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AFAtinib
Afatinib shows non-linear PK, with exposure increasing slightly more than proportional between 20 mg to 50 mg doses.
| Peak plasma levels | 2-5 hours |
| Time to reach steady state | 8 days, with 2.8x accumulation in exposure at steady state |
| Effects with food |
Administration following a high-fat meal decreased afatinib exposure by 50%. When food was consumed 3 hrs before or 1 hr after the dose, exposure decreased on average by 26%. |
| Bioavailability | Unknown |
Afatinib is equally distributed into most tissues and covalently binds to albumin and hemoglobin. It accumulates in the retina and skin.
| PPB | 95% |
| Cross blood brain barrier? | Low with single oral dosing, but accumulation occurs with repeat dosing. |
Afatinib undergoes negligible enzymatic metabolism. Metabolized through Michael addition reactions resulting in adduct formation to proteins or small nucleophilic molecules.
| Main enzymes involved |
P-gp, BCRP |
| Inactive metabolites |
Yes |
Mainly excreted as parent drug
| Half-life | 37 hours (terminal, steady state) |
| Feces | 85% |
| Urine | 4% |
- Non-small cell lung cancer (NSCLC)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
Extravasation Potential: Not applicable
The following table lists adverse effects that occurred in ≥ 10% of patients treated with afatinib in a pivotal phase III trial comparing afatinib to pemetrexed/cisplatin in patients with EGFR mutation positive metastatic adenocarcinoma of the lung. It also includes severe, life-threatening and post-marketing adverse effects from other sources.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Cardiotoxicity (<1%) (6% LVEF decrease of >20%) | E D | |||
| Hypertension (2%) | E | ||||
| Venous thromboembolism (<1%) | E | ||||
| Dermatological | Alopecia (13%) | D | |||
| Dry skin (31%) | E | ||||
| Hand-foot syndrome (7%) (1% severe) | E | ||||
| Paronychia (58%) (11% severe) | E | ||||
| Rash, pruritus (71%) (severe 14%) | E | ||||
| Stevens-Johnson syndrome (rare) | E | ||||
| Toxic epidermal necrolysis (rare) | E | ||||
| Gastrointestinal | Anorexia, weight loss (29%) | E | |||
| Constipation (13%) | E | ||||
| Diarrhea (96%) (severe 15%) | E | ||||
| Dyspepsia (4%) | E | ||||
| GI perforation (<1%) | E | ||||
| Mucositis (71%) (severe 9%) | E | ||||
| Nausea, vomiting (25%) | E | ||||
| Hematological | Myelosuppression (2%) | E | |||
| Hepatobiliary | ↑ LFTs (11%) (may be severe) | E | |||
| Pancreatitis (<1%) | E | ||||
| Infection | Infection (14%) (including herpes zoster, rarely sepsis) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (11%) (hypokalemia) | E | |||
| Musculoskeletal | Musculoskeletal pain (14%) | E | |||
| Nervous System | Dizziness (11%) | E | |||
| Dysgeusia (7%) | E | ||||
| Headache (14%) | E | ||||
| Insomnia (15%) | E | ||||
| Ophthalmic | Cataract (1%) (or blurred vision) | E D | |||
| Conjunctivitis (11%) | E | ||||
| Keratitis (2%) | E | ||||
| Renal | Proteinuria (1%) | E | |||
| Renal failure (4%) | E | ||||
| Respiratory | Cough (15%) | E | |||
| Epistaxis (17%) | E | ||||
| Other (11%) - Rhinorrhea | E | ||||
| Pneumonitis (1%) (may be severe) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for Afatinib include diarrhea, mucositis, rash, pruritus, paronychia, dry skin, anorexia, weight loss, nausea, vomiting, epistaxis, cough and insomnia.
Decreases in left-ventricular ejection fraction (LVEF) were observed in the afatinib arm of the pivotal trial, including decrease of > 20% from baseline or lower than the institution's lower limit of normal.
Severe diarrhea resulting in dehydration, hypokalemia, renal insufficiency and/or death has been reported. Diarrhea appears within the first 2 weeks of treatment, while severe cases occurred within the first 6 weeks of treatment. Patients should be adequately educated on early management and should have a sufficient supply of loperamide. Patients should avoid lactose-containing products or foods that aggravate diarrhea. Ensure hydration and electrolyte replacement is maintained if diarrhea occurs.
Gastrointestinal perforation, including fatal cases, has been rarely reported with afatinib. Patients receiving concomitant medications such as corticosteroids, NSAIDs, or anti-angiogenic agents may be at increased risk. Older patients or those with an underlying history of gastrointestinal ulceration, diverticular disease, or bowel metastases may also be at increased risk of perforation.
Keratitis has been reported with afatinib. Patients with acute or worsening ocular symptoms (e.g. eye inflammation, lacrimation, light sensitivity, blurred vision, or eye pain) should be referred promptly to an ophthalmologist. Patients should avoid the use of contact lenses during treatment, given an increased risk of keratitis.
Rash generally manifests itself as a mild to moderate erythematous and acneiform rash that may worsen with sun exposure. Patients should protect themselves from the sun. Stevens-Johnson syndrome and toxic epidermal necrolysis have also been reported rarely.
Paronychia is a common side effect. Patients should avoid trauma to nails, finger tips, and chemicals such as soaps, detergents and nail products. Topical antibiotics/antiseptics and/or steroids may be used to treat mild paronychia. For moderate to severe cases, topical or systemic antibiotics and/or steroids as well as periodic silver nitrate application may be beneficial.
Refer to protocol by which patient is being treated.
In patients with adenocarcinoma of the lung, EGFR mutation-positive status must be confirmed by a validated test before treatment.
- Safety and efficacy have not been established in patients with EGFR mutations other than exon 19-deletions (DEL19) and the exon 21 L858R point mutation.
- Evidence for activity in EGFR TKI naïve patients with uncommon EGFR mutations including the T790M is limited.
Patients must be adequately educated about the management of diarrhea and provided with loperamide when starting afatinib.
Since sunlight can exacerbate skin rash reactions, patients should be advised to avoid the sun or use adequate sun protection.
| Dose Level | Afatinib Dose (mg/day) |
| 0 | 40 |
| -1 | 30 |
| -2 | 20 |
| -3 | Discontinue |
Do not re-escalate previously reduced doses.
Refer to H – Interactions section for dosing recommendations when co-administered with P-gp inhibitors or inducers.
Note: The U.S. Prescribing Information suggests reducing afatinib dose by 10mg with P-gp inhibitors and monitoring for toxicity, and increasing afatinib dose by 10mg (as tolerated)
when used with chronic concomitant P-gp inducer therapy. Then, reducing afatinib back to the original dose 2 to 3 days after discontinuing the P-gp inducer.
Table A: Dose Modifications for Toxicity Other than Diarrhea
|
Toxicity Grade
|
Action*
|
|
Grade 1 or 2
|
Maintain same dose
|
|
Prolonged (≥ 7 days) or intolerable grade 2 (including rash, nausea, vomiting and renal impairment) despite adequate symptomatic management**
Or
Grade 3 or 4**
|
Hold until ≤ grade 1 then restart at ↓ 1 dose level
For skin reactions, consider referral to a specialist. |
|
Keratitis
|
Hold and refer to ophthalmologist; consider discontinuation
|
|
Interstitial Lung Disease
|
Hold; investigate and treat patient appropriately. Discontinue if confirmed.
|
|
LVEF below institution’s lower limit of normal
Or
Cardiac signs and symptoms
|
Hold and refer to cardiologist; consider discontinuation
|
| Severe hepatic impairment during treatment | Discontinue
|
| Gastrointestinal perforation | |
|
Bullous, blistering or exfoliating skin conditions, suspected toxic epidermal necrolysis or Stevens-Johnson syndrome
|
*Permanently discontinue afatinib for any toxicity not recovered to ≤ grade 1 within 14 days or if cannot tolerate 20 mg/day.
**Consider holding afatinib for worsening hepatic function; discontinue if severe hepatic impairment
Table B: Management of Diarrhea
Patients should have an adequate supply of loperamide readily available at the start of and during treatment.
|
Diarrhea Grade
|
Action
|
|
Any
|
Take 4mg (2 tablets) of loperamide immediately, followed by 2mg (1 tablet) with every loose bowel movement up to maximum daily dose of 20mg (10 tablets). Continue until resolved for ≥ 12 hours.
Give oral hydration (1.5L/m2/day plus equivalent of actual fluid loss) and electrolytes especially for ≥ grade 2.
Hospitalize for IV fluids if patients becomes dehydrated.
Avoid lactose containing products.
|
|
Grade 1
or
Grade 2 < 48 hrs
|
Maintain same afatinib dose.
|
|
Grade 2 lasting ≥ 48 hours despite adequate anti-diarrheal treatment
or
Grade 3
|
Hold afatinib until grade ≤ 1 then restart at ↓ 1 dose level.
Discontinue if not recovered to ≤ grade 1 within 14 days.
|
|
Grade 4
|
Discontinue
|
Similar exposure was observed in single-dose study in normal hepatic function versus mild/moderate hepatic impairment.
|
Hepatic Impairment
|
Afatinib Starting Dose / Action
|
|
Mild (Child Pugh A)
|
No dose adjustment required. Monitor closely for toxicity.
|
|
Moderate (Child Pugh B)
|
|
|
Severe (Child Pugh C)
|
Do not treat
|
Higher exposure of afatinib was observed in renal impairment, which may increase the risk of developing adverse events. Monitor patients closely for toxicities.
| CrCl (mL/min) | Afatinib Starting Dose |
| ≥ 60 | No adjustment required |
| 30-59 |
No adjustment required; monitor for adverse reactions |
| 15-29 | 30 mg daily |
| < 15 or on dialysis | Do not treat (not studied) |
No dose adjustment required. Elderly patients are more likely to experience severe adverse events, especially diarrhea. Monitor these patients closely for toxicities.
Higher exposure was observed in female patients as well as patients with lower body weight, which may increase the risk of developing adverse events. Monitor closely for toxicities.
Population pharmacokinetic analysis suggests that race does not have a clinically important effect on afatinib exposure.
The safety and efficacy of afatinib has not been established in the pediatric population.
- Tablets should be swallowed whole with a glass of water and not crushed or chewed.
- Afatinib should be taken on an empty stomach, at least 1 hour before or 3 hours after eating.
- If a dose is missed, afatinib should be taken as soon as it is remembered. If there are less than 8 hours until the next scheduled dose, patients should skip the missed dose and take the next one as scheduled.
- If vomiting occurs after taking the dose, patients should not take a replacement tablet. The next dose should be taken at its scheduled time.
- Patients should have an adequate supply of loperamide readily available at the start of, and throughout therapy.
- Store at 15 - 30oC.
-
Blister card should be stored in the original package away from moisture and light;
-
Only one pouch should be opened at a time. All the tablets in a blister card should be consumed, before opening a new one.
- Patients who have a hypersensitivity to this drug or any of its components
- Afatinib is not recommended for patients with:
- Significant or recent gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption or any other relevant disorder).
- A history of interstitial lung disease
- Severe hepatic or renal impairment
- HER-2 positive metastatic breast cancer, in combination with vinorelbine, as increased adverse effects and increased mortality have been reported.
- With hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption as afatinib tablets contains lactose.
- Use with caution in patients with:
- Abnormal LVEF or those with significant cardiac history as afatinib has not been studied in these patient populations.
- A history of keratitis, ulcerative keratitis, severe dry eye or those who use contact lenses.
- Blurred vision and keratitis have been observed; caution is required when driving or operating machinery.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Phototoxicity:
Probable
- Patients should be advised to avoid sun exposure or wear sufficient sun protection.
-
Mutagenicity:
No
-
Genotoxicity:
No
-
Embryotoxicity:
Yes
Afatinib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 2 weeks after the last dose. -
Fetotoxicity:
Yes
-
Breastfeeding:
Excretion into breast milk documented in animals.
Breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose.
-
Fertility effects:
Probable
Drug-drug interactions due to inhibition or induction of CYP enzymes or UGT1A1 by concomitant medications are unlikely.
Although afatinib is a moderate inhibitor of Pgp in vitro, clinical data suggest the drug is unlikely to affect other Pgp substrates.
Smoking and alcohol consumption had no significant effects on afatinib pharmacokinetics, while food significantly decreased drug exposure (see Pharmacokinetics).
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| P-glycoprotein inhibitors (i.e. quinidine, verapamil, cyclosporine, ritonavir) or BCRP inhibitors (i.e. ritonavir) | ↑ afatinib exposure (up to 48% observed when P-gp/BCRP inhibitor given before afatinib) | ↓ metabolism of afatinib | Avoid strong inhibitors if possible. If concomitant use is unavoidable, monitor for toxicity. Consider reducing afatinib dose if combination is not tolerated (See Dosing section). |
| P-glycoprotein inducers (i.e. rifampin) | ↓ afatinib exposure (up to 34% observed) | ↑ metabolism of afatinib | Avoid strong inducers. Consider adjusting afatinib dose for patients who require chronic therapy with a P-glycoprotein inducer (See Dosing section). |
| BCRP substrates (i.e. topotecan, rosuvastatin, sulfasalazine) | ↑ exposure of BCRP substrates (theoretical) | afatinib is a BCRP inhibitor | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline and at each visit; more frequently in patients with hepatic impairment |
Renal function tests and electrolytes (especially in patients at high risk of dehydration) |
Baseline and at each visit |
LVEF for patients with cardiac risk factors or conditions that can affect LVEF. |
Baseline and as clinically indicated |
Clinical toxicity assessment of skin and nails, diarrhea, mucositis and other GI, respiratory, ophthalmic and cardiac effects and hypersensitivity/immune reactions |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- AFAtinib - For first-line monotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC), according to specific criteria ()
Dungo RT, Keating DM. Afatinib: first global approval. Drugs (2013) 73:1503–1515.
Prescribing Information: Gilotrif® (afatinib). Boehringer Ingelheim Pharmaceuticals, Inc. October 2019.
Product Monograph: Giotrif ® (afatinib dimaleate). Boehringer Ingelheim (Canada) Ltd., June 2019.
Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013.
Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015;16(8):897-907.
Yap TA, Popat S. The role of afatinib in the management of non-small cell lung carcinoma. Expert Opin Drug Metab Toxicol 2013; 11:1529-1539.
June 2022 Updated Dose modifications, Adverse Effects, Interactions, Drug Administration and Special Precautions, Recommended Clinical Monitoring sections
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