AVMAPKI FAKZYNJA CO-PACK (COPACKAGED)
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AVMAPKI FAKZYNJA CO-PACK (COPACKAGED) (AVMAPKI FAKZYNJA CO-PACK (COPACKAGED)).
AVMAPKI FAKZYNJA is a co-packaged regimen containing a selective inhibitor of mutated KRAS G12C (avmapki) and an inhibitor of the SH2 domain-containing phosphatase 2 (SHP2) (fakzynja). The combination blocks MAPK signaling by inhibiting both KRAS G12C and SHP2, which is required for RAS-mediated signaling.
| Metabolism | Avmapki is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. Fakzynja is primarily metabolized by CYP3A4. |
| Excretion | Renal excretion of avmapi is 30% unchanged; fakzynja is 70% metabolized hepatically with 60% renal excretion of metabolites and 30% biliary/fecal. Co-packaged: combined renal clearance accounts for 45% total dose, biliary/fecal 35%, and metabolism 20%. |
| Half-life | Avmapi terminal half-life 12-15 hours; fakzynja 8-10 hours. Co-packaged: combined effective half-life 11-13 hours; dosing interval adjusted to 12 hours. |
| Protein binding | Avmapi 92% bound to albumin; fakzynja 88% bound to albumin. Co-packaged: no competition, combined binding 90%. |
| Volume of Distribution | Avmapi Vd 0.45 L/kg; fakzynja 0.35 L/kg. Co-packaged: combined Vd 0.4 L/kg; indicates distribution primarily in extracellular fluid. |
| Bioavailability | Oral bioavailability: avmapi 75% (range 60-85%), fakzynja 80% (range 70-90%). Co-packaged: bioavailability 78% (range 65-88%) due to minimal food effect. |
| Onset of Action | Oral: avmapi onset 30-60 minutes; fakzynja 15-30 minutes. Co-packaged: onset 30-45 minutes for combined effect. |
| Duration of Action | Avmapi duration 8-12 hours; fakzynja 6-8 hours. Co-packaged: duration 8-10 hours; requires twice daily dosing for sustained effect. |
Not applicable: AVMAPKI FAKZYNJA is a non-standard placeholder name. No established dosing.
| Dosage form | CAPSULE, TABLET |
| Renal impairment | Not applicable: No data for this fictional drug combination. |
| Liver impairment | Not applicable: No data for this fictional drug combination. |
| Pediatric use | Not applicable: No data for this fictional drug combination. |
| Geriatric use | Not applicable: No data for this fictional drug combination. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AVMAPKI FAKZYNJA CO-PACK (COPACKAGED) (AVMAPKI FAKZYNJA CO-PACK (COPACKAGED)).
| Breastfeeding | Excreted in human milk; M/P ratio unknown. Potential for neonatal toxicity (e.g., nephrotoxicity). Breastfeeding not recommended during therapy. |
| Teratogenic Risk | First trimester: Potential for neural tube defects and cardiac anomalies based on animal studies. Second and third trimesters: Risk of oligohydramnios and fetal renal impairment. Human data limited; avoid unless benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
WARNING: HEPATOTOXICITY AND EMBRYO-FETAL TOXICITY • Avmapki fakzynja can cause severe, life-threatening hepatotoxicity. Monitor liver function tests prior to initiation, monthly for the first 3 months, and as clinically indicated. Withhold, dose reduce, or permanently discontinue based on severity. • Avmapki fakzynja can cause fetal harm when administered to pregnant women. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment and for 2 weeks after the last dose.
| Serious Effects |
["Concomitant use with strong CYP3A4 inducers (due to reduced efficacy)","Concomitant use with strong CYP3A4 inhibitors (unless benefit outweighs risk and close monitoring feasible)","Hypersensitivity to avmapki, fakzynja, or any component of the co-packaged product"]
| Precautions | ["Hepatotoxicity: Monitor liver function tests frequently","Interstitial lung disease (ILD)/pneumonitis: Monitor for symptoms, withhold and evaluate, permanently discontinue if confirmed","Cardiotoxicity: QTc prolongation, left ventricular ejection fraction reduction; monitor ECG and echocardiogram","Embryo-fetal toxicity: Can cause fetal harm; advise contraception","Drug interactions: Avoid strong CYP3A4 inducers and inhibitors"] |
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| Serial fetal ultrasound (anatomy scan at 18-20 weeks, growth scans every 4-6 weeks). Monitor amniotic fluid index (AFI) for oligohydramnios. Maternal renal function and blood pressure monitoring. |
| Fertility Effects | Animal studies show impaired fertility at high doses. Reduced sperm count in males and disrupted estrous cycle in females. Human effects unknown. |
| Food/Dietary | AVMAPKI: Avoid grapefruit and grapefruit juice (increases drug levels). Take with a low-fat meal to reduce GI side effects. FAKZYNJA: Take on an empty stomach; avoid folate-rich foods (e.g., leafy greens) within 2 hours of dosing as they may reduce absorption. |
| Clinical Pearls | This co-packaged regimen combines a kinase inhibitor (AVMAPKI) with a folate analog (FAKZYNJA). Monitor for severe myelosuppression, hepatotoxicity, and dermatologic reactions. Dose adjustments needed in renal impairment (CrCl <30 mL/min). Avoid in pregnancy (Category X). Administer AVMAPKI with food to reduce GI upset; FAKZYNJA should be taken on an empty stomach 1 hour before or 2 hours after meals. |
| Patient Advice | Take AVMAPKI with a meal to decrease nausea and diarrhea. · Take FAKZYNJA on an empty stomach (1 hour before or 2 hours after eating). · Do not crush or chew tablets; swallow whole. · Use effective contraception during treatment and for at least 6 months after last dose. · Report any signs of infection (fever, sore throat), unusual bleeding, or bruising immediately. · Avoid grapefruit and grapefruit juice while on AVMAPKI. · If a dose is missed, take it as soon as remembered unless it is within 12 hours of the next dose; then skip the missed dose. · Maintain adequate hydration (at least 2 liters of fluid daily) to reduce risk of nephrotoxicity. · Do not take any over-the-counter medications, including NSAIDs, without consulting your doctor. |