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AFAtinib

( a-FA-ti-nib )
Funding:
Exceptional Access Program
  • AFAtinib - For first-line monotherapy treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC), according to specific criteria
Other Name(s): Giotrif® (Boehringer Ingelheim)
Appearance: tablet in various strengths and colours
A - Drug Name

AFAtinib

SYNONYM(S):   BIBW2992 MA2

COMMON TRADE NAME(S):   Giotrif® (Boehringer Ingelheim)

 
B - Mechanism of Action and Pharmacokinetics

Afatinib is an irreversible inhibitor of the ErbB family of tyrosine kinases, including epidermal growth factor receptor (EGFR), HER2 and HER4. It also inhibits transphosphorylation of HER3. EGFR inhibition plays a role in downregulating ErbB signaling, decreasing tumor cell proliferation and vascularization.



Absorption

Exposure increases 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 26%.
Bioavailability Unknown

Distribution

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.
Metabolism

Undergoes negligible enzymatic metabolism. Metabolized through Michael addition reactions resulting in adduct formation to proteins or small nucleophilic molecules.

Inhibitor of P-glycoprotein (P-gp, moderate); Breast cancer resistance protein (BCRP)
Main enzymes involved P-gp, BCRP
Inactive metabolites Afatinib adducts
Elimination

Mainly excreted as parent drug

Half-life 37 hours (terminal, steady state)
Feces 85%
Urine 4%
 
C - Indications and Status
Health Canada Approvals:

Monotherapy for treatment of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor naive patients with metastatic (including cytologically proven pleural effusion) adenocarcinoma of the lung with activating EGFR mutations(s).

Monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer of squamous histology who progressed after platinum-based chemotherapy.

 

 

Notes:

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.

Approval in EGFR tyrosine kinase naïve patients with metastatic non-small cell lung cancer (NSCLC) was based on a significant improvement in progression-free survival and objective response (LUX-Lung 3 study). No overall survival benefit was demonstrated. 



 
D - Adverse Effects

Emetogenic Potential:  

Minimal

Extravasation Potential:   Not applicable

Adverse effects noted below are based on the pivotal phase III LUX-Lung 3 study.

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
Hand-foot syndrome (7%) (1% severe) E
Paronychia (58%) (11% severe) E
Rash (71%) (severe 14%) E
Gastrointestinal Anorexia, weight loss (29%) E
Constipation (13%) E
Diarrhea (96%) (severe 15%) E
Dyspepsia (7%) E
Mucositis (71%) (severe 9%) E
Nausea, vomiting (25%) E
Hematological Myelosuppression (3%) E
Hepatobiliary ↑ LFTs (11%) (may be severe) E
Pancreatitis (<1%) E
Infection Infection (14%) 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
Pneumonitis (1%) 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.
Dose-limiting side effects are underlined.

** 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 are diarrhea, rash, mucositis, paronychia, anorexia/weight loss, nausea/vomiting, epistaxis, insomnia, cough, infection and musculoskeletal pain.

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.
 
Patients with symptoms suggestive of keratitis should be referred promptly to an ophthalmologist. Patients should avoid the use of contact lenses during treatment, given an increased risk of keratitis.
 
Rash is a mild to moderate erythematous and acneiform type 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.
 
E - Dosing

Refer to protocol by which patient is being treated.



Adults:

EGFR mutation-positive status must be confirmed by a validated test before treatment in patients with adenocarcinoma of the lung. Efficacy has 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.

Oral: 40 mg/day

Dosage with Toxicity:

 

Dose levels: 40 mg, 30 mg, 20 mg
Do not re-escalate previously reduced doses.

Table A: Dose Modifications for Toxicity Other than Diarrhea

 

Toxicity Grade
Action
Grade 1 or 2 related organ
Maintain same dose
Prolonged (≥ 7 days) or intolerable grade 2  related organ/non-hematologic despite adequate symptomatic management  
Or
Grade 2 creatinine ↑
 
Hold until ≤ grade 1 then ↓ 1 dose level
Grade  3 or 4  related organ/ non-hematologic
Hold until ≤ grade 1 then ↓ 1 dose level
 
Keratitis
 
Hold and refer to ophthalmologist; consider discontinuation
Pneumonitis
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,
Bullous, blistering, exfoliating or other severe skin reactions
Discontinue
Any toxicity not recovered to ≤ grade 1 within 14 days of afatinib hold
Discontinue

Table B: Management of Diarrhea

Patients should have an adequate supply of loperamide readily available at the start of treatment and throughout therapy.

Diarrhea grade
Action
Any grade diarrhea
·         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 ↓ 1 dose level. 
Discontinue if not recovered to ≤ grade 1 within 14 days
Grade 4
or
Grade 2-3 ≥ 14 days despite adequate hydration and afatinib discontinuation
Discontinue

 



Dosage with Hepatic Impairment:

Similar exposure was observed in single-dose study in normal hepatic function versus mild/moderate hepatic impairment.

 

Hepatic Impairment
Starting Dose / Action
Mild (Child Pugh A)
No dose adjustment recommended. Monitor closely for toxicity.
Moderate (Child Pugh B)
Severe (Child Pugh C)
Do not treat

 

 



Dosage with Renal Impairment:

Higher exposure was observed in renal impairment, which may present a higher risk of adverse events. Monitor patients closely for toxicities.

 

eGFR* (ml/min) Starting dose / action
≥ 30 no dosage adjustment recommended; monitor closely for toxicity
15 - 29 30 mg daily
< 15 or on dialysis Do not treat (not studied) 

*using MDRD formula (per product monograph)



Dosage in the elderly:

No dose adjustment recommended. Elderly patients are more likely to experience severe adverse events, especially diarrhea. Monitor these patients closely for toxicities.



Dosage based on gender:

Higher exposure was observed in female patients as well as patients with lower body weight, which may present a higher risk of adverse events. Monitor closely for toxicities.



Dosage based on ethnicity:

Population pharmacokinetic analysis suggested that race does not have a clinically important effect on afatinib exposure.



Children:

Not recommended for use in patients under 18 years of age, since safety and efficacy have not been established.



 
F - Administration Guidelines
  • Tablets are swallowed whole with a glass of water. Do not crush or chew.
  • 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, skip the missed dose and take the next one as scheduled.
  • If vomiting occurs after taking the dose, do not give a replacement tablet. Take the next dose 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;
  • Store the blister card in the original package away from moisture and light;
  • Open only one pouch at a time until all the tablets in a the blister card are consumed, before opening a new one.
 
G - Special Precautions
Contraindications:

  • Patients who have a hypersensitivity to this drug or any of its components;
  • Patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption;
  • Patients with significant or recent gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption or any other relevant disorder); 
  • Patients with a history of Interstitial Lung Disease (ILD);
  • Patients with severe hepatic or renal impairment.
  • Patients with HER-2 positive metastatic breast cancer, in combination with vinorelbine, as increased adverse effects and increased mortality have been reported.

Other Warnings/Precautions:

  • Use with caution in patients with higher exposure (females, low body weight, renal impairment) and monitor for toxicity;
  • Use with caution in patients with abnormal LVEF or those with significant cardiac history;
  • Blurred vision and keratitis have been observed; caution is required when driving or operating machinery;
  • Use with caution patients with a history of keratitis, ulcerative keratitis, severe drug eye or those who use contact lenses.


Other Drug Properties:

  • Carcinogenicity: Unknown
  • Phototoxicity: Probable

Pregnancy and Lactation:
  • 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: Documented in animals
    Breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose.
  • Fertility effects: Probable
 
H - Interactions

Drug-drug interactions due to inhibition or induction of CYP enzymes or UGT1A1 by concomitant medications are unlikely. Smoking and alcohol consumption had no significant effects on afatinib pharmacokinetics, while food significantly decreased drug exposure (see Pharmacokinetics). Although afatinib is a moderate inhibitor of Pgp in vitro, clinical data suggest the drug is unlikely to affect other Pgp substrates.

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. Caution; monitor for toxicity if used together. Based on studies, taking P-gp/BCRP inhibitors simultaneously or at least 6 hours after afatinib did not significantly alter afatinib exposure.
P-glycoprotein inducers (i.e. rifampin) ↓ afatinib exposure (up to 34% observed) ↑ metabolism of afatinib Avoid strong inducers
BCRP substrates (i.e. topotecan, rosuvastatin, sulfasalazine) ↑ exposure of BCRP substrates (theoretical) afatinib is a BCRP inhibitor Caution
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

Liver function tests

Baseline and at each visit

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

Baseline and as clinically indicated

Clinical toxicity assessment of diarrhea, skin and nails, mucositis and other GI, respiratory, ophthalmic, hypersensitivity/immune reactions

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
J - Supplementary Public Funding

Exceptional Access Program (EAP Website)

  • AFAtinib - For first-line monotherapy treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC), according to specific criteria ()

 
K - References

Dungo RT, Keating DM. Afatinib: first global approval. Drugs (2013) 73:1503–1515.
 
Product Monograph: Giotrif ® (afatinib dimaleate). Boehringer Ingelheim (Canada) Ltd., July 2017. 
 
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.
 
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.


October 2017 updated adverse effects and dosage with renal impairment sections

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

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