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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for GILOTRIF (GILOTRIF).
| Breastfeeding | No data on afatinib presence in human milk, effects on the breastfed infant, or milk production. Because of potential serious adverse reactions (e.g., diarrhea, skin reactions, interstitial lung disease), breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose. M/P ratio is unknown. |
| 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. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
["None known (no absolute contraindications in FDA labeling)"]
| 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"] |
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| 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. |