Provide a literature search on memantine in pediatric patients, specifically dosing and maximum dosing for neurocognitive toxicity of whole brain irradiation, prevention.

Comment by InpharmD Researcher

A limited number of clinical trials evaluating efficacy and safety of memantine in pediatric patients undergoing radiation therapy begin memantine treatment at low doses (e.g., 5 mg/day) prior to radiation, then escalating by increments of 5 mg up to target doses of 20 mg/day (10 mg twice daily). See Tables 1-4 for published literature describing memantine use in pediatric patients undergoing brain irradiation.

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

Memantine to Reduce Cognitive Impairment After Radiation in Children: A Pilot Study Evaluating the Feasibility of Memantine in Reducing Cognitive Impairment in Pediatric Patients after Radiation Therapy for Central Nervous System Tumors
Design	Prospective single-arm feasibility study N= 18
Objective	To assess the feasibility of memantine use in pediatric patients receiving CNS radiation therapy, focusing on adherence and tolerance
Study Groups	All patients (N= 18)
Inclusion Criteria	Patients aged 4 to 18 years with a primary CNS malignancy (excluding WHO grade 4 astrocytoma, glioblastoma) receiving intracranial RT; adequate renal and hepatic function; negative pregnancy test and adequate contraception for individuals of childbearing potential
Exclusion Criteria	Patients with WHO grade 4 astrocytoma, glioblastoma; intractable seizures; comorbid systemic illness; uncontrolled intercurrent illness; prior intracranial radiation history; contraindication or allergy to memantine; regular use of short-acting benzodiazepines
Methods	Memantine was administered starting at 5 mg once daily, titrated in 5 mg increments to a weight-based maximum (0.4 mg/kg) not exceeding 10 mg twice daily, during and for 6 months after RT. Adherence was monitored using the Medisafe Pill and Reminder application or a paper pill diary.
Duration	Study accrual: 2020 to 2022 Memantine course: 6 months
Outcome Measures	Primary: 80% drug adherence rate in 80% of patients at 1 month post-RT Secondary: Adherence rates at 3 and 6 months post-RT
Baseline Characteristics		All patients (N= 17)
	Mean age, years (range)	11 (5-16)
	Male	13 (76%)
	Diagnosis - Germ-cell tumor	6 (35%)
	Diagnosis - Craniopharyngioma	3 (18%)
	Diagnosis - Choroid plexus papilloma	2 (12%)
	Diagnosis - Ependymoma	2 (12%)
	Diagnosis - Glial/astrocytoma	2 (12%)
	Diagnosis - Medulloblastoma	1 (6%)
	Diagnosis - Meningioma	1 (6%)
	Surgical resection prior to RT	13 (76%)
	Chemotherapy	9 (53%)
	Chemotherapy sequencing - Pre-RT	8 (47%)
	Chemotherapy sequencing - Concurrent	0 (0%)
	Chemotherapy sequencing - Post-RT	1 (6%)
	Type of RT - Proton brain	9 (53%)
	Type of RT - Proton CSI	8 (47%)
	RT absolute dose (cGy) - Median	5400
	RT absolute dose (cGy) - Range	3600-5940
	No. of fractions (n) - Median	30
	No. of fractions (n) - Range	20-33
Results		1 mo after RT	3 mo after RT	6 mo after RT
	Mean (SD)	96.4% (7%)	94.0% (12.3)	87.6% (19.1%)
	Median	100%	100%	96.0%
	Range	74%-100%	55%-100%	33%-100%
Adverse Events	Grade 1 to 2 fatigue, headache, and nausea were the most common toxicity events, at least possibly related to the study drug (n = 27), without attributable grade 3+ events.
Study Author Conclusions	Memantine is a feasible, safe, and well-tolerated addition to multimodality treatment for pediatric CNS malignancies. Results of ACCL2031 are awaited to define the value of memantine in this population.
Critique	The study was limited by its small, single-institution, single-arm, nonrandomized design, which may affect the generalizability of the findings. Additionally, the study closed early, enrolling fewer than the target number of patients, limiting the ability to report a true population adherence rate within a 90% CI. Challenges with the electronic application for tracking adherence also introduced potential inaccuracies in adherence data.

Table 1 References:
[1] McKone EL, Breen WG, Foster NR, et al. Memantine to Reduce Cognitive Impairment After Radiation in Children: A Pilot Study Evaluating the Feasibility of Memantine in Reducing Cognitive Impairment in Pediatric Patients after Radiation Therapy for Central Nervous System Tumors. Int J Radiat Oncol Biol Phys. 2024;120(4):1032-1038. doi:10.1016/j.ijrobp.2024.05.031

Memantine for Prevention of Cognitive Late Effects in Children and Adolescents Receiving Radiotherapy for Brain Tumors: A Randomized, Controlled, Pilot Trial
Design	Randomized, double-blind, controlled, pilot trial N= 30
Objective	To assess the feasibility, acceptability, and preliminary efficacy of memantine for reducing cognitive late effects in children and adolescents undergoing radiotherapy
Study Groups	Memantine (n= 16) Placebo (n= 14)
Inclusion Criteria	Children and adolescents with a localized brain tumor, aged 6-21, initiating focal radiotherapy, normal lab tests and ECG, English proficiency, IQ ≥ 70, adequate vision and hearing, negative pregnancy test for females of childbearing age
Exclusion Criteria	Significant neurologic disease, psychiatric conditions precluding participation, medical disorders endangering participation, recent start of psychotropic medication, history of substance abuse
Methods	Participants were randomized to receive memantine (20 mg/d) or placebo for 12 weeks, overlapping with 6 weeks of radiation therapy. Cognitive assessments were conducted at baseline, 6 weeks, 12 weeks, and 1 year. Adherence was monitored via pill counts and side effects via structured interviews.
Duration	November 2017 to June 2023
Outcome Measures	Feasibility based on study participation, medication adherence, and cognitive assessment completion
Baseline Characteristics		All Participants (N = 30)	Memantine (n = 16)	Placebo (n = 14)	p-value
	Male	14 (47%)	9 (56%)	5 (36%)	0.2607
	White race	23 (77%)	12 (75%)	11 (79%)	0.8220
	Diagnosis Craniopharyngioma Low grade glioma Germinoma	16 (53%) 13 (43%) 1 (3%)	6 (38%) 10 (62%) 0 (0%)	10 (71%) 3 (21%) 1 (7%)	0.0419
	Tumor Location Supratentorial	26 (87%)	14 (87%)	12 (86%)	0.886
	Age at radiation therapy, years	11.93 ± 2.87	12.29 ± 3.37	11.51 ± 2.23	0.4699
	Baseline IQ	107.38 ± 14.04	108.58 ± 15.99	106.17 ± 12.39	0.6829
Results		Memantine (n= 16)
	Cogstate Identification effect size (ES)	0.61
	WJ-IV Math Fluency ES	0.81
	WJ-IV Reading Fluency ES	0.45
	PedsQL Multidimensional Fatigue Scale ES	0.72
	The evaluation of baseline cognitive performance compared to the one-year time point revealed that two measures of academic fluency, WJ-IV Math Fluency (ES = 0.71) and Reading Fluency (ES = 0.65), exhibited medium to large effect sizes with confidence intervals excluding zero. However, an observed trend suggested differences in radiation dose between the memantine and placebo groups (p = .054), attributed to one participant receiving 30 Gy. After excluding this participant from the analysis, five of the six effect sizes continued to be medium to large. Notably, WJ-IV Reading Fluency showed a decrease at the 12-week mark (ES = 0.38) but sustained a medium effect size by the one-year point (ES = 0.58).
Adverse Events	Side effects were minimal with no significant differences between groups. Placebo group reported greater symptoms 11 out of 14 times (79%).
Study Author Conclusions	Memantine as a neuroprotectant during irradiation is feasible and acceptable, with preliminary evidence for improved cognitive outcomes, warranting validation in a larger trial.
Critique	The study demonstrated feasibility and potential cognitive benefits of memantine, but the small sample size and pilot nature limit the generalizability. The study's focus on proton irradiation and limited tumor diversity may not reflect broader clinical settings. Future studies should include larger samples and diverse treatment modalities to confirm findings.

Table 2 References:
[2] Conklin HM, Khan RB, Ashford JM, et al. Memantine for Prevention of Cognitive Late Effects in Children and Adolescents Receiving Radiation Therapy for Brain Tumors: A Randomized, Controlled, Pilot Trial. Int J Radiat Oncol Biol Phys. Published online May 8, 2026. doi:10.1016/j.ijrobp.2026.04.093

Memantine to preserve memory and neurocognition following craniospinal irradiation (MEMENTO): a phase 3 randomized controlled trial
Design	Phase 3 open-label, randomized controlled trial Currently actively recruiting; estimated enrollment, N= 101
Objective	To determine benefit of memantine in pediatric and adults treated with craniospinal irradiation (CSI)
Study Groups	Mematine Standard treatment
Inclusion Criteria	Aged 5-39 years old at irradiation; planned for CSI (with or without boost dose) with or without systemic chemotherapy; Karnofsky Performance Status / Lansky Performance Status ≥ 60
Exclusion Criteria	Re-irradiation; prior exposure to memantine; inability to undergo Wechsler test
Methods	Patients will be randomized 1:1 to either the experimental arm with memantine or to standard treatment. Patients randomized to memantine therapy will be started at 5 mg once day at bedtime for 1 week, followed by 5 mg twice daily for 1 week, and finally increased to the full dose of 10 mg twice daily for 6 months.
Duration	Two years
Outcome Measures	Primary: Cognitive-deterioration-free survival at 2 years Secondary: Full-Scale Intelligence Quotient (FSIQ) in children; overall survival (OS); academic performance by scholastic performance and grades; incidence of treatment-emergent adverse events of memantine; progression-free survival (PFS); FSIQ in adults
InpharmD Researcher Critique	The study is actively recruiting, with an estimated completion date of January 2031.

Table 3 References:
[3] Gupta T, Dasgupta A, Goswami S, et al. Memantine to preserve memory and neurocognition following craniospinal irradiation (MEMENTO): a phase 3 randomized controlled trial. BMC Cancer. 2026;26(1):365. Published 2026 Feb 11. doi:10.1186/s12885-026-15627-w

Life-threatening altered mental status secondary to memantine in an adolescent undergoing cranial radiotherapy for medulloblastoma
Design	Case report
Case presentation	An 18-year-old male with relapsed, refractory medulloblastoma presented with altered mental status and worsening ataxia following initiation of palliative whole brain radiation therapy (WBRT). Initially diagnosed with non-WNT/non-SHH medulloblastoma three years prior, he underwent gross total resection, craniospinal irradiation, and chemotherapy. Despite progressing through multiple salvage regimens, including an immunotherapy-based trial and combinations of bevacizumab, irinotecan, and temozolomide, imaging showed disease progression with mild ventriculomegaly, leading to a decision for palliative WBRT. Prior to WBRT, the patient started memantine 5 mg once daily and dexamethasone 2 mg twice daily to mitigate neurocognitive toxicity and radiation-associated edema, alongside continuing valproate for headaches. Shortly after, he developed word-finding difficulty, confusion, aphasia, and worsening ataxia, which further escalated to disorientation, nausea, vomiting, and headaches. Given no acute changes in imaging and stable ventriculomegaly, these symptoms were attributed to memantine, supported by a Naranjo algorithm score of 7, indicating a probable adverse drug reaction. Symptoms improved upon withholding memantine, allowing WBRT to resume after a two-day pause. The patient was discharged after four days with complete symptom resolution and remained free of confusion for over five months, despite continued disease progression.
Study Author Conclusions	Clinicians should be aware of and consider the risk of altered mental status with memantine, given the increased utilization and upcoming clinical trials in pediatric patients.

Table 4 References:
[4] Kim KN, Shah YB, Croy C, Lustig RA, LaRiviere M, Kotch C. Life-threatening altered mental status secondary to memantine in an adolescent undergoing cranial radiotherapy for medulloblastoma. J Oncol Pharm Pract. 2023;29(2):469-472. doi:10.1177/10781552221102883