Real-World Experience of the Efficacy and Safety of Phentermine Use in Adolescents: A Case Series

Abstract

Background:

Pharmacotherapy has emerged as a practical option for weight management in pediatrics. This study aims to assess the effectiveness and safety of phentermine use in pediatric patients with obesity.

Methods:

We performed a retrospective single-center analysis of patients younger than or equal to 18 years of age, over 10 years, who underwent phentermine treatment and recommended lifestyle changes. We evaluated efficacy by the change in the percent of the 95th percentile for BMI (%BMIp95). We deemed a 5% decrease in %BMIp95 as a favorable outcome.

Results:

We identified 30 pediatric patients who were treated with phentermine. The cohort was primarily female, 63% white, with a mean (standard deviation) baseline age of 15.63 (1.97) years. The average duration of treatment was 10 months, with a period ranging from 2 weeks to 2 years. The average %BMIp95 at the start of treatment was 137%, and that at the time of analysis was 122%, with a mean reduction of 15%. Five patients, 17%, experienced side effects that resolved after dose reduction or discontinuing phentermine.

Conclusions:

Phentermine monotherapy is an effective and safe means for weight loss in pediatric patients when combined with lifestyle interventions. Twenty-one of 30 (70%) patients achieved at least a 5% decrease in %BMIp95 within a mean duration of treatment of 10 months. We noted no severe adverse events.

Introduction

Obesity is a rapidly worsening health epidemic in the United States, from which children and adolescents are not exempt.¹ Currently, 42 million children worldwide meet the criteria for pediatric obesity, and the prevalence has tripled in the past three decades leading medical researchers to seek novel interventions.¹ The current model of pediatric obesity management emphasizes lifestyle intervention as the only standard of care with minimal FDA-approved treatment options.^2–4 Unfortunately, many patients do not respond to lifestyle therapies alone, and those who initially achieve weight loss often regain weight after the cessation of lifestyle interventions.^5,6

Pharmacotherapy has emerged as a practical option to achieve sustained weight loss; however, the pediatric population has limited options.⁷ Few antiobesity medications are approved for use in children, leading to off-label use of adult medications to treat pediatric obesity.⁷ Phentermine is the most prescribed medication for weight loss in the United States, and its safety and efficacy in adults have been demonstrated in numerous studies.^3,8 Phentermine, a sympathomimetic amine, reduces the reuptake of norepinephrine, thereby stimulating the pro-opiomelanocortin neurons in the hypothalamus and affects serotonin and dopamine reuptake, which in the prefrontal cortex improves inhibitory control of appetite.⁹

The FDA approved phentermine for short-term use in adolescents and adults >16 years at doses of 15 mg, 30 mg, or 37.5 mg daily.¹⁰ Its utilization in managing pediatric obesity is limited, and only 1 study has been reported with a shorter duration of treatment of up to 12 weeks.¹¹ Concerns about long-term use in children and adolescents include increased risk of cardiovascular effects, growth impairment, and potential for misuse.^12,13 Despite these concerns, no studies have shown phentermine to be addictive, cause growth impairments, or lead to adverse cardiovascular effects.

Pediatric obesity is a chronic relapsing disease that needs chronic management.¹⁴ Phentermine may be prescribed as a safe and effective means to achieve significant sustainable weight loss in children and adolescents when combined with lifestyle therapy. Its use can potentially impact the current management of pediatric obesity and address a critical unmet need. It is important to note that weight loss medications should be used along with lifestyle therapy and that the degree to which patients adhere to lifestyle therapy can positively affect the success rate of pharmacotherapy.

Our study aimed to assess the safety and efficacy of long-term phentermine monotherapy in pediatric and adolescent patients with obesity. In children and adolescents with severe obesity, BMI Z scores correspond poorly to adiposity, with wide variations associated with age and gender. Therefore, measures such as a change in age and gender-specific percent of the 95th percentile for BMI (%BMIp95) have been recommended to be a better marker for assessing the efficacy of any intervention. This is the patient's BMI divided by the BMI value at the 95th percentile for the patient's age and gender. A 5% decrease in %BMIp95 was seen as a favorable outcome as this was associated with improved cardiometabolic status.^15,16

Methods

We utilized the Research Patient Data Registry (RPDR), a centralized clinical data warehouse, to search for pediatric patients (0–18 years) seen in the Massachusetts General Hospital Weight Center from January 2002 to January 2022, where the clinical provider notes contained “phentermine.”¹⁷ We reviewed medical records from the RPDR search to identify patients on phentermine monotherapy.

We extracted the following data from the medical record: age, biological gender, race, obesity class, obesity-related and nonrelated comorbidities (agitation, sleep disturbances, blood pressure [BP] changes, phycological effects, and abdominal pain), medication dose, duration of treatment, and concurrent use of other antiobesity medications. This retrospective study was approved by our local institutional review board protocol number 2021P003413.

After starting patients on phentermine, documentation was found to suggest that providers consented to patients on the side effect profile of the medication and when to seek medical help. Most providers schedule follow-ups within 2–4 weeks to assess for side effects. At each follow-up visit, the patient's BP was recorded. Some providers provided a BP measuring device script for patients to obtain their BP after starting therapy and until follow-up.

Our outcome of interest was a change in %BMIp95 at the start of therapy and until cessation or time of data analysis. We recorded patients' age, weights, gender, BMI, and %BMIp95 from outpatient clinical follow-up visits. We documented all side effects and their effect on drug therapy compliance. We did not analyze either obesity-related or unrelated comorbidities in this study.

Results

The search query identified 57 patients on phentermine monotherapy out of 17,619 pediatric patients with obesity seen during the 10-year period. On chart review, only 30 of the 57 patients were on phentermine monotherapy. Our study cohort was primarily female (63%). Racial demographics were (63%) white, (10%) African American, (6%) Hispanic, and (21%) other. Fifteen (50%) of the phentermine monotherapy group had known obesity-related comorbidities such as obstructive sleep apnea, hyperlipidemia, insulin resistance, nonalcoholic fatty liver disease, polycystic ovarian syndrome, asthma, and vitamin D deficiency. A single study participant had trisomy 21.

Exposure duration varied from 0.5 to 24 months, with an average of 10 months. Dose variation ranged from 8 to 37.5 mg. Twenty-four (80%) of our 30 study participants demonstrated a decrease in %BMIp95 from 4% to 54%, with an average of 15% weight reduction. The gross body weight reduction average was 10 kg (2–27.5 kg). Seven (23%) of the study participants had no change or increased their %BMIp95 from 0% to 24%, with a mean increase of 7%. This increased weight corresponded to an average increase of 9.8 kg (3–18 kg) (Table 1).

Table 1.

Pediatric Patients Treated With Phentermine

Patient no.	Gender	Age	Starting BMI (kg/m2)	Starting %BMIp95	Comorbidities	Phentermine dose (mg), QD	Phentermine duration (years)	BMI at the end of therapy (kg/m2)	Post-Tx %BMIp95	% Decrease in %BMIp95	Side effects
1	M	12	43.53	185	OSA	12	0.5	41.00	167	18	Sleep disturbances
2	M	11	33.80	144	None	15	0.4	31.00	127		None
3	M	16	29.20	107	HLD	15		24.50	83	24	None
4	F	15	37.33	133	IR	15	2	26.47	79	54	None
5	F	17	31.80	111	None	15	1	23.36	71	40	None
6	F	18	49.00	164	None	37.5	0.5	45.00	150	14	None
7	M	13	28.00	104	None	30	2	30.00	110	+6	None
8	M	17	47.00	171	None	15	0.5	44.00	158	13	None
9	F	16	35.00	121	Trisomy 21	15	0.5	29.00	101	20	None
10	F	18	41.00	140	BE	37.5	0.5	41.00	136	4	None
11	M	17	42.00	155	None	37.5	1	33.00	116	39	None
12	F	17	41.00	139	Vit D def., IDA	15	1	43.00	110	29	None
13	F	15	31.00	111	None	15	1	29.00	94	17	Agitation
14	F	13	31.00	118	None	15	1	26.00	87	31	None
15	M	17	41.76	161	Vit D def., IR	15	0.5	39.62	137	24	None
16	F	17	32.00	113	None	15	0.5	31.00	107	6	None
17	F	17	41.00	138	None	8	0.04	N/A	138	0	Abdominal pain
18	F	17	42.00	148	PCOS	8	0.1	N/A	148	0	Anxiety, elevated BP
19	F	15	43.00	155	IR	15	0.5	40.00	132	23	None
20	F	16	31.00	105	Vit D def.	15	1	29.23	93	12	None
21	M	12	36.00	149	Asthma	15	2	40.00	156	+7	None
22	F	16	30.00	106	Vit D def.	15	0.5	28.00	93	13	None
23	M	13	29.00	116	Asthma, HA	15	N/A	N/A	120	+4	None
24	F	17	38.00	130	None	15	1	32.00	107	23	Photophobia
25	F	16	43.00	147	None	15	1	48.00	158	+11	Dehydration
26	F	16	31.00	109	NAFLD	15	0.2	33.00	133	+24	None
27	M	18	40.00	140	None	15	0.4	38.00	136	4	None
28	M	15	45.00	166	NAFLD	37.5	2	39.00	134	32	None
29	F	14	37.00	138	None	30	1	33.00	121	17	None
30	F	18	51.00	174	OSA, NAFLD, PCOS	15	0.5	47.00	155	19	None

%BMIp95, percent of the 95th percentile for BMI; BP, blood pressure; BE, binge eating; F, female; HA, headaches; HLD, hyperlipidemia; IDA, iron deficiency anemia; IR, insulin resistance; M, male; N/A, not available; NAFLD, nonalcoholic fatty liver disease; OSA, obstructive sleep apnea; PCOS, polycystic ovarian syndrome; Post-Tx, post treatment; QD, daily; Vit D def., vitamin D deficiency.

As discussed previously, we deemed a 5% decrease in %BMIp95 as a favorable outcome due to its association with improved cardiometabolic outcomes. The majority, 21 of 30, 70% of patients achieved a 5% decrease in %BMIp95 within an average of 11 months (5–24 months) (Figure 1).

Figure 1.

Relative change in percent BMI.

We reviewed the patient's charts for any reported side effects after the initiation of phentermine therapy. Six (20%) of 30 study participants developed side effects, leading to discontinuation or dose reduction of phentermine. Side effects typically occurred within the first few weeks after the initiation of therapy and when there was an increase in dose. Side effects included agitation (3%), subsided with dose reduction, sleep disturbances (3%), increased BP (3%), anxiety (3%), photophobia (3%), abdominal pain (3%), and dehydration (3%). Most of the side effects occurred within the first few weeks of therapy. All the side effects were reversible once the medication was stopped. None of the patients developed significant morbidity or mortality from phentermine monotherapy (Table 2).

Table 2.

Side-Effects

Side effect	Age	Phentermine dose (mg), QD	Duration of use (years)	Weight reduction (Δ in percentile of 95 percentile)
Nervous system symptoms
Photophobia	17	15	1.0	0.145
Psychiatric symptoms
Anxiety	17	8	0.1	***
Sleep disturbances	12	12	0.5	0.038
Agitation	15	15	1.0	0.094
Vascular symptoms
Hypertension	17	8	0.1	***
Other symptoms
Dehydration	16	15	1.0	0.136

^*** No change in weight.

Discussion

Our study reports the effectiveness of long-term phentermine monotherapy in adolescents of ages 11–18 years who met the criteria for obesity. Our study participants were prescribed varying doses of phentermine, and efficacy was assessed at follow-up clinical visits. Most of our participants, 21 of 30 patients (70%), achieved at least a 5% decrease in %BMIp95, which is associated with improved cardiometabolic outcomes.¹⁶ Five patients (17%) experienced reversible side effects. To our knowledge, this is the first published report supporting the safety of long-term phentermine use in pediatric patients.

Pediatric obesity is a chronic disease that, if left untreated, can lead to worsening obesity and the development of multiple comorbidities.^14,18 The standard of care in preventing and treating pediatric obesity relies predominantly on lifestyle-based therapies such as a reduced-calorie diet and increased physical activity.² As obesity is a complex disease with underlying multifactorial biology, this simplistic approach is often ineffective at achieving sustained long-term weight loss.¹⁹ Weight loss success diminishes when we acknowledge that in racial and ethnic minority populations, social determinants such as socioeconomic status, health literacy, and racism play an undeniable role.²⁰

Limited access to affordable fresh healthy foods, concomitant housing, and food insecurity stressors make lifestyle modifications ineffective and largely irrelevant for many patients. Rates of pediatric obesity in low-income adolescent patients continue to increase, leading clinicians to reassess their management strategies²¹ and seek more efficacious interventions such as pharmacotherapy.

Our findings indicate that when combined with lifestyle changes, phentermine monotherapy can achieve significant BMI reduction and change the overall trajectory of the disease. Phentermine offers an effective pharmacological option for patients requiring additional intervention and lifestyle modification and for patients who do not qualify for aggressive forms of surgical management.² However, significant fear and apprehension surrounding the use of phentermine still exist from the Fen-Phen trial, leading to the withdrawal of fenfluramine from the market in 1997.²² This fear has dampened in the adult population as phentermine–topiramate is one of the FDA-approved medications for short-term treatment of obesity in adults.¹³

Data from randomized trials have demonstrated significant sustained weight loss without increased cardiovascular risk.²³ However, research on its safety in children is lacking. Few small studies have demonstrated weight loss without significant morbidity or mortality.²⁴ Data gathered from the Lorber trials²⁴ established safe to use in children and adolescents, from 3 to 15 years old, for 12 weeks.

Our data further support its safety as no adverse health outcomes were documented during the duration of our study. Common concerns surrounding phentermine use include increased risk of cardiac valvular disease, impaired growth velocity, and the opportunity for misuse and dependence. None of the objective health measures we used to evaluate our study participants indicated evidence of any of these concerning outcomes.

Though promising, our data are limited by the observational nature of our study design. We could strengthen our evidence by comparing the effectiveness of phentermine against placebo in a randomized controlled trial (RCT). These data exist for the phentermine/topiramate combination therapy.²⁵ However, to our knowledge, RCTs to assess the efficacy of phentermine monotherapy have yet to be conducted in the pediatric population.

In addition, our study evaluated a small sample size of 30 patients, which could have influenced the study's power and overall outcomes. In addition, the side effects listed are only those reported in the electronic medical record (EMR); therefore, there may have been other side effects that were not explicitly listed in the EMR. Finally, there is no way to determine adherence to monotherapy or eliminate the possibility of using additional weight loss medications and supplements outside the study parameters.

There is a possibility that weight gain while on phentermine may be attributed to inconsistent compliance or lack of efficacy. Conducting additional research in the form of a RCT would address some of these shortcomings and produce high-quality data that could contribute to changing the way we currently treat pediatric obesity.

Impact Statement

A retrospective study assessing the long-term effectiveness of phentermine monotherapy in adolescents of ages 11–18 years with obesity. Seventy percent of patients achieved at least a 5% decrease in percent of the 95th percentile for BMI within a mean duration of treatment of 10 months with no significant morbidity or mortality.

Authors' Contributions

A.I.A.I. was involved in methodology, formal analysis, writing review, and editing. B.M. contributed to writing original draft. F.C.S. and S.M. carried out conceptualization, supervision, and project administration.

Funding Information

This study was supported by the National Institutes of Health NIDDK Grant Nos. P30 DK040561 and L30 DK118710 (F.C.S.).

Author Disclosure Statement

S.M. is an employee of Rhythm Pharmaceuticals. A.I.A.I., B.M., and F.C.S. have no conflict of interest.