Aversion to Off-Label Prescribing in Clinical Pediatric Weight Management

The Quintessential Double Standard

Christine B. San Giovanni; Brooke Sweeney; Joseph A. Skelton; Megan M. Kelsey; Aaron S. Kelly

J Clin Endocrinol Metab. 2021;106(7):2103-2113.

Context: Pediatric obesity is now recognized as a chronic disease; yet few treatment options exist besides lifestyle modification therapy and bariatric surgery. We describe the limited availability of United States Food and Drug Administration (FDA)–approved antiobesity medications for adolescents and compare this to what is available for adults. We offer a rationale for off-label prescribing to assist with lifestyle modification therapy. We also highlight the need for more pharmacotherapy options and additional research into novel treatments for pediatric obesity.

Case Description: We describe a patient who is struggling with managing her weight and starting to develop complications of obesity. We offer a framework in which off-label prescribing may be beneficial to patients who have been engaging in lifestyle modification therapy yet fail to see improvement.

Conclusion: Lifestyle modification therapy is necessary but often insufficient in stimulating clinically meaningful weight loss when used alone in children and adolescents who struggle with weight management. Until more FDA-approved antiobesity medications are available, pediatricians may be able to help more patients achieve weight reduction goals by familiarizing themselves with the responsible use of off-label medications and implementing these tools to improve clinical outcomes. There is a critical need for more pharmacotherapy options to help pediatric patients in managing their weight and preventing or improving the insidious complications resulting from untreated obesity.

A 10-year-old Hispanic female presents to the weight management clinic for initial evaluation with a weight of 56.6 kg, body mass index (BMI) 26.44 kg/m², 97.61 percentile (%ile) for sex and age on the Centers for Disease Control growth chart. Baseline labs show borderline high AST (aspartate aminotransferase) level at 35 U/L, ALT (alanine aminotransferase) 25 U/L, elevated total cholesterol at 194 mg/dL, HDL-C (high-density lipoprotein cholesterol) 48 mg/dL, and LDL-C (low-density lipoprotein cholesterol) 100 mg/dL. Nonfasting triglycerides are 232 mg/dL and hemoglobin A1c is 5.6%. She and her family learn about decreasing portion size of meals and increasing fruit, vegetable, and water consumption. Additionally, the patient and her family are counseled on the metabolic complications related to high BMI. On follow-up with a registered dietician (RD) in 3 months, her weight increased by 2 kg (BMI 26.54 kg/m², 97.53%ile). She begins a 17-week group intervention including exercise and education at a tertiary care children's hospital 1 month later. Her weight, BMI, and blood pressure (BP) increase over the course of the 4-month intervention (61.1 kg to 64.9 kg; 27.66 kg/m² BMI, 98.08%ile to 28.96 kg/m², 98.40%ile; and BP 100/76 mmHg to 112/62 mmHg) despite learning about healthy lifestyle changes including eating more fruits and vegetables, increasing exercise, drinking more water, and decreasing sugar-sweetened beverages, as well as eating out less and cutting back on processed foods. The family struggles with adding vegetables as the mother of the child reports that she serves them, but her children do not eat them leading to food waste. The patient meets with the RD for follow-up 3 months after the conclusion of the group intervention and reports she is maintaining healthy lifestyle changes including exercising more, drinking more water, and consuming fewer sugar-sweetened beverages and snacks. However, her weight and BMI have increased further (67.6 kg and 29.18 kg/m² BMI, 98.32%ile). The patient is then lost to follow-up in weight management clinic but sees her primary care provider for a well visit at 14 years old. At the visit, the mother expresses concern about any possible metabolic abnormalities that might explain her daughter's weight gain. She agrees to go back to the weight management clinic but does not show up for her appointment until 3 months later. At the patient's 15-year-old well visit, the patient's mother expresses frustration that they have made all of these healthy lifestyle changes (no sugar-sweetened beverages, limiting tortillas, snacks and other carbohydrates, and increasing exercise) and her daughter is still "heavy." The mother reports that they have stopped attending medical appointments as she grew tired of people telling her the same things and the behavior changes not making a difference in her daughter's weight. The mother is willing to return to the weight management clinic and 3 months after the appointment with her primary care provider, she brings her now 16-year-old daughter to the clinic asking for additional assistance as she has continued to gain weight and increase her BMI (91.9 kg and 34.93 kg/m² at the 98.38%ile).

Twenty percent of children and adolescents in the United States are afflicted with obesity,^[1,2] and nearly half report attempting weight loss.^[3] Unfortunately, there is a wide racial and ethnic gap in pediatric obesity prevalence such that this chronic and refractory disease disproportionally impacts African American and Mexican American youth.^[2] Although there is a growing list of safe and effective pharmacologic treatments to support efforts at weight reduction in adults,^[4,5] few evidence-based treatment options exist for children/adolescents aside from multicomponent behavioral weight loss programs, metabolic/bariatric surgery, and a limited number of United States Food and Drug Administration (FDA)–approved antiobesity medications.

Pediatric obesity tracks strongly into adulthood and is associated with multiple comorbidities and complications.^[6] Thus, youth with obesity are more likely to have a longer term exposure to excess weight, resulting in earlier onset of obesity-driven diseases like type 2 diabetes and cardiovascular disease, greater risk for obesity-associated cancers, and detrimental musculoskeletal consequences of bearing excess weight, potentially resulting in significant disability in adulthood. Furthermore, early-onset obesity-related comorbidities, such as youth-onset type 2 diabetes, have been shown to be associated with rapidly progressing disease, early complications, and early mortality.^[7,8] The need to focus on treatment of pediatric excess weight is critical as studies have shown life expectancy may now be regressing;^[9] severity of the disease of obesity and its complications continue to worsen;^[1] complications of obesity are predicted to increase in prevalence;^[10] and the costs of medical care related to obesity have already reached unsustainable levels.^[11] It has also been shown that youth with obesity have a lower quality of life,^[12] largely due to exposure to weight-based bullying.^[13]

As a result, there is a critical need for effective, safe, and durable treatments for pediatric obesity. However, even the most intensive lifestyle modification therapies in children and adolescents result in less improvement in BMI than evidence-based behavioral modification in adults.^[14,15] Moreover, the time and resources needed to implement evidence-based pediatric interventions preclude the widespread dissemination of these therapies. Even though pediatric obesity leads to significant health consequences and reduced quality of life, youth have significantly hampered access to medical and surgical treatments that have been shown to be effective in adults. Though metabolic/bariatric surgery is an option for children and adolescents with severe obesity, uptake and access have been extremely low.^[16–18] Limited utilization of surgery is likely due to the high cost, lack of insurance coverage and access to a program serving children, and reluctance on the part of providers and patients/families of pursuing this more invasive treatment. Most children and adolescents with obesity, particularly those with severe obesity, need adjunctive treatments to supplement behavioral interventions. Medications, if effective and safe, could be a practical and scalable intervention in different settings, including both primary and specialty care.

The United States Preventive Services Task Force (USPSTF) has recommended at least 26 hours of lifestyle therapy counseling for patients with obesity 6 years and older over a period of 2 to 12 months to have positive outcomes for patients.^[14] This requires a great amount of time and commitment, and studies of lifestyle modification as monotherapy for children and adolescents have demonstrated modest effectiveness.^[14] Even if some lifestyle modification programs have been found to be successful^[19] with improvement in BMI or BMI standard deviation score, or percent overweight, these outcomes are often short-lived.^[16] Therefore, additional treatment options that are affordable and accessible to most patients/families affected by obesity are desperately needed.

Pediatric clinical practice guidelines and recommendations for the management of pediatric obesity^[20–22] are summarized in Table 1. It is important to note that there is no consensus on what constitutes clinically significant weight loss/BMI reduction in children and adolescents. The definition of success may vary by individual. A decrease in BMI z-score by more than 0.2 units may be associated with cardiometabolic improvement^[14] and be viewed as a successful outcome over time, though in treatment-seeking populations where many have severe obesity, BMI z-score is not recommended to assess change.^[23,24] In some cases, mitigating the slope of rise in BMI or maintaining BMI in a patient who had previously been gaining rapidly may be considered a success. Guidelines have suggested pharmacotherapy as an adjunctive treatment for children and adolescents with obesity who exhibit suboptimal response to lifestyle modification therapy alone.^[20,22,25] Just as the definition of clinically significant weight loss/BMI reduction varies depending on the individual, the definition of suboptimal response can be defined as either continued weight gain, failure to stabilize weight, or failure to lose the desired amount of weight, depending on age and the severity of obesity. Unfortunately, few medical options, other than within the context of a "research study,"^[22] exist—only orlistat, phentermine, and now liraglutide are approved by the FDA for the treatment of adolescent obesity (Table 2). Pharmacotherapy use for weight loss in pediatrics has increased over time; however, use among providers working in weight management clinics remains limited.^[26]

Orlistat is thought to be rarely used because of the relatively modest efficacy (about 3% BMI reduction over 12 months) and unpleasant and often intolerable side-effect profile (oily spotting and flatus with discharge), lack of insurance coverage, and prohibitive cost of over-the-counter versions.^[27] Phentermine was approved approximately 60 years ago when standards for clinical trials were much less rigorous;^[28,29] therefore, many states have old and conservative labeling and prescribing constraints, including limits on number of months, dosing, and age. The phentermine label recommends its use be limited to the short term (often interpreted as 12 weeks). This short-term recommendation is in conflict with what is now known about the chronic and refractory nature of obesity necessitating long-term treatment, requiring providers to prescribe in an "off-label" fashion if treatment is sustained. Recent data in adults support the safety and efficacy of long-term use (12–24 months)^[30] and demonstrate lack of addiction potential.^[31] Randomized, placebo-controlled pediatric studies of phentermine are lacking, yet a report of the clinical outcomes of phentermine at a dose of 15 to 37.5 mg daily over 6 months suggests it has a modest to moderate treatment effect on BMI (approximately 4% BMI reduction) in youth with obesity.^[32] Potential side effects of phentermine, increased heart rate and BP,^[32] are similar to those associated with medications such as methylphenidate or amphetamine derivatives^[33] commonly prescribed in children for the treatment of attention deficit hyperactivity disorder. Therefore, these side effects are well known to primary care providers who monitor children on these medications. More recently, liraglutide 3 mg was approved by the FDA for the treatment of obesity in adolescents ages 12 to less than 18 years.^[34] Though demonstrated to be safe and effective (mean BMI reduction of 4.5%), lack of insurance coverage will likely be a major barrier and out of pocket costs for this medication are extremely high. Moreover, liraglutide is administered with subcutaneous injection, which may not be acceptable to some patients.

Other medications such as topiramate, metformin, and exenatide have been evaluated for the treatment of pediatric obesity and have demonstrated a moderate degree of BMI reduction (approximately 3–4%) above and beyond that of lifestyle modification therapy.^[14,35–37] However, despite comparable weight loss outcomes compared with approved medications, utilizing these medications for weight management is considered "off-label" since there is no FDA-labeled indication for obesity. Moreover, 6 antiobesity medications are approved for use in adults for weight loss and 1 agent for binge eating disorder, though most do not currently include an indication for use in children or adolescents^{[4,5,38–40]} (Table 2). Despite these limitations, recent clinical recommendations suggest that these medications can be responsibly used in pediatric patients within the context of specialized settings with appropriately trained medical providers.^[25] Some providers have begun judicious use of off-label medications in a controlled setting with multidisciplinary approaches to treatment,^[26] since some medications have evidence of safety and efficacy but are not yet FDA approved.^[25,41–43]

With only 3 antiobesity medications approved by the FDA for the pediatric population, providers may choose to prescribe medications off-label in an attempt to help patients manage their weight.^[26] Off-label prescribing is common in the field of pediatrics;^[44] an average of 1 out of every 5 office-based pediatric clinical visits results in an off-label prescription. Moreover, many commonly used medications in pediatrics have not been tested at all in children, and the safety and efficacy of medications used in children are frequently supported by low-quality evidence. Previous policy statements from the American Academy of Pediatrics and the standard of care for many medical conditions support the necessity of off-label use if there is a lack of 1 of the following: (1) licensed, effective, or safe medications for a specific disease; (2) standard therapy or alternate forms of medication; or (3) clinical trials for treatment of a specific disease.^[45] Additionally, FDA approval to license medication requires a large amount of money and time; thus, pharmaceutical companies may have limited motivation to seek pediatric-specific FDA approval in a timely fashion, given that children often make up a small subset of the population prescribed these medications. This may also necessitate off-label use of medications in pediatrics.^[46,47] Pandolfini and Bonati examined 30 pediatric studies between 1985 and 2004 and off-label and unlicensed prescription rates were as high as 80%,^[46] with higher rates found in younger patients. Examples of common off-label uses for children are high-dose amoxicillin for acute otitis media, morphine for pain, and intranasal desmopressin for nocturnal enuresis.

The American Academy of Pediatrics statement on Off-Label Use of Drugs in Children published in 2014 discussed that, when the gold standard of clinical trials is not available, pediatric medicine usually relies on expert opinion or evidence from another population.^[45] The committee on drugs writes, "Use of drug, whether off or on label, should be based on sound scientific evidence, expert medical judgement or published literature whenever possible."^[45] With labeling of pediatric information on less than 50% of products, pediatricians are left to rely heavily on expert opinion or guidelines. The committee further states that off-label use is more likely to happen with a rare disease or a "sparse" population such as neonates.^[45] One study found that among 1064 prescriptions for 49 medications in the neonatal intensive care unit, 312 (29.2%) were licensed and 63 (5.9%) unlicensed, and 693 (64.8%) were off-label use.^[48]

Obesity is 1 of the most common chronic diseases in children and adolescents, and lifestyle modification therapy, while necessary to implement throughout treatment and serving as the backbone of therapy, is often ineffective when used as a stand-alone strategy and would be appropriately supplemented with medication that can help change patients' internal physiologic environment. Yet, there are few medication options, and in a field that frequently uses medications off-label, hesitancy to prescribe medications off-label for a chronic, complex, and insidious disease like obesity is notable. This could be due to lack of familiarity with certain medications; however, providers are generally accustomed to prescribing and managing medicines such as stimulants, topiramate, and metformin.

Alternatively, this hesitancy could be due to misperceptions about obesity, including a belief that weight loss simply requires hard work and perseverance and that pharmacotherapy is the "easy way out." These attitudes represent a double standard compared with other pediatric diseases for which off-label medications are regularly used and are often manifest as either implicit or explicit provider biases against obesity.^[49] Yet, if we consider the complexity of the gut–brain axis in regulation of hunger and satiety, and the potential role that variation in this axis plays in excess weight gain and/or lack of success in losing weight,^[50] it is rational to view medications as a necessary and logical adjunct to treat underlying physiologic dysregulation to improve adherence to lifestyle modification therapy Table 3.

Patients would likely benefit from a fundamental change in how obesity is viewed by medical providers. Indeed, if obesity were perceived as a primarily biologically driven disease, in line with a significant and growing of body of evidence,^[51] for which medications could alter the patients' internal physiological milieu and assist them in effectively making healthy lifestyle changes,^[52] it could lead to positive outcomes for many children and adolescents struggling with their weight. In adults, pharmacotherapy is indicated at a BMI as low as 27 kg/m² with a comorbidity or BMI of 30 kg/m² without a comorbidity. In contrast, perhaps due to weight bias, the typical tendency in pediatrics is to wait for severe obesity (BMI ≥120% of the 95%ile) to surface before intervening with more intensive treatment.^[20,22,26] Waiting until this later point to start medication can cause undue stress and discouragement to patients and families. In the meantime, patients may also develop obesity-driven complications. Perhaps starting medication earlier, closer to an equivalent acceptable time in adults, could help children and adolescents obtain a healthier BMI earlier in life and prevent development of obesity complications.

When our now 16-year-old patient arrived back in weight management clinic asking for additional help, she had been engaged in healthy lifestyle changes and tertiary care weight management for 5 years. At this visit, she was found to have similar or improved labs (total cholesterol 152 mg/dL, HDL-C 46 mg/dL, LDL-C 88 mg/dL, fasting triglycerides at 90 mg/dL; AST 20 U/L, ALT 15 U/L, and hemoglobin A1C 5.7%) indicating improved dietary changes despite lack of weight loss. She had been hesitant to return to weight management as she was unsure what else could be offered. She was also found to have some headaches occurring 2 or 3 times per week, which were bifrontal and requiring nonsteroidal ani-inflammatory drugs for relief 2 times per week. These headaches kept her out of school once per month. At this time, she was started on topiramate for headache suppression and assistance in weight loss^[53] (25 mg daily for 5 days and then 25 mg twice a day). She was seen back in weight management clinic with the RD in 2 months and her weight decreased by 0.8 kg (91.1 kg and BMI 34.41 kg/m², 98%ile). She was having only 1 or 2 headaches per month and not missing school. She was eating more fruits and vegetables, still trying to decrease snacking and eating smaller portions as well as limiting grains to 1 serving at lunch as a sandwich. She reported feeling like the topiramate was assisting her in implementing and maintaining these nutrition changes. She continued on the topiramate for the next 6 months and at 17 years 8 months, she was at a weight of 85.2 kg, BMI 32.2 kg/m², 97%ile, amounting to a 7.2% weight reduction.

In conclusion, given the continued rise in pediatric obesity, the widening racial and ethnic disparity gaps, the high likelihood of future health complications, and increased healthcare costs associated with obesity, more options are needed to augment and support traditional behavioral and dietary interventions. Contemporary pediatric treatment approaches are typically focused on implementing lifestyle changes to combat the external obesogenic environment with no consideration of deploying adjunctive therapies that target the internal physiological environment responsible for energy regulation.^[52] For children with obesity, especially those with severe obesity, an inability to lose weight may not be due to lack of adherence to treatment recommendations, but rather failure on the part of their medical provider to offer treatments that address the underlying biological drivers of increased weight. More research is needed to advance the discipline of pediatric obesity medicine, including greater attention and discussion of off-label medication use, and extension of safety and efficacy studies to children. The investment in trials of antiobesity medications paired with lifestyle modification therapy in children and adolescents should focus on predictors of response as well as long-term safety and efficacy. Advocacy is needed to improve the consistency of insurance coverage for both antiobesity medications and family-based behavioral treatment. Due to the limited number of tertiary care pediatric weight management programs, future research should address treatment strategies that could be safely and effectively delivered within a primary care setting. While the challenge ahead will be difficult to overcome, proper investment of time, energy, and resources into research and education aimed at improving pediatric obesity clinical care will offer the opportunity to meaningfully address this ongoing healthcare crisis.

References

Abbreviations
%ile, percentile; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BP, blood pressure; FDA, United States Food and Drug Administration; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; RD, registered dietician.

Acknowledgments
Financial Support
There was no funding to support the writing of this paper.

Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Table 1. Treatment for BMI ≥95th percentile in pediatrics
Screening	Setting	Frequency of visits	Management	When to progress to next stage of treatment
≥2 years old and BMI ≥85th percentile	Primary care office with physician and dietician If available, refer to weight management program with physician, dietician, physical therapist, psychologist, and social worker	Visits at least every 3 months but increase to weekly if possible and deemed necessary	Lifestyle modification therapy: Identify comorbid medical and behavioral conditions, causes of iatrogenic weight gain, and conduct behavioral intervention with motivational interviewing Goal setting about physical activity, dietary changes, sleep and sedentary time	Visits consist of checking progress in meeting healthy goals If patient is having trouble meeting set goals and/or BMI continues to increase despite setting goals and proper follow-up, consider pharmacotherapy in addition to continuing lifestyle modification
≥6 years old and BMI ≥95th percentile in presence of weight related co-morbidities or BMI ≥1.2 × 95th percentile irrespective of comorbidities	Primary care office with physician and dietician and/or weight management program and/or subspecialist	Visits at least every 1–3 months but increase to weekly if possible and deemed necessary	Pharmacotherapy: In addition to lifestyle modification, treat with potential pharmacotherapy interventions for obesity management (Table 3) while considering patient's comorbidities, current medications, and family history	If patient has trouble meeting goals and/or BMI continues to increase, consider increasing medication dose or adding another medication to treatment plan in addition to continuing lifestyle modification
≥10 years old and BMI ≥1.2 times 95th percentile with weight related comorbidities or BMI ≥1.4 times 95th percentile irrespective of comorbidities	Surgeon, physician, dietician, psychologist, and social worker. Patient needs close follow up with weight management program or primary care provider prior to and after surgery	Usually monthly visits leading up to and after surgery	Metabolic and bariatric surgery: Continue lifestyle modification and pharmacotherapy as patient is preparing for surgery

Table 2. FDA-approved antiobesity medications for adolescents and adults
Adolescents	Adults
Liraglutide (12+ years)
Orlistat (12+ years)
Phentermine (16+ years)
	Naltrexone XR + bupropion
	Phentermine + topiramate
	Lorcaserin (recently withdrawn from market)

Table 3. Potential pharmacotherapy interventions for obesity management
Medication name (trade)	Mechanism(s) of action on weight loss	FDA approval	Placebo-subtracted % body weight loss	Dosing	Comorbidity and risk factor outcomes	Side effects	Contraindications caution notes
Exenatide (Byetta, Bydureon) (37, 54, 55)	Central effect on hypothalamus (appetite) and slowing of gastric motility/CNS effect	18+ years T2DM	3–5% in peds, limited data in adults	Subcutaneous, 10 μg twice daily before meals; 2 mg once weekly	Adult and pediatric data limited; possibly improves glucose tolerance and reduces blood pressure	Nausea; abdominal pain; diarrhea; vomiting	History of pancreatitis or personal/family history of medullary thyroid carcinoma or multiple endocrine neoplasia
Liraglutide (Saxenda) (34, 56)	Central effect on hypothalamus (appetite) and slowing of gastric motility/CNS effect (satiety)	10+ years for T2DM 12+ years for obesity	5–6% in peds and adults	Subcutaneous. 8 mg/day for DM; 3 mg/day for obesity	Pediatric data: No difference noted in comorbidity and risk factors; Adult: Reduces blood pressure, glucose, HbA1c, insulin, CRP, and PAI-1; improves lipids; increases adiponectin; reduces incidence of T2DM	Increased heart rate; nausea; vomiting; diarrhea; hypoglycemia; constipation; headache; dyspepsia; fatigue; dizziness; abdominal pain; increased lipase	Pregnancy; personal or family history of MTC or MEN 2 Caution with pancreatitis, gall bladder disease, and insulin use
Lisdexamfetamine (Vyvanse) (39, 57)	Norepinephrine and dopamine reuptake inhibitor	6+ years for ADHD; 18+ years for binge eating disorder	No adult or pediatric weight loss trials	Initial 20–30 mg/day 50–70 mg/day for BED	No evidence	Increased heart rate and blood pressure, palpitations, insomnia, irritability, restlessness, paresthesia, vomiting, diarrhea, constipation,	MAOI use Caution with cardiovascular, liver, kidney disease or other stimulants/drug use
Lorcaserin (Belviq) (58)	Selective serotonin 5-HT2c receptor agonism	18+ years for obesity	3–5%	10 mg twice/day	Adult: Reduces glucose, insulin, HOMA-IR, CRP, and fibrinogen; improves lipids	Headache; dizziness; fatigue; nausea; dry mouth; constipation	Pregnancy FDA requested manufacturer to voluntarily withdraw from market February 2020 due to cancer concerns
Metformin (Glucophage) (59–61)	Activation of AMP-activated protein kinase	10+ for T2DM	3% in peds, limited data in adult use	Up to 1000 mg twice daily, XR once daily	Pediatric: modestly reduces glucose, insulin, and HOMA-IR Adult: Reduces incidence of T2DM;	Nausea; vomiting; diarrhea/loose stools; reduced vitamin B12	History of lactic acidosis Caution in renal or liver disease
Naltrexone XR + bupropion XR (Contrave) (62, 63)	Opioid receptor antagonism; dopamine and norepinephrine reuptake inhibition	18+ years for obesity	5% in adults	32 mg/360 mg twice daily	Adult: Reduces glucose, insulin, HOMA-IR, and CRP; improves lipids	Nausea; vomiting; diarrhea; constipation; headache, dizziness; insomnia; dry mouth; increased heart rate and blood pressure; worsening depression or suicidal ideation in youth	Uncontrolled hypertension; seizure disorders; anorexia; bulimia; MAOI use; pregnancy
Orlistat (Xenical, OTC -Alli) (27, 64)	Gastric/pancreatic lipase inhibition, inhibit absorption of fats by 30%	12+ years for obesity	3% for peds and adults	Rx: 120 mg TID OTC: 60 mg TID with meals	Adult: Reduces LDL and incidence of T2DM	Oily spotting; flatus with discharge; fecal urgency; fatty/oily stool; decreased absorption of fat-soluble vitamins	Chronic malabsorption syndrome or cholestasis caution with levothyroxine, antiepileptics, liver disease or renal impairment
Adipex-P, Suprenza, Lomaira (30, 32, 65)	Norepinephrine reuptake inhibition	16+ years for obesity	4–5% for peds and adults	15–37.5 mg once/day in morning 8 mg 2–3 times/day	Limited data	Increased heart rate and blood pressure; dry mouth, palpitations; ischemic events; primary pulmonary hypertension; valvular disease; restlessness; insomnia; potential abuse/dependence; ability to engage in potentially hazardous tasks	History of cardiovascular or drug use; MAOI use; hyperthyroidism; glaucoma; agitated states; pregnancy; nursing; hypersensitivity to sympathomimetic amines Caution with high blood pressure, congenital heart disease, SSRI use, insulin use, and renal impairment Label recommends short term use but data in adults show safety and efficacy when used long term
Phentermine + topiramate XR (Qsymia) (66–68)	Norepinephrine reuptake inhibition; modulation of GABA	18+ years for obesity	7% for mid-dose and 9% for high-dose in adults	7.5 mg/46 mg; 15 mg/92 mg	Adolescent results expected in 2021 Adult: Reduces blood pressure, glucose, insulin, HOMA-IR, and CRP; improves lipids; increases adiponectin	Paresthesia; dizziness; dysgeusia; insomnia; constipation; dry mouth	Pregnancy; MAOI use; hyperthyroidism; glaucoma; hypersensitivity to sympathomimetic amines, other psychostimulant use
Semaglutide (Ozempic, Rybelsus) (69)	Glucogon-like peptide-1 agonist	18+ T2DM; Not yet FDA approved for obesity	12% in adults with 2.4 mg dose	oral 3–14 mg, subcutaneous: 1.0–2.4 mg (not yet available)	Adult: Reduce cardiovascular events in adults with T2DM (GLP-1RA class)	Diarrhea; constipation; hypoglycemia; pancreatitis	Personal or family history of MTC; patients with MEN2; Pregnancy; Breastfeeding; Caution with renal or liver disease
Topiramate (Topamax, Trokendi XR) (36, 70)	Modulation of GABA, carbonic anhydrase inhibition	2+ years for seizures; 12+ years for migraines	3% in peds, 5–8% in adults (at higher doses)	Oral, up to 200 mg twice daily	Pediatric data limited Adult: Reduces systolic blood pressure and glucose	Paresthesia, difficulty with concentration and memory, depression, language problems, psychomotor slowing	Acute myopia, secondary angle closure, glaucoma, Suicidal Ideation, metabolic acidosis, teratogenic Wean off to avoid seizures

Abbreviations: CNS, central nervous system; T2DM, type 2 diabetes mellitus; CRP, C-reactive protein; PAI-1, plasminogen activator inhibitor-1; MTC, medullary thyroid cancer; MEN 2, multiple endocrine neoplasia type 2; ADHD, attention deficit hyperactivity disorder; BED, binge eating disorder; MAOI, monoamine oxidase inhibitors; OTC, over the counter; LDL, low-density lipoprotein cholesterol; SSRI, selective serotonin reuptake inhibitor; GABA, gamma-aminobutyric acid; HOMA-IR, homeostatic model assessment of insulin resistance; TID, three times a day.