Afatinib – Uses, Dosage, Side Effects, Interaction

Recently, as of January 2018, the US FDA approved a supplemental New Drug Application for Boehringer Ingelheim’s Gilotrif (afatinib) for the first line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test [rx]. The new label includes data on three additional EGFR mutations: L861Q, G719X and S768I rx].

Mechanism of Action

Afatinib is a potent and selective, irreversible ErbB family blocker. Afatinib covalently binds to and irreversibly blocks signaling from all homo and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. In particular, afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions. Moreover, afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.

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Afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in the downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions. Afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2. Treatment with afatinib resulted in the inhibition of tumor growth in nude mice implanted with tumors either overexpressing wild-type EGFR or HER2 or in an EGFR L858R/T790M double mutant model.

Indications

  • Afatinib is a kinase inhibitor indicated as monotherapy for the first-line treatment of (a) Epidermal Growth Factor Receptor (EGFR) TKI (tyrosine kinase inhibitor)-naive adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant EGFR mutations as detected by an FDA-approved test, and (b) adult patients with locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy. Recently, as of January 2018, the US FDA approved a supplemental New Drug Application for Boehringer Ingelheim’s Gilotrif (afatinib) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an FDA-approved test. The new label includes data on three additional EGFR mutations: L861Q, G719X, and S768I.
  • Giotrif as monotherapy is indicated for the treatment of Epidermal Growth Factor Receptor (EGFR) TKI-naïve adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s); locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy.
  • Treatment of all conditions included in the category of malignant neoplasms (excluding central nervous system, hematopoietic and lymphoid tissue neoplasms), Treatment of malignant neoplasms of the central nervous system.
  • Afatinib is a kinase inhibitor indicated as monotherapy for the first-line treatment of (a) Epidermal Growth Factor Receptor (EGFR) TKI (tyrosine kinase inhibitor)-naive adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have non-resistant EGFR mutations as detected by an FDA-approved test and (b) adult patients with locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy [rx].
  • EGFR Mutation-Positive, Metastatic Non-Small Cell Lung Cancer: For the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have non-resistant epidermal growth factor receptor (EGFR) mutations as detected by an approved test.
  • Previously Treated, Metastatic Squamous NSCLC: For the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.
  • Metastatic Non-Small Cell Lung Cancer
  • Refractory, metastatic squamous cell Non-small cell lung cancer

Use in Cancer

Afatinib dimaleate is approved to treat:

Afatinib dimaleate is also being studied in the treatment of other types of cancer.

Contraindications

  • Any life-threatening bullous, blistering, or exfoliative skin lesions.
  • Confirmed interstitial lung disease (ILD)
  • Severe drug-induced hepatic impairment.
  • Persistent ulcerative keratitis.
  • Symptomatic left ventricle dysfunction.
  • Severe or intolerable adverse reaction occurring at a dose of 20 mg per day.
  • inflammation of the cornea of the eye
  • left ventricular heart failure
  • stomach or intestinal ulcer
  • diverticulitis
  • damage to the liver and inflammation
  • excessive diarrhea
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • lung tissue problem
  • chronic kidney disease stage 4 (severe)

Dosage

Strengths: 30 mg; 40 mg; 20 mg

Non-Small Cell Lung Cancer

  • 40 mg orally once a day until disease progression or intolerance by the patient
  • Take on an empty stomach at least 1 hour before or 2 hours after a meal.
  • Epidermal growth factor receptor (EGFR) mutation status should be established prior to therapy initiation.
  • Do not take a missed dose within 12 hours of the next dose.

Renal Dose Adjustments

  • Mild to moderate renal impairment (CrCl 30 mL/min or greater): No adjustment recommended.
  • Severe renal impairment (CrCl 15 to 29 mL/min): 30 mg orally once a day
  • End stage renal disease (CrCl less than 15 mL/min) or dialysis: Data not available

Liver Dose Adjustments

  • Mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment: No adjustment recommended.
  • Severe (Child-Pugh C) hepatic impairment: Closely monitor the patient and adjust the dose if not tolerated.

Dose Adjustments

Dose Modifications for Adverse Reactions:
WITHHOLD THERAPY FOR:

  • National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3 or higher.
  • Diarrhea Grade 2 or higher persisting for 2 or more consecutive days while taking antidiarrheal medication.
  • Cutaneous reactions of Grade 2 that are prolonged (lasting more than 7 days) or intolerable.
  • Renal impairment Grade 2 or higher

Resume therapy when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1. Reinstitute therapy at a reduced dose (e.g., 10 mg per day less than the dose at which the adverse reaction occurred).

PERMANENTLY DISCONTINUE THERAPY FOR:

  • Life-threatening bullous, blistering, or exfoliative skin lesions
  • Confirmed interstitial lung disease (ILD)
  • Severe drug-induced hepatic impairment
  • Persistent ulcerative keratitis
  • Symptomatic left ventricular dysfunction
  • The severe or intolerable adverse reactions occurring at a dose of 20 mg per day

Dose Modifications for Drug Interactions:

  • P-gp Inhibitors: Reduce the daily dose by 10 mg if not tolerated for patients who require therapy with a P-glycoprotein (P-gp) inhibitor. Resume the previous dose after discontinuation of the P-gp inhibitor as tolerated.
  • P-gp Inducers: Increase the daily dose by 10 mg as tolerated for patients who require chronic therapy with a P-gp inducer. Resume the previous dose 2 to 3 days after discontinuation of the P-gp inducer.

Administration advice:

  • Swallow tablets whole with water.
  • In case of swallowing difficulties, the tablets may be dispersed (not crushed) in approximately 100 mL of noncarbonated water. The dispersion may also be given via a gastric tube.
  • Take on an empty stomach.
  • Do not take a missed dose within 12 hours of the next dose.

Side Effects

The Most Common

  • cracking or swelling of the lips or sores in the corners of the mouth
  • dry skin or itching
  • loss of appetite
  • nail infection
  • acne
  • nose bleeds
  • diarrhea
  • dry mouth, dark urine, decreased sweating, dry skin, and other signs of dehydration
  • decreased urination
  • swelling of the arms, hands, feet, ankles, or lower legs
  • rash
  • pain, redness, peeling, or blistering of skin
  • difficulty breathing
  • shortness of breath
  • rapid, irregular, or pounding heartbeat
  • sudden weight gain
  • cough
  • fever
  • excessive tiredness
  • pain in the right upper part of the stomach
  • unusual bruising or bleeding
  • nausea
  • vomiting
  • yellowing of the skin or eyes
  • dark urine
  • red, swollen, painful, or teary eyes
  • sudden changes in vision, including blurred vision
  • sensitivity to light

More common

  • Bloody or cloudy urine
  • burning, dry, or itching eyes
  • diarrhea
  • difficult, burning, or painful urination
  • discharge or excessive tearing
  • fever
  • frequent urge to urinate
  • redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
  • redness, swelling, or pain of the skin
  • scaling of the skin on the hands and feet
  • tingling of the hands and feet
  • ulceration of the skin
  • Cough
  • difficult breathing
  • Blemishes on the skin
  • canker sores
  • chapped, red, or swollen lips
  • decreased appetite
  • decreased weight
  • dry skin
  • itching skin or rash
  • loosening of the fingernails
  • nosebleeds
  • pimples
  • redness or soreness around the fingernails
  • runny nose
  • scaling, redness, burning, pain, or other signs of inflammation of the lips
  • sores, ulcers, or white spots on the lips or tongue or inside the mouth

Rare

  • Bloody, black, or tarry stools
  • heartburn
  • indigestion
  • nausea
  • severe abdominal pain, cramping, or burning
  • vomiting of material that looks like coffee grounds, severe and continuing
  • Dizziness
  • headache
  • lack or loss of strength
  • stomach pain
  • vomiting

Drug Interactions

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Pregnancy and Lactation

US FDA pregnancy category: Not assigned. 

Pregnancy

Based on findings from animal studies and its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. There are no available data on the use of GILOTRIF in pregnant women. Administration of afatinib to pregnant rabbits during organogenesis at exposures approximately 0.2 times the exposure in humans at the recommended dose of 40 mg daily resulted in embryotoxicity and, in rabbits showing maternal toxicity, increased abortions at late gestational stages [see Data]. Advise a pregnant woman of the
potential risk to a fetus.

Lactation

No information is available on the clinical use of afatinib during breastfeeding. Because afatinib is about 95% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 37 hours and it might accumulate in the infant. the manufacturer recommends that breastfeeding be discontinued during afatinib therapy and for 2 weeks after the last dose.

How should this medicine be used?

Afatinib comes as a tablet to take by mouth. It is usually taken on an empty stomach once a day, at least 1 hour before or 2 hours after eating a meal or snack. Take afatinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take afatinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may temporarily or permanently stop your treatment or decrease the dose if you experience serious side effects of afatinib. Talk to your doctor about how you are feeling during your treatment. Continue to take afatinib even if you feel well. Do not stop taking afatinib without talking to your doctor. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking afatinib,

  • tell your doctor and pharmacist if you are allergic to afatinib, any other medications, or any of the ingredients in afatinib tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: amiodarone (Cordarone, Pacerone); certain antifungal medications such as itraconazole (Sporanox) and ketoconazole (Nizoral); cyclosporine (Gengraf, Neoral, Sandimmune); erythromycin (E.E.S., Erythrocin, others); certain medications for human immunodeficiency virus (HIV) such as nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Invirase); certain medications for seizures such as carbamazepine (Carbatrol, Equetro, Tegretol), phenobarbital, and phenytoin (Dilantin); quinidine (in Nuedexta); rifampin (Rimactane, Rifadin, in Rifater); tacrolimus (Prograf); and verapamil (Calan, Covera, Isoptin, Verelan). Many other medications may also interact with afatinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor what herbal products you are taking, especially St. John’s wort.
  • tell your doctor if you are of Asian descent or have or have ever had lung or breathing problems (other than lung cancer); eye problems, including dry eyes; heart problems; liver or kidney disease; or any other medical condition. Also, tell your doctor if you wear contact lenses.
  • tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while you are taking afatinib and for at least 2 weeks after your treatment. Talk to your doctor about birth control methods that you can use during your treatment. If you become pregnant while taking afatinib, call your doctor immediately. Afatinib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are taking afatinib.
  • plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Afatinib may make your skin sensitive to sunlight. Exposure to sunlight increases the risk that you will develop a rash or acne during your treatment with afatinib.

Monitoring

Afatinib has several monitoring requirements. These include:

  • Given that dermatology adverse reactions are the most commonly reported adverse reactions during treatment, patients should be advised to avoid sun exposure if possible or utilize adequate sun protection.
  • Monitor for signs and symptoms of volume depletion in patients with diarrhea
  • Hepatic impairment was commonly observed in clinical trials; it is advised to monitor liver function periodically during treatment.
  • The patient’s renal function requires periodic monitoring.
  • Keratitis is one of the rare adverse effects but reported in clinical trials – therapy should be interrupted with any suspected keratitis.
  • Recommended to reduce the dose in case of paronychia
  • Monitor patients for any signs and symptoms that raise concern for pulmonary toxicity – interstitial lung disease occurred in a small percentage of patients.
  • Assess left ventricle function before and during treatment in high-risk cardiac patients. This drug should be used with caution in patients with cardiac risk factors and/or decreased left ventricle heart failure as patients with significant cardiac history met exclusion criteria for clinical trials.

Takahashi T. et al. studied using afatinib trough plasma concentrations in patients with non-small-cell lung cancer to improve the safety and efficacy of afatinib therapy.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/201292s017lbl.pdf
  3. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-broadens-afatinib-indication-previously-untreated-metastatic-nsclc-other-non-resistant-egfr
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Afatinib
  5. https://pubchem.ncbi.nlm.nih.gov/compound/Afatinib-dimaleate
  6. https://go.drugbank.com/drugs/DB08916
  7. https://www.drugs.com/dosage/afatinib.html
  8. https://www.cancer.gov/about-cancer/treatment/drugs/afatinibdimaleate
  9. https://www.ncbi.nlm.nih.gov/books/NBK542248/
  10. https://medlineplus.gov/druginfo/meds/a613044.html
  11. https://en.wikipedia.org/wiki/Afatinib
  12. https://www.mayoclinic.org/drugs-supplements/afatinib-oral-route/side-effects/drg-20061227?p=1
  13. https://www.webmd.com/drugs/2/drug-164730/afatinib-oral/details/list-contraindications
  14. NCI Thesaurus Tree
  15. Guide to Pharmacology Target Classification
  16. PubChem
  17. Protein Kinase Inhibitors
  18. Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
  19. NCBI