By: Luxi Wang, PharmD Candidate c/o 2015, Lev Gurevich, PharmD Candidate c/o 2015, and Gladys El-Chaar, PharmD, Clinical Professor, Department of Clinical Pharmacy Practice, St. John’s University College of Pharmacy and Health Sciences
A 17-year-old female presented to the ED after experiencing a tonic-clonic seizure with loss of consciousness lasting 5 minutes while she was at the mall with her friends. The patient had a history of one previous episode of tonic-clonic seizure 5 months prior to admission. The patient is currently enrolled in 10th grade and receives passing grades. She lives at home with her mother, while her father lives in China. The patient denied use of tobacco and illicit drugs and admitted to drinking alcohol occasionally at parties. There is no family history of seizures.
In the ED, the patient was recorded as weighing 56.8 kg with a height of 160cm. Her weight and height fell in the 50th percentile for her age. There were no significant physical exam findings and her vital signs were within normal limits. Laboratory values were within normal limits except for a mild decrease in magnesium upon admission, and a mild increase in sodium 2 days following date of admission (see Appendix A). The patient had a blood pressure of 106/73, respiratory rate of 16, temperature of 98.2°F, and pulse of 73, and her oximetry was at 99%. Her urine toxicology results were negative. She reported occasionally taking acetaminophen (Tylenol®) for headaches as per package instructions and “diet pills”. She was admitted to the hospital’s pediatric unit and was placed on levetiracetam 250mg po BID to control her seizures. The dose was then increased to 500mg po BID after 2 days to reach the recommended dosage; however, the patient did not experience any additional seizure episodes throughout admission. The pediatric medical team asked us, the pharmacy team, for assistance in understanding the content and potential adverse effects of the weight loss products the patient was taking. An extensive interview with the patient in Mandarin Chinese revealed that she had experienced her first seizure 5 months ago, a month after she began consuming products marketed for weight loss. She revealed that she had been taking two different products: a “Yanhee” product from Thailand, and the weight loss product Apidexin®. The patient claimed to take 8 doses per day of the “Yanhee” product, as per package instructions, and she took Apidexin® intermittently, usually upon running out of the “Yanhee” product. The patient reported never stopping her regimen for more than a few days.
The patient has been struggling with her body image for a long time and perceived herself as “chubby”, which propelled her to take these medications and go on a strict diet, avoiding carbohydrates and meat altogether. She would typically eat one small meal per day, consisting of plain salads, fruits, tofu and eggs in small amounts, and drank only water. In addition she would run on the treadmill for at least an hour a day for exercise. As a result, she had lost 20 kg over a period of 6 months, an average of 0.83 kg per week. Her most recent height and weight were appropriate for her age. To us, she admitted feeling depressed, agitated, and tired since beginning to take the aforementioned weight loss products. She mentioned that, in the past five months, she had been alerted to a low thyroid stimulating hormone level by her primary care physician. She also reported experiencing blurry vision, particularly when reading. The patient developed suicidal ideation, without any attempts or plans. Approximately one week prior to day of admission, patient experienced significant worsening of depression and agitation. The patient’s mother was aware of her use of these weight loss products and had also noticed the behavioral changes. Following further discussion with the patient and her mother, it became apparent that she has a great deal of psychological dependence on the weight loss products. The patient believed that the episode of seizure was an “isolated incident” since none of her friends experienced it even though they were also taking the “Yanhee” product. She also asked about the drug interaction between the weight loss product and levetiracetam, indicating that she was planning on continuing with these weight loss products. We informed the pediatric medical team of our findings, which significantly influenced the discharge plan. Subsequently, during her hospitalization, the patient developed an increased amount of anxiety and agitation, possibly due to the withdrawal effect of certain ingredients of the weight loss products, particularly the amphetamine-like components. One dose of lorazepam 0.5mg IV was effective in reducing her anxiety. Upon discharge the patient was referred to a 24-hour inpatient eating disorder unit at a different medical facility.
Patient was brought to the ED a few hours following discharge for experiencing auras of seizure. Patient did not develop a seizure and was discharged on the same day. The exact events leading up to the ED visit were unknown. However, there are strong suspicions that the patient had reinitiated her weight loss products.
A literature search was conducted for the contents of each product as well as evidence for toxicity and efficacy of each component. We also consulted with the NS-LIJ-St John’s University drug information center for further assistance.
Thermo-Diamine®, scientifically known as evodiamine, was tested on rats for weight loss. As the name suggests, Thermo-Diamine® was demonstrated to simultaneously induce heat loss and production to dissipate energy from food. This would prevent accumulation of fat and excessive weight gain.11 Efficacy in humans has not been tested, and a study showed evodiamine to have significant negative chronotropic effects on the heart as well as hypotensive action. Seizures were not reported.12
Cyanocobalamin is an essential vitamin which aids in the normal bodily functions of metabolism and energy utilization. It is a water-soluble vitamin with limited blood brain barrier penetration and little accumulation. However, there are still notable adverse effects associated with toxicity including abnormal gait, anxiety, ataxia, dizziness, headache, hypoesthesia, nervousness, pain, and paresthesia. Toxicity is rare, although taking this supplement daily without an actual deficiency could potentiate the aforementioned adverse effects, especially with prolonged use.13
The other weight loss supplement, the “Yanhee” product, originates in Thailand. Although not available on the US market, it can be easily obtained from websites such as eBay. The manufacturing of “Yanhee” products is highly unregulated, and the ingredients vary among different brands and preparations. Discrepancies between labeled ingredients and the actual contents are common. Some of the popular ingredients among different “Yanhee” product preparations include phentermine, amphetamine, sibutramine, fenfluramine, diuretics, and caffeine. Unfortunately, the amount of each ingredient in “Yanhee” product is unspecified. Some of these ingredients are either banned or labeled as controlled substances in the United States due to toxicity and dependence liability.
One of the labeled ingredients of “Yanhee” product is phentermine, which has been approved by the FDA for the treatment of obesity. The two prescription drugs containing phentermine that are currently available on the US market are Apidex-P® and Qsymia®, which is a combination of phentermine and topiramate that was approved by the FDA in 2012. Phentermine is a sympathomimetic anorectic that stimulates the release of norepinephrine into the hypothalamus. As a result, blood leptin concentration increases, causing suppression of appetite. 14Although shown to be efficacious for weight loss, phentermine also carries certain risks. Phentermine is contraindicated in patients with hyperthyroidism and agitated states, both of which the patient reported to have experienced. The package insert also warns against the use of phentermine in patients with history of seizure disorders. In addition, phentermine is not indicated for chronic use due to the possible risks of tolerance and dependence.15
Fenfluramine, a racemic mixture of the two isomers levofenfluramine and dexfenfluramine, was approved by the FDA in 1973 for adjunctive treatment for obesity. It is a sympathomimetic that promotes the release of endogenous serotonin while inhibiting its reuptake. The 5-HT2C serotonin receptor has been implicated in both satiety and seizure susceptibility.16 The combination product of fenfluramine and phentermine, also known as Fen-Phen®, gained popularity in the 1980s and 1990s.17 However, it was withdrawn from the market in 1997 due to serious cardiac adverse events.18 In 2000, a series of five case reports was published in the journal Epilepsy & Behavior reporting the possible association between the uses of Fen-Phen® and seizures. In two of these cases, patients developed new onset of seizures without a prior history of seizures following treatment with Fen-Phen®. In the other three cases, patients with a history of idiopathic generalized epilepsy in remission experienced episodes of seizure following treatment with Fen-Phen®. One of the patients experienced recurrent seizure upon re-initiation of Fen-Phen®.19
Sibutramine is a combined norepinephrine and serotonin reuptake inhibitor that has been marketed for the treatment of obesity. Its sympathomimetic effect induces satiety and increases energy expenditure. However, all sibutramine preparations were recalled by the FDA in 2010 due to significant increases in the risk of nonfatal myocardial infarction and nonfatal stroke in patients with preexisting cardiovascular conditions. Case reports have also demonstrated dose-dependent correlation between the use of sibutramine and the onset of recurrent seizures. The exact mechanism of this association is unclear, however sibutramine is believed to lower seizure thresholds similarly to tricyclic antidepressants. In addition, sibutramine may induce psychotic symptoms such as paranoia and manic episodes.20 In September of 2013, the FDA issued a mandatory recall of over the counter weight loss products that had been tainted with sibutramine due to increased risk of seizures and other serious adverse health effects.21
Amphetamine, a C-II controlled substance that is present in ADHD medications such as Adderall®, was also detected in certain preparations of “Yanhee” products. Amphetamine, a sympathomimetic and central nervous system stimulant, promotes the release of norepinephrine and dopamine from presynaptic nerve terminals. It should be used with caution in patients with history of seizure disorder due to the seizure threshold lowering effect. New onset and breakthrough seizures have been reported following the first dose of amphetamine.22 As a result, preparations containing amphetamine should be discontinued at the occurrence of seizure.15 In addition, prolonged use of amphetamine can also lead to dependency and drug abuse. Clinical presentations of amphetamine withdrawal include anxiety and agitation that can last for weeks.23 The patient in this case report presented with symptoms similar to that of amphetamine withdrawal during her course of hospital stay.
Caffeine is a commonly consumed substance that also possesses proconvulsant properties. Caffeine blocks the adenosine receptors and subsequently increases the turnover of many neurotransmitters, such as monoamines and acetylcholine. Studies have shown that caffeine lowers the seizure threshold and, when administered in high doses, produces seizure.22 Incidents of recurrent seizure following ingestion of caffeinated beverages have been reported.24
A diuretic is another common ingredient in weight loss products. Although a diuretic is not shown to have any effect on body fat, it can cause temporary and rapid weight loss due to the elimination of water weight from the body. During this patient’s 5 days of hospital stay, she gained 2.2 kg, which is an abnormal amount of weight gain for such short period of time, since the patient was not ingesting an adequate caloric intake to gain this weight. It can be attributed to a possible dehydrated status on admission, though there was no mention of dehydration on her physical exam on admission and her vital signs were stable. Although the direct association between the use of a diuretic and seizures is unclear, diuretic-induced hyponatremia and can precipitate seizure.25 It is known that disorders of vitamin, electrolyte, and endocrine metabolites may disrupt neuronal excitability by influencing neurotransmitter function and the ionic microenvironment. Fluctuation in electrolytes and endocrine metabolites may precipitate seizures.26 The association of electrolyte imbalance and seizure in this patient remains to be a speculation, since patient’s blood electrolyte values were close to or within normal range upon admission.
The patient’s complaint of blurred vision was not reported with any ingredients of the weight loss products above. Her report of depression was unexpected in the context of her consumption of fenfluramine and sibutramine, essentially SSRIs such as those typically indicated in the treatment of depression. However, the patient experienced the adverse effects of agitation (amphetamine-like substance) and suicidal ideation (SSRIs).
Barring a past medical history, the occurrence of seizures at least two times following the ingestion of this patient’s weight loss products points to a great potential for these products to either induce seizures or lower this patient’s threshold for seizures. On the Naranjo scale, this adverse event would be classified as “Definite” with a total score of 9 (see Appendix B). It seems that the “Yanhee” product was used more frequently by this patient. At least four ingredients in this preparation have been linked to seizures, including phetermine, fenfluramine, sibutramine, and amphetamines. The inclusion of caffeine and a diuretic may further produce dehydration and excessive sodium, magnesium, and calcium losses as well as an osmotic shift to precipitate seizure activity, though this was less likely in our patient given her normal laboratory values and vital signs on admission. Apidexin® use, though sporadic, has been associated with some adverse effects on the CNS; however we were unable to find seizures reported with this agent to date.
On admission, this patient’s weight and height were in the 50th percentile for her age and gender and she was not emaciated. We repeatedly attempted to explain that her current diet and exercise regimens alone should be very sufficient to maintain her body weight. Unfortunately, this was a more complex issue, common among adolescent females preoccupied with their body image.
Through research, the pharmacy team was able to address critical associations between patient’s use of weight loss products and her recurrent seizure episodes. In addition, we were able to identify other risks factors, such as dependence and abuse related to these weight loss products. This knowledge may have helped establish a more appropriate discharge facility for continuation of care. Although the use of over-the-counter weight loss products among adolescents is widespread, dietary and behavioral modifications are the only recommended interventions per AMA guideline on the management of childhood obesity.27 An intense counseling program is necessary to help this patient control her weight while avoiding the use of non-FDA approved and potentially dangerous weight loss products.
|Lab (normal range)||Day of admission||2 days following admission|
|WBC (4.0-10.5 K/µL)||8.3|
|Hgb (12.0-15.0 g/dL)||12.5|
|Plt (150-450 k/µL)||300|
|MCH (26-32 pg)||27|
|MCHC (32-36 g/dL)||32|
|MCV (78-95 fl)||83|
|RDW (11.5-14.0 %)||14.1 H|
|Lymphocyte (25-33%)||44 H|
|Absolute neutrophil (1.1-5.0 K/uL)||4.2|
|Absolute lymphocyte (1.8-9.0 K/uL)||3.7|
|Absolute monocyte ( 0.0-0.1 K/uL)||0.3|
|Absolute eosinophil (0.0-0.7 K/uL)||0.2|
|Specific gravity (1.002-1.035 RI)||1.009|
|Urine color (yellow)||Yellow|
|Urine Protein (Negative)||Negative|
|Urine Glucose (Negative)||Negative|
|Urine Ketone (Negative)||Negative|
|Urine Bilirubin (Negative)||Negative|
|Urine Blood (Negative)||Negative|
|Leukocyte Esterase (Negative)||Negative|
|Urine Nitrite (Negative)||Negative|
|Urine Clarity (Clear)||Clear|
|Sodium (138-145 mEQ/L)||140||147 H|
|Potassium (3.7-5.2 mEQ/L)||cancelled by lab due to hemolysis||4.6|
|Chloride (103-112 mEQ/L)||105||109|
|CO2 (23-33mEQ/L)||19 L||28|
|BUN (8-21 mg/dL)||11||11|
|SCr (0.6-1.2 mg/dL)||0.7||0.5 L|
|Glucose (73-107 mg/dL)||89||96|
|Calcium (8.6-10.3 mg/dL)||9.4||8.9|
|Phosphate (2.7-4.7 mg/dL)||4.5|
|Magnesium (1.7-2.2 mg/dL)||1.6 L|
|Total CK (42-284 IU/L)||291 H|
|Troponin-I (<0.6 ng/mL)||<0.0|
|Naranjo Adverse Drug Reaction Probability Scale 28|
|Question||Yes||No||Do Not Know||Score|
|Are there previous conclusive reports on this reaction?||+1||0||0||+1|
|Did the adverse event appear after the suspected drug was administered?||+2||‐1||0||+2|
|Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?||+1||0||0||+1|
|Did the adverse event reappear when the drug was re‐administered?||+2||‐1||0||+2|
|Are there alternative causes (other than the drug) that could on their own have caused the reaction?||‐1||+2||0||+2|
|Did the reaction reappear when a placebo was given?||‐1||+1||0||0|
|Was the drug detected in blood (or other fluids) in concentrations known to be toxic?||+1||0||0||0|
|Was the reaction more severe when the dose was increased or less severe when the dose was decreased?||+1||0||0||0|
|Did the patient have a similar reaction to the same or similar drugs in any previous exposure?||+1||0||0||+1|
|Was the adverse event confirmed by any objective evidence?||+1||0||0||0|
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[pubmed_related keyword1=”weight” keyword2=”loss” keyword3=”seizure”]