KOSELUGO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KOSELUGO (KOSELUGO).
Selective inhibitor of MEK1 and MEK2, downstream kinases in the RAS/RAF/MEK/ERK signaling pathway. Inhibits cell proliferation and induces apoptosis in tumor cells with activating mutations in BRAF or RAS.
| Metabolism | Primarily metabolized by UGT1A1 and UGT1A3 via glucuronidation; minor metabolism by CYP3A4. Metabolites are excreted in feces and urine. |
| Excretion | Primarily excreted via feces (94%) with minimal renal excretion (<1% unchanged in urine). Biliary excretion accounts for a minor pathway. |
| Half-life | Terminal elimination half-life is approximately 23-25 hours, supporting once-daily dosing with steady-state achieved within 5 days. |
| Protein binding | Highly protein bound (97%) primarily to albumin. |
| Volume of Distribution | Volume of distribution is approximately 76 L (1.09 L/kg for a 70 kg person), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is not formally determined but is estimated to be low (~10-15%) due to first-pass metabolism; food does not significantly affect absorption. |
| Onset of Action | Oral: Clinical effect (MAPK pathway inhibition) begins within 2-4 hours post-dose; tumor response may be observed within 8-12 weeks. |
| Duration of Action | The pharmacodynamic effect (MEK inhibition) persists for the dosing interval (24 hours) due to sustained target occupancy; continuous dosing required for ongoing antitumor activity. |
600 mg orally twice daily on an empty stomach (at least 1 hour before or 2 hours after a meal).
| Dosage form | CAPSULE |
| Renal impairment | For GFR 15-29 mL/min: reduce to 400 mg twice daily. For GFR <15 mL/min or ESRD: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce to 400 mg twice daily. Child-Pugh C: not recommended. |
| Pediatric use | Not approved for pediatric use; no established dosing. |
| Geriatric use | No specific dose adjustment required based on age; monitor renal function as elderly may have decreased GFR. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for KOSELUGO (KOSELUGO).
| Breastfeeding | No data on the presence of selumetinib or its metabolites in human milk, effects on the breastfed child, or milk production. However, due to the potential for serious adverse reactions in nursing infants, advise women not to breastfeed during treatment and for at least 1 week after the last dose. |
| Teratogenic Risk | KOSELUGO (selumetinib) is a MEK inhibitor with known embryofetal toxicity. Based on animal studies, it causes teratogenicity (e.g., cardiovascular, skeletal malformations) when administered during organogenesis. In humans, there are no adequate data; however, given its mechanism, there is a potential risk of fetal harm if used during pregnancy. Avoid use in pregnant women; verify pregnancy status before initiation. Use effective contraception during treatment and for at least 1 week after last dose. |
■ FDA Black Box Warning
No FDA boxed warning.
| Serious Effects |
None known.
| Precautions | ["Cardiomyopathy (decreased left ventricular ejection fraction)","Ocular toxicity (retinal vein occlusion, retinal pigment epithelial detachment)","Interstitial lung disease/pneumonitis","Hemorrhage (including gastrointestinal and central nervous system)","Severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome)","Increased creatine phosphokinase (CPK) and rhabdomyolysis","Risk of veno-occlusive disease (VOD) when co-administered with mTOR inhibitors"] |
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| Fetal Monitoring | Pregnancy testing is recommended prior to initiation of therapy and periodically during treatment. Women of reproductive potential should use effective contraception. If pregnancy occurs, immediately discontinue Koselugo and refer to maternal-fetal medicine for counseling and monitoring. Fetal ultrasound may be considered if exposure occurs. |
| Fertility Effects | Based on animal studies, Koselugo may impair male and female fertility. In female dogs, reduced ovarian follicle counts and corpora lutea were observed. In male dogs, reduced testicular weights and hypospermia occurred. Reversibility of these effects is unknown. Advise patients of potential impact on fertility. |