GILOTRIF
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GILOTRIF (GILOTRIF).
GILOTRIF (afatinib) is an irreversible inhibitor of the ErbB family of tyrosine kinases, including EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4. It binds covalently to the ATP-binding pocket of the kinase domain, blocking downstream signaling pathways involved in cell proliferation, survival, and angiogenesis.
| Metabolism | Primarily metabolized by non-enzymatic covalent adduct formation and enzymatic conjugation with glutathione. Minimal involvement of CYP450 enzymes (<1% of dose); mainly excreted in feces (85%) and urine (2%). |
| Excretion | Approximately 88% of the administered dose is eliminated via feces (with 85% as unchanged parent drug), and 8% via urine (with <5% as unchanged drug). Biliary excretion is the primary route for unchanged drug. |
| Half-life | Terminal elimination half-life is approximately 41 hours, supporting once-daily dosing. Steady-state is reached within 8 days. |
| Protein binding | Approximately 95% bound to plasma proteins (primarily albumin and alpha-1 acid glycoprotein). |
| Volume of Distribution | Volume of distribution (Vd) is approximately 2100 L, indicating extensive tissue distribution. After oral administration, the apparent Vd is high (mean 2100 L), suggesting extensive extravascular distribution. |
| Bioavailability | Oral bioavailability is approximately 96% (fasting). Food decreases the extent of absorption (AUC reduced by 50%) and delays absorption; therefore, it should be taken at least 1 hour before or 2 hours after a meal. |
| Onset of Action | No defined onset of action; clinical effect (tumor response) is typically assessed after several weeks of continuous daily oral dosing. Maximum plasma concentrations occur 2-5 hours post-dose. |
| Duration of Action | Duration of action is sustained over the dosing interval (24 hours) due to long half-life. Once-daily dosing maintains continuous EGFR inhibition. Duration of clinical effect is variable and depends on tumor response and tolerability. |
| Molecular Weight | 487.5 |
40 mg orally once daily for first-line treatment of EGFR mutation-positive non-small cell lung cancer; may be increased to 50 mg if tolerated.
| Dosage form | TABLET |
| Renal impairment | For GFR 30-49 mL/min: 30 mg orally once daily. For GFR <30 mL/min: 20 mg orally once daily. Not recommended for severe renal impairment (end-stage renal disease) due to lack of data. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: 30 mg orally once daily. Child-Pugh C: 20 mg orally once daily. |
| Pediatric use | Safety and effectiveness not established in pediatric patients. |
| Geriatric use | No specific dose adjustment required based on age alone; monitor renal function and adjust dose per renal guidelines if applicable. |
| 1st trimester | Based on animal studies, afatinib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. Advise pregnant women of the potential risk to the fetus. |
| 2nd trimester | Afatinib is contraindicated in pregnancy due to teratogenicity and embryotoxicity observed in animal models. Avoid use in second trimester unless no alternative therapy exists. |
| 3rd trimester | Use in third trimester may cause oligohydramnios and neonatal renal impairment. Discontinue 1-2 weeks before expected delivery if possible. |
Clinical note
Comprehensive clinical and safety monograph for GILOTRIF (GILOTRIF).
| Placental transfer | Afatinib crosses the placenta in animal models. Human data are limited, but based on molecular weight (487.5 Da) and protein binding, placental transfer is expected. |
| Breastfeeding | It is not known whether afatinib is excreted in human milk. However, due to the potential for serious adverse reactions in nursing infants, advise women not to breastfeed during treatment with afatinib and for at least 2 weeks after the last dose. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
PregnancyBreastfeedingSevere hypersensitivity to afatinib or any excipients
| Precautions | Interstitial lung disease (ILD)/pneumonitis: monitor for pulmonary symptoms; discontinue if confirmed, Diarrhea: can lead to severe dehydration and renal impairment; manage with antidiarrheals and fluid replacement, Hepatotoxicity: monitor liver function tests; dose reduction or discontinuation may be required, Bullous and exfoliative skin disorders: including Stevens-Johnson syndrome; withhold or discontinue, Keratitis: evaluate for ocular symptoms, Left ventricular dysfunction: assess cardiac function in patients with cardiac risk factors, Fetal harm: can cause fetal harm when administered to pregnant women |
| Food/Dietary | GILOTRIF should be taken on an empty stomach (at least 1 hour before or 2 hours after a meal). Avoid grapefruit and grapefruit juice as they may increase drug levels. High-fat meals can reduce absorption; avoid concurrent intake. No other specific dietary restrictions. |
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| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | Based on animal studies and its mechanism of action (EGFR inhibitor), afatinib is teratogenic and embryotoxic. In pregnant rats and rabbits, afatinib caused embryo-fetal death, reduced fetal weight, and skeletal anomalies at maternal exposures below the human AUC at the 40 mg dose. There are no adequate human studies. Use is contraindicated in pregnancy. First trimester exposure poses the highest risk for major malformations; second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and fetal renal impairment. |
| Fetal Monitoring | For pregnant patients inadvertently exposed, monitor fetal growth (ultrasound for growth restriction), amniotic fluid volume (oligohydramnios), and renal function. Postnatal monitoring for EGFR inhibitor-related toxicities (e.g., skin rash, diarrhea, ocular toxicity). |
| Fertility Effects | Based on animal studies, afatinib may impair female fertility. In female rats, afatinib caused disruption of estrous cycles and reduced fertility at doses 0.6 times the human AUC at 40 mg. Reversibility not established. Male fertility effects unknown. |
| Clinical Pearls | GILOTRIF (afatinib) is an irreversible ErbB family blocker indicated for EGFR mutation-positive non-small cell lung cancer. Monitor for diarrhea, which can be severe; initiate antidiarrheal agents promptly. Interstitial lung disease (ILD) occurs in 1.6% of patients; discontinue if ILD suspected. Severe hepatotoxicity can occur; monitor LFTs monthly. Dose reduction for adverse reactions: first reduction to 40 mg, second to 30 mg. Avoid use with strong P-gp inducers (e.g., rifampin) or inhibitors (e.g., ritonavir). |
| Patient Advice | Take GILOTRIF on an empty stomach, at least 1 hour before or 2 hours after a meal. · Swallow the tablet whole with a glass of water; do not crush or chew. · If you miss a dose, skip it if the next dose is within 12 hours; do not double up. · Contact your doctor immediately if you experience severe diarrhea, vomiting, or dehydration. · Seek emergency medical help for symptoms of ILD: new or worsening shortness of breath, cough, or fever. · Use effective contraception during treatment and for at least 2 weeks after the last dose. · Avoid grapefruit and grapefruit juice while taking GILOTRIF. |