Obesity in Children Medication

Orlistat (Alli, Xenical), a pancreatic lipase inhibitor, is approved for long-term obesity management in adult patients in the United States. Remaining available weight loss products in the US for short-term use in adults include phentermine (Adipex-P) and diethylpropion.

FDA weight loss drug withdrawals

Sibutramine

Sibutramine (Meridia),^{[35, 36]} a selective serotonin norepinephrine reuptake inhibitor (SNRI), was withdrawn from the US market on October 8, 2010 because of an increased risk of myocardial infarction (MI) and stroke.^[37] Europe suspended sibutramine from the market earlier in 2010.

The US Food and Drug Administration (FDA) requested the market withdrawal after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT),^[37] which was initiated as part of a postmarket requirement to look at the cardiovascular safety of sibutramine after the European approval of this drug. The trial demonstrated a 16% increase in the risk of serious heart events, including nonfatal MI, nonfatal stroke, the need to be resuscitated once the heart stopped, and death, in a group of patients given sibutramine and another given placebo. A very small difference (2.5%) in weight loss was noted between the placebo group and the group that received sibutramine.^[37]

Rimonabant

Rimonabant (Acomplia), an anorectic agent with specific cannabinoid receptor inhibition, was approved in several European countries in 2006; however, it was unanimously denied approval by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee in June 2007. The FDA committee said that more detailed long-term safety information with larger patient numbers was needed with regard to neurologic and psychiatric side effects that have been associated with the drug, including seizures, depression, anxiety, insomnia, aggressiveness, and suicidal thoughts. Nonetheless, rimonabant is approved for sale in 42 countries and is marketed for obesity with associated cardiovascular risk in 20 countries.

Fenfluramine and dexfenfluramine

Two previously and widely used agents, the serotoninergic drugs fenfluramine and dexfenfluramine, were withdrawn from the commercial market because of their association with valvular heart disease and primary pulmonary hypertension. These drugs were also associated with drowsiness, insomnia, tremor, and short-term memory loss. High doses of fenfluramine and dexfenfluramine are neurotoxic in rats and monkeys, raising concerns about the long-term use of other serotoninergic preparations (eg, fluoxetine) in children.

Long-term weight loss and/or life-style modifications

Sibutramine may be classified as an anorectic drug, whereas orlistat's mechanism of action involves induction of lipid maldigestion. Although each of these medications significantly increases weight loss when compared with placebo, in long-term studies, the anorectic agents have also been shown to maintain effectiveness only in conjunction with an appropriate diet and exercise program.

Indeed, these drugs mediate only modest effects on total body weight, with long-term weight losses amounting to 2-10 kg in adults with obesity. Furthermore, responses of individuals to drug therapy widely vary. Most weight loss is achieved within the first 6 months of treatment, followed either by weight stabilization or by a slight regain of lost weight. Discontinuation of drug therapy is usually accompanied by rebound weight gain and loss of the selective advantage over placebo, unless significant lifestyle modifications have been achieved. Other older anorectic agents approved in the US include benzphetamine (Didrex), diethylpropion, phendimetrazine (Bontril), and phentermine (Ionamin).

Adverse effects

All of these weight loss drugs are associated with significant side effects that often limit their use. With orlistat, resulting nausea, bloating, and discomfort from steatorrhea are common, although these symptoms tend to decrease with long-term use. Sibutramine may cause dry mouth, insomnia, nervousness, diaphoresis, hypertension, nausea, and constipation.

Tolerance to most adverse effects is achieved within 2 weeks of continuous treatment. Contraindications to the use of noradrenergic agents include angina and other forms of atherosclerotic disease, cardiac arrhythmias, hyperthyroidism, and/or the concomitant use of monoamine oxidase inhibitors (MAOIs). Several adrenergic drugs have either been withdrawn from the market in the US (eg, phenylpropanolamine, mazindol) or are banned by the FDA (eg, ephedrine alkaloids ephedra, ma huang) as the consequence of potentially fatal cardiovascular effects.

Pediatric experience

Pediatric experience with the use of weight loss drugs is beginning to emerge. One multicenter, randomized trial of orlistat in obese adolescents demonstrated weight stabilization and reduced body fat in the orlistat group, whereas significant weight gain was observed in patients receiving placebo.^[38] However, a second study failed to demonstrate any significant benefit from orlistat treatment.^[39] Regarding the use of anorectic agents, a 12-month, randomized placebo-controlled trial of sibutramine in 498 adolescents demonstrated a significant, drug-associated reduction in body mass index (BMI) (sibutramine, -8.2% vs placebo, 0.8%,without any observed cardiodynamic effects.^[35]

Despite some of these promising findings, anorectic drugs should never be routinely used for the prevention or treatment of obesity in childhood or adolescence. Clearly, these agents must be absolutely proscribed for prepubertal children until carefully controlled clinical studies are performed to assess their safety and efficacy. Administration of anorectic drugs may be considered in the postpubertal adolescent, but only after the patient has failed to respond to vigorous attempts to modify behavior, diet, and family interactions. Unless prohibited by a specific investigational protocol, all adolescents who are prescribed anorectic agents should receive concurrent nutritional and family counseling and should implement a plan of regular exercise and physical activity.

Class Summary

Anorexiants are administered to manage obesity. Indications include weight loss and maintenance of weight loss, in conjunction with a reduced calorie diet, specifically in patients who are obese with an initial body mass index (BMI) of 30 or 27 mg/m² and other risk factors (eg, diabetes mellitus, dyslipidemia, hypertension).

Orlistat (Alli, Xenical)

Orlistat is a gastrointestinal lipase inhibitor that induces weight loss by inhibiting nutrient absorption. The effectiveness of this agent in producing weight loss does not depend on systemic absorption, and it may reduce the absorption of some fat-soluble vitamins (A, D, E, K) and beta-carotene. Administer a daily oral multivitamin supplement containing fat-soluble vitamins 2 hours before meals or 1 hour after meals.

Class Summary

Adrenergic agonists are stimulants that release tissue stores of epinephrine, causing subsequent alpha- and/or beta-adrenergic stimulation. These drugs have provided benefits to patients with obesity and are approved in adults for short-term use (8-12 wk).

Caffeine

Caffeine is a natural xanthine derivative that directly stimulates all levels of the central nervous system (CNS), cardiovascular system, and voluntary muscles. This agent increases gastric acid secretion and renal blood flow and also has mild diuretic activity.

Phentermine (Adipex-P)

Phentermine is a sympathomimetic amine that increases the release and reuptake of norepinephrine and dopamine. The anorexiant effect of this agent occurs as result of satiety-center stimulation in the hypothalamic and limbic areas of brain. Phentermine is the pharmacologic component of a comprehensive weight-reduction program (including behavioral modification, caloric restriction, exercise) intended for patients with an initial body mass index (BMI) of 30 or 27 kg/m2 and other risk factors (eg, diabetes, hyperlipidemia, hypertension).

Diethylpropion

Diethylpropion is a sympathomimetic amine that is effective as an adjunct for anoretic therapy of exogenous obesity. The anorexiant effect of this drug occurs as a result of satiety-center stimulation in the hypothalamic and limbic areas of brain. Note that diethylpropion is a controlled substance with high potential for abuse and addiction.