Usage
- Afatinib dimaleate is prescribed for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. It is also used in patients with metastatic squamous NSCLC who have progressed after platinum-based chemotherapy.
- Pharmacological Classification: Afatinib is a kinase inhibitor, specifically an irreversible ErbB family blocker.
- Mechanism of Action: Afatinib irreversibly binds to and inhibits ErbB family receptors, including EGFR (ErbB1), HER2 (ErbB2), and ErbB4. This inhibition blocks downstream signaling pathways involved in cell growth and proliferation, leading to tumor regression.
Alternate Names
- INN: Afatinib
- Brand Name: Gilotrif
How It Works
- Pharmacodynamics: Afatinib inhibits ErbB family receptors, resulting in decreased tumor cell growth and proliferation.
- Pharmacokinetics:
- Absorption: Administered orally, Afatinib is absorbed with peak plasma concentrations occurring 2-5 hours after administration. Food reduces its absorption.
- Metabolism: Minimal hepatic metabolism; primarily excreted unchanged.
- Elimination: Predominantly excreted in the feces with a half-life of approximately 37 hours.
- Mode of Action: Irreversible binding and inhibition of ErbB family receptors (EGFR, HER2, ErbB4), disrupting downstream signaling and inducing apoptosis in tumor cells.
- Receptor Binding: Covalent binding to the kinase domain of ErbB family receptors.
- Elimination Pathways: Primarily fecal excretion; minor renal excretion.
Dosage
Standard Dosage
Adults:
- First-line NSCLC (EGFR mutation-positive): 40 mg orally once daily. A dose escalation to a maximum of 50 mg/day may be considered in patients who tolerate 40 mg/day in the first cycle of treatment and have not had a prior dose reduction.
- Previously treated metastatic squamous NSCLC: 40 mg orally once daily.
- Administer on an empty stomach at least one hour before or two hours after a meal.
Children:
- The safety and efficacy of afatinib have not been established in pediatric patients.
Special Cases:
- Elderly Patients: No dose adjustment is required but close monitoring for adverse effects, especially diarrhea, is recommended.
- Patients with Renal Impairment: In patients with severe renal impairment (creatinine clearance <30 mL/min), a reduced dose of 30 mg once daily is recommended.
- Patients with Hepatic Dysfunction: No dose adjustment is required for mild or moderate hepatic impairment. Close monitoring is necessary. Use with caution in patients with severe hepatic impairment.
- Patients with Comorbid Conditions: Close monitoring is necessary for patients with a history of keratitis, ulcerative keratitis, or severe dry eye.
Clinical Use Cases
Afatinib dimaleate is specifically indicated for certain types of NSCLC. It is not indicated for Intubation, Surgical Procedures, Mechanical Ventilation, ICU use, or emergency situations such as status epilepticus or cardiac arrest.
Dosage Adjustments
Dose reductions or treatment interruption may be required for managing adverse events, especially diarrhea, skin reactions, and stomatitis. Specific dose reduction schedules are available in the full prescribing information.
Side Effects
Common Side Effects:
- Diarrhea
- Rash/Acne
- Stomatitis (mouth sores)
- Paronychia (nail infection)
- Dry skin
- Anorexia (loss of appetite)
- Nausea/Vomiting
- Pruritus (itching)
Rare but Serious Side Effects:
- Interstitial lung disease (ILD)
- Hepatic toxicity (liver damage)
- Gastrointestinal perforation
- Keratitis (corneal inflammation)
Long-Term Effects:
- The potential long-term effects of afatinib are still under investigation.
Adverse Drug Reactions (ADR):
- Severe diarrhea can lead to dehydration, renal failure, and even death.
- Bullous, exfoliative, and other severe skin reactions.
Contraindications
- Hypersensitivity to afatinib or any component of the formulation.
Drug Interactions
- Strong P-gp inhibitors: Co-administration may increase afatinib exposure. Administer P-gp inhibitors simultaneously with or after afatinib.
- Strong P-gp inducers: May decrease afatinib exposure. Dose adjustment of afatinib may be necessary.
- H2-receptor antagonists and proton pump inhibitors: May decrease afatinib absorption. Avoid concomitant use.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D
- Afatinib can cause fetal harm. Women of childbearing potential should use effective contraception during treatment and for at least 2 weeks after the last dose.
- Breastfeeding: Afatinib is likely excreted in breast milk. Breastfeeding should be avoided during treatment and for at least 2 weeks after the last dose.
Drug Profile Summary
- Mechanism of Action: Irreversible ErbB family inhibitor.
- Side Effects: Diarrhea, rash, acne, stomatitis, paronychia, dry skin, decreased appetite.
- Contraindications: Hypersensitivity to afatinib.
- Drug Interactions: Strong P-gp inhibitors and inducers, H2-receptor antagonists, proton pump inhibitors.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended during breastfeeding.
- Dosage: 40 mg once daily (adjustments may be necessary).
- Monitoring Parameters: Liver function tests, monitor for diarrhea and skin reactions.
Popular Combinations
Afatinib is typically used as monotherapy and not in combination with other drugs for the approved indications.
Precautions
- General Precautions: Confirm EGFR mutation status prior to starting therapy. Monitor for diarrhea, skin reactions, and liver function.
- Specific Populations: Refer to dosage adjustments sections for elderly, renally impaired, and hepatically impaired patients. Avoid use in pregnant women and breastfeeding mothers. Pediatric use not recommended.
- Lifestyle Considerations: Avoid or minimize sun exposure due to photosensitivity risk. Advise against driving if experiencing visual disturbances or other adverse effects.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Afatinib dimaleate?
A: The recommended dose for adults is 40 mg once daily, taken on an empty stomach. Dose adjustments may be necessary depending on individual patient characteristics and adverse effects.
Q2: What are the most common side effects?
A: The most common side effects include diarrhea, rash/acne, stomatitis, paronychia, and dry skin.
Q3: How should diarrhea be managed in patients taking afatinib?
A: Diarrhea should be managed proactively with antidiarrheal medications and close monitoring for dehydration. Dose reduction or treatment interruption may be necessary in severe cases.
Q4: What are the contraindications to afatinib therapy?
A: Known hypersensitivity to afatinib or any component of the formulation is a contraindication.
Q5: Can afatinib be used in pregnant or breastfeeding women?
A: Afatinib is contraindicated during pregnancy due to the potential for fetal harm. Breastfeeding should also be avoided during treatment.
Q6: How does afatinib interact with other drugs?
A: Afatinib interacts with strong P-gp inhibitors and inducers. Concomitant use of H2-receptor antagonists and proton pump inhibitors should be avoided.
Q7: What is the mechanism of action of afatinib?
A: Afatinib irreversibly inhibits ErbB family receptors, including EGFR, HER2, and ErbB4, blocking downstream signaling pathways essential for tumor cell growth and survival.
Q8: Are there any specific monitoring parameters for patients on afatinib?
A: Liver function tests should be monitored periodically. Patients should also be closely monitored for diarrhea, skin reactions, and other adverse effects.
Q9: Can afatinib be crushed or dispersed in water?
A: If swallowing whole tablets is not possible, afatinib tablets can be dispersed in approximately 100 mL of non-carbonated water. Consume the dispersion immediately, then rinse the glass with another 100 mL of water and consume that as well. The dispersion can also be administered via a gastric tube.
