatinib) treatment at the current dose
  • A topical steroid can be administered at a moderate strength twice daily

Grade 2:

  • Continue GIOTRIF® (afatinib) treatment at the current dose
  • A topical steroid can be administered at a moderate strength twice daily
  • Oral histamines could be added to treatment plan

Grade ≥3 or intolerable Grade 2:

  • Refer to a dermatologist
  • Interrupt GIOTRIF® (afatinib), resuming treatment at a reduced dose (10 mg lower) if patient recovers to grade ≤1. Permanent discontinuation should be considered in patients who cannot tolerate 20 mg/day of GIOTRIF® (afatinib) treatment
  • Consider oral antihistamines and a GABA modulator – gabapentin or pregabalin

Dry Skin

Grade 1:

  • Continue GIOTRIF® (afatinib) treatment at the current dose
  • OTC moisturising cream or ointment can be applied twice daily

Grade 2:

  • Continue GIOTRIF® (afatinib) treatment at the current dose
  • OTC moisturising cream or ointment can be applied twice daily
  • Salicylic acid 6% cream twice daily as an alternative option for the body

Grade ≥3 or intolerable Grade 2:

  • Refer to a dermatologist
  • Interrupt GIOTRIF® (afatinib), resuming treatment at a reduced dose (10 mg lower) if patient recovers to grade ≤1. Permanent discontinuation should be considered in patients who cannot tolerate 20 mg/day of GIOTRIF® (afatinib) treatment
  • OTC moisturising cream or ointment can be applied twice daily
  • Salicylic acid 6% cream twice daily as an alternative option for the body
  • Add topical steroid to eczematous areas twice daily

Advice for patients14,8

  • Use skin creams and lotions that moisturise the skin and prevent dryness
  • Minimise exposure to the sun
  • Use mild bath cleansers without soap to prevent skin irritation
  • Bath or shower in warm water – not hot
  • Avoid fabrics that can make skin itch (e.g. wool and synthetics). Wear loose-fitting, cotton or other soft fabrics and switch to cotton blankets and bed sheets
  • Use mild soaps when washing sheets and clothing
  • Avoid overheating the house, as warm, dry air can make skin dry
  • A cool cloth over the affected area can help to relieve itching

Grading12

summary5

Adapted from CTCAE version 3.12

Adverse event management: rash & acne

Rash and acne

Rash generally manifests as a mild or moderate erythematous and acneiform rash, which may occur or worsen in areas exposed to the sun.1

Bullous, blistering and exfoliative skin conditions have also been reported, including rare cases suggestive of Stevens-Johnson syndrome and toxic epidermal necrolysis.1

GIOTRIF® (afatinib) treatment should be interrupted or discontinued if the patient develops any severe bullous, blistering or exfoliating conditions.1

Management recommendations1,14

Grade 1:

  • Continue GIOTRIF® (afatinib) at the current dose
  • Topical steroids could be administered
  • Topical antibiotics (clindamycin or metronidazole) can be taken twice daily

Grade 2:

  • Continue GIOTRIF® (afatinib) at the current dose
  • Stop topical antibiotic if being used
  • Topical steroids could be administered
  • Oral antibiotic could be used for 6 weeks (100 mg doxycycline or minocycline twice daily)

Grade 3–4 or prolonged‡ or intolerable Grade 2:

  • Refer to a dermatologist
  • Interrupt GIOTRIF® (afatinib), resuming treatment at a reduced dose (10 mg lower) if patient recovers to grade ≤1. Permanent discontinuation should be considered in patients who cannot tolerate 20 mg/day of GIOTRIF® (afatinib) treatment
  • Oral antibiotic could be used for 6 weeks (100 mg doxycycline or minocycline twice daily)
  • If infection is suspected: switch to oral antibiotic with broad-spectrum/gram-negative cover, consider skin swab for bacterial culture and the use of topical steroids
  • When used to manage EGFR TKI-induced rash, prophylactic minocycline treatment (4 weeks) has been associated with a decrease in severe rashes without affecting efficacy outcomes, making prophylactic minocycline a potential treatment option15

Advice for patients14

  • Minimise sunlight exposure, especially to direct sunlight
  • Wear light protective clothing that covers the head, face, hands, arms and legs
  • Use high factor sunscreen (SPF >30 with UVA/UVB; protection); apply generously every 2 hours or more frequently if sweating or swimming

Grading12

summary6

Adapted from CTCAE version 3.12

Adverse event management: stomatitis

Management recommendation1,16

Grade 1-2:

  • Continue GIOTRIF® (afatinib) treatment at current dose

Grade ≥3 or intolerable Grade 2:

  • Interrupt GIOTRIF® (afatinib), resuming treatment at a reduced dose (10 mg lower) if patient recovers to grade ≤1. Permanent discontinuation should be considered in patients who cannot tolerate 20 mg/day of GIOTRIF® (afatinib) treatment

All Grades:17

  • Stomatitis may be managed through palliation with: bland saline rinses, topical lidocaine anaesthetics, mucosal coating agents or analgesics
  • This choice of management should be driven by patient preference

Advice for patients8,16,17

  • Brush teeth and gums gently with a soft toothbrush and rinse with warm salt water, after every meal and before bed. Avoid alcohol-based mouthwashes
  • Eat foods cold or at room temperature; hot and warm food can irritate a tender mouth
  • Avoid acidic, spicy or salty juices and food which may irritate the mouth. Also avoid foods which require a lot of chewing
  • Drink plenty of water and use a straw to drink liquids
  • Use lip balm or petroleum jelly for dry lips
  • When needed, numb the mouth with ice chips or flavoured ice blocks

Grading12

summary7

Adapted from CTCAE version 3.12

Footnotes:

  • *Topical antibiotics/antiseptics include: clindamycin 1%, chloramphenicol 1% and iodine ointment
  • †Vinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes every day
  • ‡>7 days
  • AE, adverse event; ADR, adverse drug reaction; ADL, activities of daily living; CTCAE, common terminology criteria for adverse events; GABA, gamma-aminobutyric acid; NSCLC, 
    non-small-cell lung cancer; OTC, over-the-counter; SPF, sun protection factor; TPN, total parenteral nutrition; UVA, ultraviolet A; UVB, ultraviolet B.

References

  1. GIOTRIF® (afatinib), Summary of Product Characteristics, 2020.

  2. Sequist LV, et al. J Clin Oncol 2013;31(27):3327–3334.

  3. Wu YL, et al. Lancet Oncol 2014;15(2):213–222.

  4. Park K, et al. Lancet Oncol 2016;17(5):577–589.

  5. Soria JC, et al. Lancet Oncol 2015;16(8):897–907.

  6. Halmos B, et al. Lung Cancer 2019;127:103–111.

  7. Arriola E, et al. Future Oncol. 2015;11(2):267–277.

  8. Aw DC, et al. Asia-Pac J Clin Oncol 2018;14(1):23–31.

  9. Yang JC, et al. Ann Oncol 2016;27(11):2103–2110.

  10. Hirsh V, et al. ASCO. 3–7 June 2016. Chicago, IL, USA. Poster: 369.

  11. Cancer.Net. Appetite Loss. Available at: www.cancer.net/all-about-cancer/treating-cancer/managing-side-effects/ap.... Last accessed April 2019.

  12. Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.

  13. Yang JC, et al. Expert Rev Anticancer Ther 2013;13(6):729–736.

  14. Lacouture ME, et al. Expert Rev Anticancer Ther 2013;13(6):721–728.

  15. Melosky B, et al. Curr oncol 2015;22(2):123-132.

  16. Bensinger W, et al. J Natl Compr Canc Netw 2008;6(Suppl 1):S1-21.

  17. Gupta A, West H. JAMA Oncol 2016;2(10):1379.

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