Selumetinib 10 mg is indicated for patients aged 2 years and older with neurofibromatosis type 1 (NF1) and inoperable pelvic neurofibromas.

Selumetinib instructions

Product Name: LuciSelume

Manufacturer: Lucius Pharmaceuticals

Chinese name: selumetinib

English name: Selumetinib

Drug approval number: 03 L 1074/24

 

 

【Summary】

Selumetinib is an inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are important components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in a variety of cancers. In animal experiments, Selumetinib can inhibit ERK phosphorylation in NF1 mice and reduce the number, volume and proliferation of neurofibromas.

 

【Indications】

Indicated for children 2 years and older with neurofibromatosis type 1 (NF1) and inoperable pelvic neurofibromas.

 

【Specification】

10mg/capsule, 60 capsules/bottle.

 

【Storage】

Store at 20°C to 25°C (68°C to 77°F); short-distance transport is permitted at a temperature range of 15 to 30°C (59–86°F).

 

【Usage and Dosage】

1. 25 mg/m², twice a day (approximately once every 12 hours), orally administered until disease progression or unacceptable toxicity occurs;

2. Take on an empty stomach (1 hour before or 2 hours after meals);

3. Swallow the capsule whole. Do not chew, dissolve or open the capsule.
Recommended dose based on body surface area:

【Adverse Reactions】

>10%:

1. Cardiovascular diseases: cardiomyopathy (23%), edema (20%), facial edema (<20%), hypertension (<20%), reduced ejection fraction (22%), sinus tachycardia (20%)

2. Skin: acneiform rash (50%-54%), hair changes (32%), dermatitis (36%), eczema (28%), maculopapular rash (39%), paronychia (48%), pruritus (46%), skin infection (20%), rash (80%-91%), xeroderma (60%)

3. Endocrine metabolism: serum albumin decreased (51%), serum potassium decreased (18%), serum sodium decreased (16%), amylase increased (18%), serum potassium increased (27%), serum sodium increased (18%), weight gain (<20%)

4. Gastrointestinal: abdominal pain (76%), constipation (34%), decreased appetite (22%), diarrhea (70%-77%; severe diarrhea: 24%), increased serum lipase (32%), nausea (66%), stomatitis (50%), vomiting (82%), dry mouth (20%)

5. Urogenital system: hematuria (22%), proteinuria (22%)

6. Blood and tumors: anemia (24%), neutropenia (33%, ≥ grade 3: 4%), lymphopenia (20%, ≥ grade 3: 2%)

7. Liver: Elevated serum alanine aminotransferase (35%), elevated serum alkaline phosphatase (18%), elevated serum aspartate aminotransferase (41%)

8. Nervous system: fatigue (56%), headache (48%)

9. Neuromuscular and skeletal: elevated creatine phosphokinase in blood samples (76%-79%), musculoskeletal pain (58%)

10. Ophthalmology: blurred vision (≤15%), cataract (≤15%), high intraocular pressure (≤15%), periorbital edema (<20%), photophobia (≤15%), visual impairment (<20%)

11. Kidney: Acute renal failure (<20%)

12. Breathing: dyspnea (<20%), nosebleed (28%), hypoxia (24%)

13. Others: Fever (56%)

 

【 Notes 】

1. Risk of bleeding: Selumetinib capsules contain vitamin E. Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent coagulation factors. Exceeding the recommended daily intake of vitamin E may increase the risk of bleeding. If the daily vitamin E intake (supplements plus the vitamin E content in selumetinib capsules) exceeds the recommended or safe limit, vitamin E supplementation is not recommended.

Patients taking vitamin K antagonists or antiplatelet antagonists with selumetinib may have an increased risk of bleeding; monitor for bleeding. Increase INR monitoring (as appropriate) in patients taking vitamin K antagonists. Monitor anticoagulation parameters (including INR or PT) more frequently and adjust the dose of the vitamin K antagonist or antiplatelet agent as needed.

2. Cardiac toxicity: Cardiomyopathy, defined as a left ventricular ejection fraction (LVEF) ≥10% below baseline, was reported in almost a quarter of children treated with selumetinib in the neurofibromatosis type 1 (NF1) study. A small number of patients had a left ventricular ejection fraction below the lower limit of normal (LLN). Grade 3 LVEF decreases leading to dose reductions rarely occurred. Echocardiographic examinations all revealed a decrease in left ventricular ejection fraction. LVEF reductions were resolved in most patients.

3. Increased CPK (serum creatine phosphokinase): In the NF1 study, more than three-quarters of pediatric patients treated with selumetinib experienced increased CPK, including grade 3 or 4 events. Increased CPK led to dose reductions in a small number of patients. Increased CPK with myalgia also occurred (there were few reports of permanent discontinuation of myalgia).

Obtain serum CPK prior to initiating selumetinib and periodically during treatment as clinically indicated. If CPK increases, evaluate for rhabdomyolysis or other causes. CPK elevations may require treatment interruption, dose reduction, or permanent discontinuation (depending on severity).

4. Skin toxicity: In NF1 studies, rash commonly occurred in pediatric patients receiving selumetinib; grade 3 rash has occurred. The most common types of rash include acneiform dermatitis, maculopapular rash, and eczema. Rash may require interruption of treatment or reduction of selumetinib dose.

Other skin toxicities, including severe palmar-plantar dysesthesia syndrome, have also occurred in adults receiving selumetinib as a single agent or in combination with other anticancer agents (selumetinib is not approved for use in adults). Monitor for severe rash. Depending on severity, skin toxicity may require treatment interruption, dose reduction, or permanent discontinuation of treatment.

5. Gastrointestinal toxicity: Most children receiving selumetinib experienced diarrhea, including grade 3 diarrhea. The median time to first diarrhea was 17 days, and the median duration was 2 days. Diarrhea led to treatment interruption in some patients, and a few patients had their doses reduced or permanently discontinued.

Serious gastrointestinal toxicities, including perforation, colitis, and intestinal obstruction, have been reported in adults receiving selumetinib alone or in combination with other anticancer agents (selumetinib is not approved for use in adults).

Colitis has been reported in pediatric patients taking selumetinib for conditions other than NF1. Patients should begin antidiarrheal medications (e.g., loperamide) promptly after the first episode of unformed/loose stools and increase fluid intake during episodes of diarrhea. Depending on severity, GI toxicity may require interruption of treatment, dose reduction, or permanent discontinuation of the drug.

6. Ocular toxicity: In NF1 studies, pediatric patients experienced blurred vision, photophobia, cataracts, and hypertension. In a small number of patients, blurred vision led to treatment interruption. Most patients with ocular toxicity were relieved. Severe ocular toxicity, including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED), occurred in adults receiving selumetinib as a single agent or in combination with other anticancer drugs (selumetinib is not approved for use in adults).

RPED (requiring permanent discontinuation) has also occurred in pediatric patients receiving selumetinib (as a single agent). Perform a comprehensive ophthalmologic evaluation prior to initiating selumetinib and periodically during treatment, as well as upon the emergence of new or worsening visual changes.

Permanently discontinue selumetinib if RVO (retinal vein occlusion) occurs. Withhold selumetinib in patients with RPED, evaluate with optical coherence tomography every 3 weeks until it resolves, and resume selumetinib at a reduced dose. For other ocular toxicities, reduce the dose or permanently discontinue selumetinib (based on the severity of the adverse event).

7. Hepatic impairment: Selumetinib exposure is increased in patients with moderate to severe hepatic impairment. Dose modification may be required.

8. Drug Interactions: Potentially important interactions may exist, requiring adjustment of dose or frequency, additional monitoring, or selection of alternative therapy.

9. Propylene glycol: Some dosage forms may contain propylene glycol; it has a large amount of potential toxicity and is associated with hyperosmolarity, lactic acidosis, seizures, and respiratory depression; use with caution.

10. Fetal toxicity: Based on the mechanism of action and data from animal reproduction studies, selumetinib may cause harm to the fetus.

 

【Efficacy and safety】

The Phase I clinical trial of selumetinib showed that it achieved good results in the treatment of neurofibromatosis type I and inoperable plexiform neurofibromas. This trial recruited 24 children, including 13 males and 11 females, with a median age of 10.9 years (the youngest was 3 years old and the oldest was 18.5 years old). The average median tumor volume of the children at the time of enrollment was 1205 ml. After enrollment, the children received long-term treatment with selumetinib, with a median treatment cycle of 30 (120 weeks).

After treatment, all children in the group were observed to have a reduction in tumor volume (an average reduction of 31%), and the median number of treatment cycles to achieve the best efficacy was 20 (80 weeks). Among the 24 children enrolled, 17 were effective, with an effective rate of 71%. Among them, 9 people in the 20 mg group were effective (a total of 12 people), 5 people in the 25 mg group were effective (a total of 6 people), and 3 people in the 30 mg group were effective (a total of 6 people). Children who have achieved efficacy will continue to take the drug and their efficacy will be maintained, with a median maintenance cycle of 23.

Studies have found that even a small shrinkage of neurofibromas can reduce pain, physical deformities, and improve motor function in children. Selumetinib, a new drug for the treatment of neurofibromas, has significant efficacy and few side effects, and long-term use of the drug does not produce drug resistance.

 

【Taboo】

none