Koselugo (selumetinib sulfate)

Dosage of selumetinib sulfate is expressed in terms of selumetinib.

If adverse reactions occur during selumetinib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage reduction is required, the dosage of selumetinib should be reduced based on BSA as described in Table 3 for selumetinib capsules and Table 4 for selumetinib granules. If more than 2 dosage reductions are required, permanently discontinue selumetinib.

Table 3. Recommended Dosage Reduction for Selumetinib Capsule Toxicity.

BSA (m2) First Dosage Reduction Second Dosage Reduction 0.55-0.69 m2 Reduce selumetinib Reduce selumetinib dosage to 10 mg twice dosage to 10 mg once daily daily 0.70-0.89 m2 Reduce selumetinib Reduce selumetinib dosage to 20 mg in the dosage to 10 mg twice morning and 10 mg in the daily evening 0.90-1.09 m2 Reduce selumetinib Reduce selumetinib dosage to 25 mg in the dosage to 10 mg twice morning and 10 mg in the daily evening 1.10-1.29 m2 Reduce selumetinib Reduce selumetinib dosage to 25 mg in the dosage to 20 mg in the morning and 20 mg in the morning and 10 mg in the evening evening 1.30-1.49 m2 Reduce selumetinib Reduce selumetinib dosage to 25 mg twice dosage to 25 mg in the daily morning and 10 mg in the evening 1.50-1.69 m2 Reduce selumetinib Reduce selumetinib dosage to 30 mg twice dosage to 25 mg in the daily morning and 20 mg in the evening 1.70-1.89 m2 Reduce selumetinib Reduce selumetinib dosage to 35 mg in the dosage to 25 mg in the morning and 30 mg in the morning and 20 mg in the evening evening >=1.90 m2 Reduce selumetinib Reduce selumetinib dosage to 35 mg twice dosage to 25 mg twice daily daily

Table 4. Recommended Dosage Reduction for Selumetinib Granule Toxicity.

BSA (m2) First Dosage Reduction Second Dosage Reduction 0.40-0.59 m2 Reduce selumetinib Reduce selumetinib dosage to 10 mg twice dosage to 7.5 mg twice daily daily 0.60-0.69 m2 Reduce selumetinib Reduce selumetinib dosage to 12.5 mg twice dosage to 10 mg twice daily daily 0.70-0.89 m2 Reduce selumetinib Reduce selumetinib dosage to 15 mg twice dosage to 12.5 mg twice daily daily 0.90-1.09 m2 Reduce selumetinib Reduce selumetinib dosage to 20 mg twice dosage to 15 mg twice daily daily 1.10-1.29 m2 Reduce selumetinib Reduce selumetinib dosage to 22.5 mg twice dosage to 15 mg twice daily daily 1.30-1.49 m2 Reduce selumetinib Reduce selumetinib dosage to 25 mg twice dosage to 25 mg in the daily morning and 10 mg in the evening 1.50-1.69 m2 Reduce selumetinib Reduce selumetinib dosage to 30 mg twice dosage to 25 mg in the daily morning and 20 mg in the evening 1.70-1.89 m2 Reduce selumetinib Reduce selumetinib dosage to 35 mg in the dosage to 25 mg in the morning and 30 mg in the morning and 20 mg in the evening evening >=1.90 m2 Reduce selumetinib Reduce selumetinib dosage to 35 mg twice dosage to 25 mg twice daily daily

If an adverse reaction occurs, modify dosage accordingly (see Table 5).

Table 5. Dosage Modification for Selumetinib Toxicity.

Adverse Reaction and Severity Modification Left Ventricular Dysfunction Asymptomatic decrease in LVEF of Withhold therapy until >=10% from baseline and less than cardiomyopathy resolves, and then the LLN resume at reduced dosage Symptomatic decreased LVEF Permanently discontinue Grade 3 or 4 decreased LVEF Permanently discontinue Ocular Toxicity Retinal pigment epithelial Withhold therapy until RPED detachment (RPED) resolves, and then resume at reduced dosage Retinal vein occlusion Permanently discontinue GI Toxicity Grade 3 diarrhea Withhold therapy until diarrhea improves to grade 0 or 1, and then resume at same dosage If grade 3 diarrhea does not improve within 3 days, permanently discontinue Grade 4 diarrhea Permanently discontinue Grade 3 or 4 colitis Permanently discontinue Dermatologic Toxicity Grade 3 or 4 Withhold therapy until toxicity improves, and then resume at reduced dosage Musculoskeletal Effects Grade 4 elevation of CK Withhold therapy until elevated CK concentration concentration improves to grade 0 or 1, and then resume at reduced dosage If grade 4 elevation of CK concentration does not improve within 3 weeks, permanently discontinue Elevated CK concentration (any Withhold therapy until elevated CK grade) and myalgia concentration and myalgia improve to grade 0 or 1, and then resume at reduced dosage < If elevated CK concentration and myalgia do not improve within 3 weeks, permanently discontinue Rhabdomyolysis Permanently discontinue Other Toxicity Grade 2 (intolerable) Withhold therapy until toxicity improves to grade 0 or 1, and then resume at reduced dosage Grade 3 Withhold therapy until toxicity improves to grade 0 or 1, and then resume at reduced dosage Grade 4 Withhold therapy until toxicity improves to grade 0 or 1, and then resume at reduced dosage or consider discontinuance of therapy

Selumetinib is available in two oral dosage forms: capsules and granules. The granules should be prescribed to patients who have difficulty swallowing the capsules.

Selumetinib capsules may be administered without regard to meals. Do not administer selumetinib to patients who are unable to swallow an intact capsule. Capsules must be swallowed whole; do not open, chew, or crush capsules.

Selumetinib granules should be sprinkled on or mixed with a small amount (about 1 to 3 teaspoons) of smooth yogurt, or fruit puree containing the following fruits: apple, banana, pear, or strawberry. The patient should consume the preparation within 30 minutes; if not consumed within 30 minutes, discard and prepare a new dose. If a dose was partially consumed within 30 minutes of preparation, discard the remainder of the dose. The patient should not prepare a new dose in this situation but rather should aim to complete dosing within 30 minutes with the next preparation.

Selumetinib granules should be free-flowing. The granules should not be used if clumped or stuck inside the capsule shell. The capsule shells of the selumetinib granules should be discarded after use. The capsule shells should not be swallowed, chewed, or dissolved. Selumetinib oral granules should not be chewed or crushed and should not be added to liquids. The granules should also not be mixed in grapefruit or any juice, fruit puree, or jam containing Seville orange.

If a dose of capsules or granules is missed by <=6 hours, the missed dose should be taken as soon as the patient or caregiver remembers. If a dose is missed by >6 hours, the missed dose should be skipped.

If vomiting occurs following administration of selumetinib capsules or granules, a replacement dose should not be administered, and the next dose should be taken at the regularly scheduled time.

Selumetinib capsules should be stored at 20-25degreesC (excursions permitted to 15-30degreesC). The capsules should be dispensed and stored in the original container to protect from light and moisture.

Selumetinib oral granules should be stored and transported under refrigeration (2-8degreesC). After dispensing, patients can store the granules at room temperature 20-25degreesC not exceeding 30degreesC. The oral granules may clump together or stick to the capsule shell if exposed to high temperatures; this may lead to an underdose of selumetinib.

The dessicant should not be removed from the capsule or granule bottle and the bottle should be tightly closed after initial opening.

No dosing information is available for this tab.

Selumetinib is primarily metabolized by cytochrome P-450 (CYP) 3A4 and, to a lesser extent, by CYP isoenzymes 2C19, 1A2, 2C9, 2E1, and 3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. Metabolism of selumetinib to the active metabolite N-desmethyl selumetinib is mediated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6. N-Desmethyl selumetinib is metabolized via the same routes as selumetinib.

In vitro, selumetinib does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, or 2E1. Selumetinib does not induce CYP isoenzymes 3A4, 1A2, or 2B6.

Selumetinib does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K transporters. The drug is a substrate of BCRP and P-gp transporters.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selumetinib/Strong And Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may increase the metabolism of selumetinib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and selumetinib may result in decreased levels and clinical effectiveness of selumetinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of selumetinib recommends avoiding concurrent use with strong or moderate CYP3A4 inducers due to potential decrease in exposure to selumetinib and loss of efficacy.(1) Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and selumetinib should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of 22 healthy subjects, rifampin 600 mg daily (a strong CYP3A4 inducer) decreased selumetinib area-under-curve (AUC) and maximum concentration (Cmax) by 51% and 26%, respectively.(2) Concomitant use of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease selumetinib AUC and Cmax by 38% and 22%, respectively.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selumetinib/Strong And Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of selumetinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from selumetinib, including vomiting, diarrhea, skin rashes, ocular toxicity (e.g., blurred vision, visual loss), cardiomyopathy, and rhabdomyolysis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of selumetinib states that the coadministration of selumetinib with strong or moderate CYP3A4 inhibitors should be avoided. If coadministration cannot be avoided, the dosage of selumetinib should be reduced as follows: -If the current dose is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily. -If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily. If the strong or moderate CYP3A4 inhibitor is discontinued, resume the selumetinib dose that was taken prior to the initiation of the inhibitor after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)

DISCUSSION: In a study of 26 healthy subjects, itraconazole 200 mg twice daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of selumetinib 25 mg by 49% and 19%, respectively. Fluconazole 400 mg loading dose then 200 mg daily (a moderate CYP3A4 inhibitor and strong CYP2C19 inhibitor) increased AUC and Cmax of selumetinib (25 mg) by 53% and 26%.(1,2) In a pharmacokinetic model, erythromycin (a moderate CYP3A4 inhibitor) was predicted to increase selumetinib AUC and Cmax by 41% and 23%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib and voriconazole.(3) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3)

There are no moderate interactions for this drug.

*None.

• Lactation

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic heart failure
• Colitis
• Diarrhea
• Disease of liver
• Increased creatine kinase level
• Pregnancy
• Retinal pigment epithelial detachment

There are no moderate contraindications for this drug.

Adverse effects reported in >=40% of pediatric patients include vomiting, diarrhea, increased CPK, dry skin, paronychia, nausea, dermatitis acneiform, and pyrexia.

Adverse effects reported in >=40% of adult patients include rash (all), dermatitis acneiform, and diarrhea.

Less Frequent

• Acute kidney injury
• Anemia
• Cardiomyopathy
• Cataracts
• Colitis
• Dyspnea
• Elevated serum lipase
• Hyperkalemia
• Hypertension
• Hypokalemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Left ventricular failure
• Lymphopenia
• Neutropenic disorder
• Ocular hypertension
• Retinal vascular occlusion

Rare or Very Rare

• Retinal pigment epithelial detachment
• Rhabdomyolysis

More Frequent

• Abnormal hepatic function tests
• Acneiform eruption
• Acute abdominal pain
• Diarrhea
• Dry skin
• Fatigue
• Fever
• Headache disorder
• Increased creatine kinase level
• Musculoskeletal pain
• Nausea
• Paronychia
• Pruritus of skin
• Skin rash
• Stomatitis
• Vomiting

Less Frequent

• Alopecia
• Anorexia
• Blurred vision
• Constipation
• Eczema
• Edema
• Epistaxis
• Facial edema
• Hair discoloration
• Hematuria
• Maculopapular rash
• Myalgia
• Periorbital edema
• Photophobia
• Proteinuria
• Skin and skin structure infection
• Skin inflammation
• Tachycardia
• Visual changes
• Weight gain
• Xerostomia

Rare or Very Rare

• Central serous chorioretinopathy
• Gastroenteritis
• Subretinal fluid
• Upper respiratory infection

No enhanced messaging available.

The safety and efficacy of selumetinib have been established in pediatric patients >=1 year of age with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas.

The safety and efficacy of selumetinib have not been established in pediatric patients <1 year of age.

The expanded approval of selumetinib capsules and granules to pediatric patients >=1 year of age was based on adequate bridging between the oral granule and approved capsule formulations in a relative bioavailability study in healthy adults and exposure matching between the pediatric patient populations in the SPRINT study (capsule formulation, >=2 years of age) and the SPRINKLE study (oral granule formulation, >=1 year of age). Similar exposure between the formulations supported extrapolation of efficacy from pediatric patients >=2 to >=1 year of age.

In 3-month general toxicology studies, growth plate dysplasia occurred in male rats receiving selumetinib at a dosage approximately 60 times the human exposure based on AUC at the recommended dosage of 25 mg/m2 twice daily).

Because of the intended chronic use of the drug for pediatric patients with NF-1 plexiform neurofibromas, growth and development should be monitored long-term.

Selumetinib may cause fetal harm if administered to pregnant women based on its mechanism of action, animal findings, and data from clinical trials. In the KOMET study, a patient experienced a first trimester spontaneous abortion while receiving selumetinib.

Pregnancy status should be verified in females of reproductive potential prior to initiation of selumetinib therapy.

Selumetinib and its active metabolites are distributed into milk in rats; it is not known whether selumetinib or its active metabolites are distributed into human milk. Because of the potential for serious adverse reactions to selumetinib in breast-fed infants, women should be advised not to breast-feed while receiving the drug and for 1 week after the last dose. The effects of the drug on breast-fed infants or on the production of milk are unknown.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Clinical studies did not include a sufficient number of patients >=65 years of age to determine whether response to selumetinib is different from younger patients.