(For additional information see "Selumetinib: Pediatric drug information")
Neurofibromatosis type 1 (NF1):
Children ≥2 years with a BSA of ≥0.55 m2 (able to swallow whole capsule) and Adolescents: Oral: Doses are based on BSA (see following table) and administered twice daily (approximately every 12 hours). Continue therapy until disease progression or unacceptable toxicity.
|
Daily Dosing of Selumetinib (Ages 2 to 18 Years) | |
|---|---|
|
Body Surface Area Dosing: Based on a dose of 25 mg/m2/dose. | |
|
Body Surface Area |
Recommended Dosage |
|
0.55 – 0.69 m2 |
20 mg in the morning and 10 mg in the evening |
|
0.7 – 0.89 m2 |
20 mg twice daily |
|
0.9 – 1.09 m2 |
25 mg twice daily |
|
1.1 – 1.29 m2 |
30 mg twice daily |
|
1.3 – 1.49 m2 |
35 mg twice daily |
|
1.5 – 1.69 m2 |
40 mg twice daily |
|
1.7 – 1.89 m2 |
45 mg twice daily |
|
≥1.9m2 |
50 mg twice daily |
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
Children ≥2 years and Adolescents: Oral: Note: Although resolution of toxicity may occur, doses should not be reescalated. If a dose-limiting toxicity (excluding cardiac) recurs while patient is on a reduced dose, the dose may be reduced a second time (Dombi 2016). Discontinue therapy if unable to tolerate after 2 dosage reductions.
Dosage reduction levels:
|
Body Surface Area |
First Dose Reduction |
Second Dose Reduction | ||
|
Morning |
Evening |
Morning |
Evening | |
|
0.55 – 0.69 m2 |
10 mg |
10 mg |
10 mg once daily | |
|
0.7 – 0.89 m2 |
20 mg |
10 mg |
10 mg |
10 mg |
|
0.9 – 1.09 m2 |
25 mg |
10 mg |
10 mg |
10 mg |
|
1.1 – 1.29 m2 |
25 mg |
20 mg |
20 mg |
10 mg |
|
1.3 – 1.49 m2 |
25 mg |
25 mg |
25 mg |
10 mg |
|
1.5 – 1.69 m2 |
30 mg |
30 mg |
25 mg |
20 mg |
|
1.7 – 1.89 m2 |
35 mg |
30 mg |
25 mg |
20 mg |
|
≥1.9 m2 |
35 mg |
35 mg |
25 mg |
25 mg |
Dose modification for adverse events:
Cardiomyopathy:
Asymptomatic decrease in left ventricular ejection fraction (LVEF) of ≥10% from baseline and less than lower level of normal: Withhold until resolution, resume at reduced dose.
Symptomatic decreased LVEF: Permanently discontinue.
Grade 3 or 4 decreased LVEF: Permanently discontinue.
Ocular toxicity:
Retinal pigment epithelial detachment: Withhold until resolution, resume at reduced dose.
Retinal vein occlusion: Permanently discontinue.
Gastrointestinal toxicity:
Grade 3 diarrhea: Withhold until improved to grade 0 or 1. Resume at same dose. Permanently discontinue if no improvement within 3 days.
Grade 4 diarrhea: Permanently discontinue.
Grade 3 or 4 colitis: Permanently discontinue.
Skin toxicity (eg, rash, eczema): Grade 3 or 4: Withhold until improvement, resume at reduced dose.
Increased creatine phosphokinase (CPK):
Grade 4 CPK: Withhold until improved to grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.
Myalgia AND any increase in CPK: Withhold until improved to grade 0 or 1. Resume at reduced dose. Permanently discontinue if no improvement within 3 weeks.
Rhabdomyolysis: Permanently discontinue.
Other adverse reactions:
Intolerable grade 2: Withhold selumetinib until improvement to grade 0 or 1. Resume at reduced dose.
Grade 3: Withhold selumetinib until improvement to grade 0 or 1. Resume at reduced dose.
Grade 4: Withhold selumetinib until improve to grade 0 or 1. Resume at reduced dose. Consider discontinuation.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥2 years with BSA ≥0.55 m2 and Adolescents: Oral:
Kidney impairment (any): No dosage adjustment necessary.
End-stage kidney disease: No dosage adjustment necessary.
Children ≥2 years with BSA ≥0.55 m2 and Adolescents: Oral:
Moderate hepatic impairment (Child-Pugh B): Reduce dose to 20 mg/m2 twice daily as follows:
|
Dosage Adjustment for Moderate Hepatic Impairment (20 mg/m2 Twice Daily) | ||
|---|---|---|
|
Body Surface Area |
Moderate Hepatic Impairment | |
|
Morning |
Evening | |
|
0.55 – 0.69 m2 |
10 mg |
10 mg |
|
0.7 – 0.89 m2 |
20 mg |
10 mg |
|
0.9 – 1.09 m2 |
20 mg |
20 mg |
|
1.1 – 1.29 m2 |
25 mg |
25 mg |
|
1.3 – 1.49 m2 |
30 mg |
25 mg |
|
1.5 – 1.69 m2 |
35 mg |
30 mg |
|
1.7 – 1.89 m2 |
35 mg |
35 mg |
|
≥1.9 m2 |
40 mg |
40 mg |
Severe hepatic impairment (Child-Pugh C): There are no dosing adjustments provided in the manufacturer's labeling; in patients with hepatic impairment, dose-normalized total AUC0-inf increases by ~57% and unbound AUC0-inf increases 3.2-fold compared to patients with normal hepatic function.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as sulfate:
Koselugo: 10 mg [contains carrageenan]
Koselugo: 25 mg [contains carrageenan, corn starch, fd&c blue #2 (indigotine)]
No
Oral: Administer on an empty stomach; do not consume food 2 hours before or 1 hour after each dose. Swallow capsule whole with water; do not chew, dissolve, or open capsule. Do not administer to patients unable to swallow capsule whole. If vomiting occurs, do not take additional dose, continue with next scheduled dose.
Missed doses: Do not take a missed dose unless ≥6 hours until next scheduled dose.
Neurofibromatosis type 1: Treatment of neurofibromatosis type 1 in pediatric patients ≥2 years of age who have symptomatic, inoperable plexiform neurofibromas.
Selumetinib may be confused with binimetinib, cobimetinib, selpercatinib, SORAfenib, SUNitinib, trametinib.
This medication is in a class the Institute for Safe Medication Practices included among its lists of drug classes that have a heightened risk of causing significant patient harm when used in error.
Capsules contain vitamin E that may increase bleeding risk. Anemia, hematuria, and epistaxis are commonly reported adverse reactions.
Mechanism: Dose-related; vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors.
Risk factors:
• Exceeding recommended daily vitamin E intake; avoid supplemental vitamin E if daily vitamin E intake (supplements plus vitamin E content from selumetinib capsules) will exceed recommended or safe limits
• Concomitant use with vitamin K antagonists or antiplatelet antagonists; may require dosage adjustments
Cardiomyopathy, defined as a left ventricular reduced ejection fraction (LVEF) ≥10% below baseline, was commonly reported in clinical trials; decreased LVEF resolved in the majority of these patients. May result in treatment interruption, dosage adjustment, or discontinuation.
Risk factors:
• It is unknown if a history of impaired LVEF or a baseline decreased LVEF is a risk factor for selumetinib-induced cardiomyopathy
May commonly cause increased creatine phosphokinase (CPK) in blood specimen with or without musculoskeletal pain. In clinical trials, >75% of pediatric patients experienced increased CPK; however, <10% were grades 3 or 4. May result in treatment interruption, dosage adjustment, or discontinuation. If increased CPK occurs, evaluate for rhabdomyolysis or other causes.
May commonly cause dermatologic toxicities, including acneiform eruption, dermatitis, eczema, maculopapular rash, paronychia, skin rash, and xeroderma. In clinical trials, >90% of pediatric patients experienced some type of skin rash; however, <10% were grades ≥3. Mild to moderate dermatologic toxicities usually resolved with drug interruption and/or dose reduction (Ref). May result in treatment interruption, dosage adjustment, or discontinuation.
Mechanism: Dose-related (Ref); class-effect toxicity of mitogen-activated extracellular kinase (MEK) inhibitors. Selumetinib, a second-generation MEK inhibitor, has shown similar toxicities potentially through inhibition of the RAS/RAF/MEK/ERK (mitogen-activated protein kinase [MAPK]) pathway (Ref).
Onset: Varied (Ref).
May commonly cause GI toxicities, including abdominal pain, constipation, diarrhea (including grades ≥3 severe diarrhea), nausea, stomatitis, and vomiting. Diarrhea is the most frequently reported of the GI toxicities and often resulted in treatment interruption or dosage adjustment in clinical trials; permanent discontinuation may also be required. The median duration of diarrhea in clinical trials was 2 days.
Onset: Intermediate; median time to onset in clinical trials was 17 days.
Ocular toxicities were commonly reported in clinical trials, including blurred vision, photophobia, cataracts, ocular hypertension, periorbital edema, or visual impairment; resolution of toxicity occurred in >80% of patients. May result in treatment interruption, dosage adjustment, or discontinuation.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Cardiomyopathy (23%), edema (20%), facial edema (<20%), hypertension (<20%), reduced ejection fraction (22%), sinus tachycardia (20%)
Dermatologic: Acneiform eruption (50% to 54%), changes of hair (32%), dermatitis (36%), eczema (28%), maculopapular rash (39%), paronychia (48%), pruritus (46%), skin infection (20%), skin rash (80% to 91%), xeroderma (60%)
Endocrine & metabolic: Decreased serum albumin (51%), decreased serum potassium (18%), decreased serum sodium (16%), increased amylase (18%), increased serum potassium (27%), increased serum sodium (18%), weight gain (<20%)
Gastrointestinal: Abdominal pain (76%), constipation (34%), decreased appetite (22%), diarrhea (70% to 77%; severe diarrhea: 24%), increased serum lipase (32%), nausea (66%), stomatitis (50%), vomiting (82%), xerostomia (<20%)
Genitourinary: Hematuria (22%), proteinuria (22%)
Hematologic & oncologic: Anemia (24%), decreased neutrophils (33%, grades ≥3: 4%), lymphocytopenia (20%, grades ≥3: 2%)
Hepatic: Increased serum alanine aminotransferase (35%), increased serum alkaline phosphatase (18%), increased serum aspartate aminotransferase (41%)
Nervous system: Fatigue (56%), headache (48%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (76% to 79%), musculoskeletal pain (58%)
Ophthalmic: Blurred vision (≤15%), cataract (≤15%), ocular hypertension (≤15%), periorbital edema (<20%), photophobia (≤15%), visual impairment (<20%)
Renal: Acute renal failure (<20%)
Respiratory: Dyspnea (<20%), epistaxis (28%), hypoxia (24%)
Miscellaneous: Fever (56%)
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Cardiotoxicity: A small percentage of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 LVEF decline resulting in dose reduction occurred rarely. All patients with decreased LVEF were asymptomatic and were identified during routine echocardiography. In an expanded access program in pediatric patients with NF1, LVEF resulting in permanent selumetinib discontinuation occurred. Permanent selumetinib discontinuation due to left ventricular dysfunction or decreased LVEF also occurred in adults with multiple tumor types (selumetinib is not approved for use in adults).
• CPK elevations: Rhabdomyolysis has been reported in adults who received selumetinib as a single agent (selumetinib is not approved for use in adults).
• Dermatologic toxicity: Dermatologic toxicities, including severe palmar-plantar erythrodysesthesia syndrome, have occurred in adults who received selumetinib either as a single agent or in combination with other anticancer agents (selumetinib is not approved for use in adults).
• GI toxicity: Serious GI toxicities, including perforation, colitis, ileus, and intestinal obstruction, have been reported in adults who received selumetinib either as a single agent or in combination with other anticancer agents (selumetinib is not approved for use in adults). Colitis has been reported in pediatric patients who received selumetinib for uses other than NF1. Patients should begin an antidiarrheal agent (eg, loperamide) immediately after the first unformed/loose stool episode and increase fluid intake during diarrhea episodes.
• Ocular toxicity: Serious ocular toxicities, including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED), occurred in adults who received selumetinib either as a single agent or in combination with other anticancer agents (selumetinib is not approved for use in adults). RPED (requiring permanent discontinuation) also occurred in pediatric patients who received selumetinib (as a single agent).
Disease-related concerns:
• Hepatic impairment: Selumetinib exposure is increased in patients with moderate to severe hepatic impairment. May require dosage modification.
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007).
Substrate of BCRP/ABCG2, CYP1A2 (minor), CYP2A6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor), UGT1A1, UGT1A3; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Selumetinib may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Selumetinib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Selumetinib. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Selumetinib. Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose. For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Selumetinib. Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose. For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Vitamin E (Systemic): Selumetinib may enhance the adverse/toxic effect of Vitamin E (Systemic). Management: If selumetinib is combined with additional vitamin E supplements, ensure that the total daily intake of vitamin E (including the amount of vitamin E in selumetinib and the supplement) does not exceed the recommended or safe limits. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Selumetinib may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Following a high-fat meal (1,000 calories; 50% from fat) in healthy adults administered a single 75 mg dose, the mean selumetinib Cmax and AUC decreased by 50% and 16%, respectively. Tmax was delayed by ~1.5 hours following a high-fat meal.
Following a low-fat meal (400 calories; 25% from fat) in healthy adults administered a single 50 mg dose, the mean selumetinib Cmax and AUC decreased by 60% and 38%, respectively. Tmaxwas delayed by ~0.9 hours following a low-fat meal.
Evaluate pregnancy status prior to use in females of reproductive potential.
Females of reproductive potential should use effective contraception during therapy and for 1 week after the last selumetinib dose. Males with female partners of reproductive potential should use effective contraception during therapy and for 1 week after the last dose of selumetinib.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to selumetinib may cause fetal harm.
It is not known if selumetinib is present in breast milk.
Due to the potential for adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 1 week after the last selumetinib dose.
The 10 mg selumetinib capsule contains vitamin E 32 mg (as D-alpha-tocopheryl polyethylene glycol 1000 succinate; TPGS), and the 25 mg selumetinib capsule contains vitamin E 36 mg (as TPGS).
Monitor LFTs at baseline and as clinically necessary; serum CPK prior to selumetinib initiation, periodically during treatment, and as clinically indicated. Assess ejection fraction (by echocardiogram) prior to selumetinib treatment initiation, every 3 months during the first year, every 6 months thereafter, and as clinically indicated. If selumetinib treatment is interrupted for decreased left ventricular ejection fraction (LVEF), obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon resolution of decreased LVEF to ≥ the institutional lower limit of normal, obtain an echocardiogram or a cardiac MRI every 2 to 3 months or as directed by the cardiology consult. Conduct comprehensive ophthalmic assessments prior to selumetinib initiation, at regular intervals during treatment, and with new or worsening visual changes. If retinal pigment epithelial detachment occurs, follow up with optical coherence tomography assessments every 3 weeks until resolution. Evaluate pregnancy status prior to use (in females of reproductive potential).
Monitor for bleeding in patients who also receive vitamin-K antagonists or antiplatelet agents. Increase INR monitoring (as appropriate) in patients receiving a vitamin-K antagonist. Monitor anticoagulant parameters (including INR or prothrombin time) more frequently and adjust the dose of vitamin-K antagonists or anti-platelet agents as appropriate. Monitor for signs/symptoms of dermatologic toxicity, diarrhea, GI toxicity, ocular toxicity, rhabdomyolysis (especially if CPK elevation occurs). Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Selumetinib is a selective mitogen-activated extracellular kinase (MEK) inhibitor which inhibits MEK protein kinases 1 and 2 (Dombi 2016). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different cancer types. In mouse neurofibromatosis type 1 (NF1) models genetically modified to mirror human NF1 genotype and phenotype, selumetinib inhibited ERK phosphorylation, and reduced neurofibroma numbers, volume, and proliferation.
Distribution: Children ≥2 years and Adolescents: Vss: 78 to 171 L.
Protein binding: 98.4%; to serum albumin (96%) and alpha-1 acid glycoprotein (<35%).
Metabolism: Hepatic, primarily via CYP3A4 (and to a lesser extent by CYP2C9, CYP1A2, CYP2C9, CYP2E1, and CYP3A5); also undergoes glucuronidation by UGT1A1 and UGT1A3. Approximately 56% of intrinsic selumetinib clearance can be attributed to CYP metabolism; ~29% is attributed to direct UGT enzymatic glucuronidation. CYP2C19 and CYP1A2 (with some contribution by CYP2C9 and CYP2A6) generate the active metabolite N-desmethyl selumetinib, which is then metabolized via the same pathways as selumetinib. N-desmethyl selumetinib represents <10% of selumetinib levels in human plasma, but is ~3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.
Bioavailability: 62%.
Half-life elimination: Children ≥2 years and Adolescents: 6.2 hours.
Time to peak: Children ≥2 years and Adolescents: 1 to 1.5 hours.
Excretion: Feces (59%, 19% as unchanged drug); urine: 33% (<1% as parent drug).
Hepatic function impairment: Following administration of a single selumetinib dose, the normalized total AUC0-∞ decreased by 14% in subjects with mild impairment (Child-Pugh class A), and increased by 59% in subjects with moderate impairment (Child-Pugh class B) and by 57% in subjects with severe impairment (Child-Pugh class C), compared to subjects with normal hepatic function. Selumetinib unbound AUC0-∞ decreased by 31% in subjects with mild impairment, and increased by 41% in subjects with moderate impairment, and by 3.2-fold in subjects with severe impairment, compared to subjects with normal hepatic function.
Capsules (Koselugo Oral)
10 mg (per each): $101.08
25 mg (per each): $252.69
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