AFATINIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AFATINIB (AFATINIB).
Afatinib is an irreversible, covalent-binding inhibitor of the ErbB family of tyrosine kinases, including EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4. It blocks downstream signaling pathways such as PI3K/AKT and MAPK, leading to inhibition of tumor cell proliferation and survival.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP3A4-independent pathways including flavin-containing monooxygenase (FMO). Excretion mainly via feces (85%) and urine (4%) as unchanged drug and metabolites. |
| Excretion | Primarily fecal (85%) as unchanged drug and metabolites; renal excretion accounts for <4% of the dose. |
| Half-life | Terminal half-life is approximately 37 hours; supports once-daily dosing with steady-state achieved within 8 days. |
| Protein binding | Approximately 95% bound to plasma proteins, primarily to albumin. |
| Volume of Distribution | Volume of distribution is approximately 2300 L (about 33 L/kg for a 70 kg individual), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 92% relative to an oral solution; food reduces exposure, so take on an empty stomach. |
| Onset of Action | Oral: Clinical effect (tumor response) observed within 2–4 weeks; maximum plasma concentration achieved at 4–6 hours. |
| Duration of Action | Duration of receptor inhibition (EGFR) persists beyond plasma half-life due to irreversible binding; clinical effects last throughout dosing interval (24 hours). |
40 mg orally once daily, continuously.
| Dosage form | TABLET |
| Renal impairment | No starting dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended for severe renal impairment (CrCl <30 mL/min) due to safety concerns. |
| Liver impairment | Child-Pugh A: 40 mg once daily. Child-Pugh B: Reduce dose to 30 mg once daily. Child-Pugh C: Not recommended due to lack of data. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no specific dosing recommendations. |
| Geriatric use | No specific dose adjustment recommended based on age alone; monitor renal function and tolerability, as elderly patients may have decreased renal function or comorbidities. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AFATINIB (AFATINIB).
| Breastfeeding | No human data on afatinib excretion in breast milk; however, animal studies indicate drug presence in milk. M/P ratio is unknown. Due to potential for serious adverse effects in breastfed infants, breastfeeding is contraindicated during therapy and for at least 2 weeks after the last dose. |
| Teratogenic Risk | Afatinib is classified as Pregnancy Category D. First trimester exposure is associated with increased risk of major congenital malformations, including cardiac, skeletal, and neural tube defects based on animal studies showing embryotoxicity and teratogenicity at doses below human exposure. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and impaired renal function due to inhibition of EGFR signaling critical for fetal development. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None reported","Relative contraindications: pre-existing severe hepatic impairment, severe renal impairment, pregnancy, and breastfeeding"]
| Precautions | ["Severe diarrhea (including dehydration and acute kidney injury)","Interstitial lung disease (ILD)/pneumonitis","Severe hepatotoxicity (elevated liver enzymes, hepatitis)","Left ventricular dysfunction (assess LVEF at baseline and during treatment)","Severe bullous, blistering, and exfoliative skin reactions (e.g., Stevens-Johnson syndrome)","Gastrointestinal perforation","Ocular toxicities (keratitis, conjunctivitis)","Renal toxicity (proteinuria, nephrotic syndrome)","Fetal harm (embryo-fetal toxicity)","Drug interactions with CYP3A4 inducers or inhibitors"] |
| Food/Dietary | Take on an empty stomach (at least 1 hour before or 2 hours after food). Avoid grapefruit, grapefruit juice, and Seville oranges as they may alter drug metabolism. High-fat meals reduce absorption. |
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| Fetal Monitoring | Monitor pregnancy status before initiation (negative pregnancy test) and advise effective contraception during treatment and for 2 weeks after. During pregnancy, if exposed, perform detailed fetal ultrasound including cardiac assessment around 20-24 weeks gestation and monitor amniotic fluid volume; maternal monitoring includes periodic renal and hepatic function tests, blood pressure, and proteinuria due to risk of severe hypertension and proteinuria. |
| Fertility Effects | Afatinib may impair fertility in females based on animal studies showing ovarian atrophy and disrupted estrous cycles at clinically relevant doses; effects on male fertility (spermatogenesis impairment) observed in animal studies with reversible changes. Human data are lacking. |
| Clinical Pearls | Monitor for diarrhea, which can be severe; consider loperamide and hydration. Assess for interstitial lung disease (ILD) and hepatotoxicity. Dose reduction required for severe renal impairment (CrCl 15–29 mL/min). For patients with EGFR exon 19 deletion or exon 21 L858R mutation, first-line use improves PFS. Avoid P-glycoprotein strong inducers (e.g., rifampin) during treatment. |
| Patient Advice | Take afatinib at least 1 hour before or 2 hours after a meal. · Do not crush, chew, or split tablets; swallow whole with water. · Seek medical help for severe or persistent diarrhea, cough, or difficulty breathing. · Avoid grapefruit and Seville oranges during treatment. · Report signs of liver problems (yellowing skin/eyes, dark urine). · Use effective contraception during and for 2 weeks after stopping therapy. · Avoid direct sunlight exposure; use sunscreen. |