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ASPARTAME

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aspartame is a dipeptide ester of two L-amino acids that is used as an artificial sweetner with a nutritive value of 4 calories/gram (Anon, 1983).

Specific Substances

    1) Methyl ester of L-aspartyl-L-phenylalanine
    2) 1-methyl-N-L-alpha-aspartyl-L-phenylalanine
    3) Methyl N-L-alpha-aspartyl-L-phenylalinate
    4) 3-Amino-N-(alpha-methoxycarbonylphenethyl)succinamic acid
    5) CAS 22839-47-0

Available Forms Sources

    A) FORMS
    1) Aspartame is available by the brand name Nutra-Sweet(R) (Searle).
    2) As a common sweetner for the dining table, it may be found under the trade name Equal(R). Each tablet contains 18 mg and each packet 36 mg.
    3) Each serving of aspartame-sweetened product (i.e., cereal, pudding, gelatin) contains about 55 mg of aspartame.
    4) FOREIGN TRADE NAMES
    1) Canderel (Belgium, France, UK)
    2) D sucril (France)
    3) Flix (UK)
    4) Glucal Aspartam (South Africa, France)
    5) Nozucar (Spain)
    6) Pouss-suc (France)
    7) Sukami (France)
    5) There are approximately 40 to 50 milligrams of aspartame per 100 milliliters soft drink.
    6) 500 milligrams of aspartame is equivalent to 280 milligrams of phenylalanine, 226 milligrams of aspartic acid and 54 milligrams of methanol (Horwitz & Bauer-Nehrling, 1983).
    7) METHANOL CONTENT: A liter of sweetened beverage contains 56 milligrams of methanol (1/3 the amount of methanol present in a normal fruit juice of this size).
    8) PHENYLALANINE CONTENT: The amount of phenylalanine in 1 liter of soft drink is approximately 400 to 500 milligrams, which is equivalent to the amount of phenylalanine found in 1 egg, 1 ounce of cheddar cheese, or six ounces of baked beans (Yellowlees, 1983).
    9) SOFT DRINKS: The amount of aspartame per soft drink brand/lot may vary. Many manufacturers use an aspartame/saccharin blend. One Canadian reference estimates approximate 50 milligrams/100 milliliters of soft drink (pp 32-33) if aspartame were the sole sweetening agent.
    10) Aspartame content of commercial soft drinks (Prod Info, 1988):
    a) Bottles or cans
    1) diet Coke 92 mg/6 fluid ounces
    2) caffeine-free diet Coke 92 mg/6 fluid ounces
    3) diet cherry Coca-Cola 92 mg/6 fluid ounces
    4) diet Minute Maid Lemon Lime 80 mg/6 fluid ounces
    5) diet Minute Maid Orange 94 mg/6 fluid ounces
    6) TAB (blend with saccharin) 14 mg/6 fluid ounces
    7) caffeine-free TAB 14 mg/6 fluid ounces (blend with saccharin)
    8) diet Sprite 87 mg/6 fluid ounces
    9) Fresca 87 mg/6 fluid ounces
    11) Fountain form of commercial soft drinks listed below contain a blend of aspartame and saccharin:
    1) diet Coke
    2) caffeine-free diet Coke
    3) diet cherry Coke
    4) diet Minute Maid Lemon-Lime
    5) diet Minute Maid Orange
    6) TAB
    7) caffeine-free TAB
    8) diet Sprite
    9) Fresca
    B) USES
    1) Aspartame is part of many different breakfast cereals, diet sweets, and both carbonated and non-carbonated beverages. It is present in over 280 food products (Thomas-Dobersen, 1989).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Aspartame is a dipeptide sweetner. The primary concerns regarding this agent have centered around chronic use or ingestions of very large amounts. The agent has a very wide therapeutic index.
    2) Phenylketonuric "challenge" (done with approximately 100 to 180 mg/kg phenylalanine) may produce symptoms of irritability, restlessness, and increases in deep tendon reflexes, and rarely seizures and hypoglycemia.
    3) Single ingestions of less than 10 g are unlikely to produce symptoms unless the patient is a phenylketonuric. The acceptable daily dose (ADI) for aspartame in Canada is 40 milligrams/kilogram, and 50 milligrams/kilogram in the United States.
    0.2.7) NEUROLOGIC
    A) ANIMAL STUDIES - Rat studies imply that aspartame may double or triple the amount of brain phenylalanine. The effect these changes have in rats, and their implication for humans is controversial.
    B) WITH THERAPEUTIC USE
    1) There is some concern that aspartame may cause some of the neurologic effects seen with glutamates. This has yet to be demonstrated in humans.
    0.2.17) METABOLISM
    A) WITH THERAPEUTIC USE
    1) This substance releases phenylalanine upon metabolism. Individuals with phenylketonuria must be aware that ingestions may produce toxic effects. Doses of 34 mg/kg and 100 mg/kg of aspartame, administered to individuals heterozygous for PKU, did not produce enough phenylalanine to induce toxic effects. Normal intake of aspartame is estimated at 7 to 9 mg/kg/day.
    2) Aspartame in doses up to 10 times current consumption in PKU heterozygotes resulted in plasma phenylalanine well below values associated with known adverse effects.
    0.2.20) REPRODUCTIVE
    A) In normal or excessive usage, aspartame is not expected to be a risk in pregnancy.

Laboratory Monitoring

    A) Phenylketonurics who have ingested large amounts may need to have serum phenylalanine and glucose levels monitored.
    B) If large amounts (in excess of 10 g) have been ingested by a small child, methanol levels may be indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Up to 100 milligrams/kilogram has been given chronically without toxic effects. There is no acute toxic dose. Ingestion of 100 doses of aspartame would only produce 1 gram of phenylalanine upon metabolism. This is a potential danger only in phenylketonurics. Approximately 500 milligrams of aspartame will produce 55 milligrams of methanol. For a patient to receive even 1000 milligrams of methanol, over 9,200 milligrams of aspartame must be ingested.
    B) Gastric decontamination is unlikely to be necessary unless very large amounts (greater than 10 g) have been ingested. Single ingestions of less than 10 g are unlikely to produce symptoms unless the patient is a phenylketonuric.
    C) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    D) If greater than 10 g of aspartame has been ingested in a small child, consider a methanol level.
    E) PHENYLKETONURICS
    1) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    a) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    b) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.

Range Of Toxicity

    A) ASPARTAME - Up to 100 mg/kg has been given chronically without toxic effects. There is no acute toxic dose. Small children have ingested 25 to 100 tablets without adverse effects.
    B) PHENYLALANINE - 100 doses of aspartame would only produce 1 g of phenylalanine upon metabolism. This is a potential danger only in phenylketonurics.
    C) METHANOL - 500 mg of aspartame will produce 55 mg of methanol. For a patient to receive even 1000 mg of methanol, over 9,200 mg of aspartame must be ingested.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Aspartame is a dipeptide sweetner. The primary concerns regarding this agent have centered around chronic use or ingestions of very large amounts. The agent has a very wide therapeutic index.
    2) Phenylketonuric "challenge" (done with approximately 100 to 180 mg/kg phenylalanine) may produce symptoms of irritability, restlessness, and increases in deep tendon reflexes, and rarely seizures and hypoglycemia.
    3) Single ingestions of less than 10 g are unlikely to produce symptoms unless the patient is a phenylketonuric. The acceptable daily dose (ADI) for aspartame in Canada is 40 milligrams/kilogram, and 50 milligrams/kilogram in the United States.

Neurologic

    3.7.1) SUMMARY
    A) ANIMAL STUDIES - Rat studies imply that aspartame may double or triple the amount of brain phenylalanine. The effect these changes have in rats, and their implication for humans is controversial.
    B) WITH THERAPEUTIC USE
    1) There is some concern that aspartame may cause some of the neurologic effects seen with glutamates. This has yet to be demonstrated in humans.
    3.7.2) CLINICAL EFFECTS
    A) DRUG INTERACTION
    1) WITH THERAPEUTIC USE
    a) ASPARTAME/MSG INTERACTION - There is some concern that aspartame may cause some of the neurotoxic effects seen with glutamates (both are dicarboxylic amino acid compounds). It is possible that the two agents might be given in the same meal (glutamate as MSG).
    1) A study where normal adults were given 34 mg/kg of both MSG and aspartame failed to increase plasma or erythrocyte levels above what was expected from the meal itself (Horwitz & Bauer-Nehrling, 1983).
    2) In another study, where individuals who had experienced MSG symptoms were given aspartame, MSG-type symptoms were not seen (Stegink et al, 1981).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Additional studies are needed to clarify the issue of the effect of chronic intake of aspartame and headache (Lipton et al, 1989; Lipton et al, 1988).
    b) Schiffman et al (1987) performed a double-blind, crossover trial of challenges with 30 mg/kg of aspartame or placebo in 40 subjects who reported having headaches repeatedly after consuming products containing aspartame and found no difference in the incidence rate of headache after aspartame (35%) and after placebo (45%) (p<0.50).
    c) In a controlled 13 week, double-blind, randomized, cross-over study in 11 migraine headache sufferers, the mean (SD) number of migraines while receiving aspartame 300 mg four times daily was 3.55 (2.58) vs 1.55 (0.93) for placebo vs 1.72 (1.42) for baseline (Koehler & Glaros, 1988).
    1) Limitations of this study included small subject population and inherent probabilities of bias associated with self reports of the subjects.
    d) In a double-blind placebo controlled, crossover study of 32 volunteers with self-identified headaches following aspartame use, among the subset of individuals who were "very sure" prior to the study that aspartame triggered some of their headaches, there were more headaches on aspartame days (0.37) than on placebo (0.18, p<0.001) (Eeden et al, 1994). The authors concluded that there may be a subset of individuals who are particularly susceptible to headaches induced by aspartame.
    1) Schiffman (1995) noted that a single subject with headaches on 13 of 14 days with aspartame and 1 of 14 days with placebo, accounted for nearly the entire statistically significant differences reported. Various confounding elements in this patient's headache history were not adequately explored.
    e) Some individuals may be susceptible to the effects of aspartame, as noted by three women with migraines who could provoke headaches by chewing sugarless gum which contained aspartame (HSDB , 2001).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) The occurrence of seizures has been postulated. The Centers for Disease Control found no convincing evidence of an association of seizures with aspartame ingestion (CDC, 1984).
    b) ANECDOTAL CASES - Unexplained seizures associated with large ingestions of aspartame-containing beverages have been reported (Wurtman, 1987; Wurtman, 1985).
    c) CASE SERIES/PEDIATRIC - Ten children with newly diagnosed, but untreated generalized absence seizures had spike-wave discharges studied by EEG following aspartame (40 mg/kg) in a sucrose-controlled, double-blind manner on two consecutive days (Camfield, 1992). Although the number of spike-wave discharges/hour and mean length of spike-wave discharges increased in the aspartame group, the results were not significant. However, the total duration of spike wave discharge/hour was significantly increase after aspartame.
    1) Shaytwitz (1993) suggested that the use of an active control (sucrose) influenced the spike-wave discharge. The length of baseline period was also thought to be too short, since spike-wave discharges are markedly variable.
    d) CASE SERIES/LACK OF EFFECT - 18 individuals with a history of seizure which were thought to be due to aspartame were evaluated by EEG (Shaywitz, 1993). Over 5 continuous days, there were NO clinical seizures and no effect of aspartame on quantitative EEGs compared with placebo or baseline recordings. In another study of 10 children with seizure disorders, five of whom had absence seizures, there were NO clinical seizures and no differences between aspartame and placebo at doses of up to 50 mg/kg.
    1) In another small study (n=18; 16 adults, 2 children) Rowan et al (1995) also reported no seizure activity or other adverse events following aspartame consumption.
    e) FDA FINDINGS - Analysis of the FDA passive surveillance data between 1986 and 1990 noted 251 reports of seizures which did not support the claim that the occurrence of seizures were linked to aspartame consumption (Tollefson & Barnard, 1992).
    D) DEPRESSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) A randomized, placebo-controlled, crossover study of adverse reactions to aspartame (30 mg/kg/d for 7 days) in 13 patients, eight with a history of treatment for major depression and a Brief Psychiatric Rating Scale rating of no greater than 6 at the time of the study, and 5 non-depressed controls was performed (Walton et al, 1993). Investigators found a statistically significant difference in total adverse reactions in patients with a history of major depression with regard to both number and severity of symptoms.
    1) Butchko (1994) reported that the above study was terminated prior to the planned 40% patient enrollment due to two non-aspartame related adverse events.
    E) LACK OF EFFECT
    1) WITH THERAPEUTIC USE
    a) NEUROPSYCHIATRIC EFFECTS - A double-blind crossover study of 10 healthy volunteers given a single dose of aspartame 15 mg/kg failed to demonstrate any change in mood, cognition, reaction time, and memory. There was no significant difference in subjective symptoms, such as sedation, hunger, and headache, between the placebo and treated groups (Lapierre et al, 1990).
    b) In a double-blinded placebo-controlled crossover study of unmedicated children with attention deficit disorder given either aspartame or placebo no clinically significant differences on cognitive or behavioral assessments were observed (Shaywitz et al, 1994). Wolraich et al (1994) also did not observe any cognitive or behavioral differences in healthy preschool children given either sucrose or aspartame.
    c) No significant differences were observed with regard to neuropsychiatric tests, adverse events, amino acid, insulin and glucose values, or EEG's compared by sex or treatment in healthy volunteers given either sucrose, placebo, or aspartame (high {45 mg/kg/d} and low {15 mg/kg/d}) (Spiers et al, 1998).
    d) Young college women (n=120) received either aspartame or sucrose-sweetened beverages and were then administered mood questionnaires before and 1 hour after the beverages were ingested (Pivonka & Grunewald, 1990). Changes in mood were similar following aspartame or water, however, increased sleepiness during the last half-hour of observation was noted following sucrose ingestion.
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) OTHER NON-SPECIFIC
    a) ANIMAL STUDIES - Rat studies imply that aspartame may double or triple (if taken with a carbohydrate load) the amount of brain phenylalanine (Wurtman, 1983). The effects of these changes in rats, and their implication for humans is controversial.

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) LACK OF EFFECT
    a) WITH THERAPEUTIC USE
    1) The clinical and biochemical effects of a single dose of 15 mg/kg aspartame vs skim milk (phenylalanine content equimolar to aspartame) was studied a randomized, placebo-controlled, unlabeled, three-way crossover design in 13 patients with chronic, alcoholic liver disease (Herelendy et al, 1992). There were no clinical derangements in encephalopathic indices, methanol accumulation, or biochemical changes in liver status.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CELLULITIS
    1) WITH THERAPEUTIC USE
    a) GRANULOMATOUS PANNICULITIS - Aspartame-induced granulomatous panniculitis has been reported (Novick, 1985).
    b) LOBULAR PANNICULITIS was reported in a 57-year-old diabetic male following ingestion of 210 to 245 mg of aspartame as packets and 36 to 48 ounces of aspartame-containing soft drinks daily. Subcutaneous nodules resolved within 12 days after discontinuation of aspartame, and returned within 5 days after double-blind challenge with 300 mg twice daily. Biopsy of the nodules showed lobular panniculitis with focal necrosis (McCauliffe & Poitras, 1991).

Endocrine

    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) ANIMAL STUDIES - Doses of 300 mg/kg/day failed to make any changes in endocrine function/needs in mice, rats, or rabbits tested (Saunders et al, 1980).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS
    1) A 23-year-old female developed itching, erythema, pruritus, and urticaria in 3 double-blind, placebo-controlled challenges with 25 and 50 mg aspartame (Kulczycki, 1986).
    2) A 42-year-old woman developed intermittent angioedema and urticaria associated with ingestion of aspartame-containing drinks, which was confirmed in a double-blind, placebo-controlled challenge (Kulczycki, 1986).
    b) CASE SERIES
    1) Single-blinded challenge with up to 2000 mg of aspartame failed to elicit reproducible results in 20 patients with self-reported aspartame hypersensitivity. Hives occurred in one patient after single-blind challenge, but could not be reproduced on two subsequent double-blind challenges (Garriga et al, 1991).
    2) A multicenter, randomized, double-blind, crossover, placebo-controlled trial of 21 subjects who had experienced urticaria and or angioedema allegedly associated with ingestion of an aspartame-containing product, demonstrated NO difference between aspartame and placebo; there were 2 allergic reactions in both the placebo and aspartame group (Geha et al, 1993).
    3) Kulczycki (1995) noted that the above study had design limitations which potentially discouraged individuals who were likely to have allergic reactions from participating in the study. Also, potential other causes of urticaria were not controlled for during the observation period.

Reproductive

    3.20.1) SUMMARY
    A) In normal or excessive usage, aspartame is not expected to be a risk in pregnancy.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) RATS - In rats exposed to aspartame (0.007%, 0.036%, 0.18% or 0.9% w/v) in their drinking water for 12 days prior to conception until the pups were 38 days old, no differences were noted in reflex development, morphological development, or spatial memory when compared to control rats given plain water (Holder, 1989).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    ASPARTAMEB*
    *Risk Factor C in women with phenylketonuria
    Reference: Briggs et al, 1998
    B) LACK OF EFFECT
    1) The 3 components of aspartame metabolism were tested in humans to evaluate their risk in pregnancy (Sturtevant, 1985).
    a) CONCLUSIONS - In normal or excessive usage, aspartame should not be a risk in pregnancy (Levy & Waisbren, 1987; Stegink & Krause, 1987). Deliberate overdose should be evaluated based on the following data.
    b) ASPARTIC ACID - Doses of 200 mg/kg as a single oral dose, and 100 mg/kg/hour intravenously, were tried in rhesus monkeys. Although maternal plasma levels rose 80 micromoles/dL, fetal levels rose only 1 micromole/dL.
    1) Conclusions were that it was virtually impossible for humans to consume enough aspartame to result in significant fetal circulation.
    c) PHENYLALANINE is concentrated on the fetal side of the placenta in a ratio of 1.3 to 1. Maternal levels under 60 micromoles/dL have not been associated with offspring mental retardation, levels greater than 110 micromoles/dL usually are.
    1) Doses of 10 mg/kg every 2 hours for 3 doses, and 34 mg/kg as a single dose resulted in levels of 14 to 16 micromoles/dL in PKU heterozygotes.
    2) A 100 mg/kg dose in the same patients produced 42 micromoles/dL, 100 mg/kg in normal subjects produced 20 micromoles/dL, 200 mg/kg produced 49 micromoles/dL.
    d) METHANOL - Single oral doses of methanol corresponding to 200 mg/kg of aspartame produced levels of 2.6 mg/dL at 2 hours and baseline in 24 hours.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Stegnik et al (1979) found that high doses of maternal aspartame do not affect the infant's phenylalanine level.
    a) In a study they conducted with 6 healthy women with well established lactation of 42 to 159 days, 50 mg/kg of aspartame caused the maternal phenylalanine level to increase four-fold over fasting values 45 minutes after aspartame. These levels returned to baseline by 4 hours.
    b) Plasma phenylalanine did not change following a lactose load. Small effects on milk levels of aspartate, phenylalanine and tyrosine were shown following aspartame ingestion. Aspartate levels in milk increased from 2.3 to 4.8 mmol/dL.
    2) The American Academy of Pediatrics recommends that mothers or infants with phenylketonuria need to monitor their intake of phenylalanine, and classifies aspartame as an agent to be used with caution in this patient population (Briggs et al, 1998).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) Experimental animal studies have failed to show any evidence of neoplastic changes attributable to aspartame. The Food and Drug Administration has also concluded that aspartame is safe in terms of risk of neoplasia ((Anon, 1981); Reno et al, 1975; Ishii, 1981).
    2) BRAIN TUMORS - An analysis of data from the National Cancer Institute's public data base does not support an association between the use of aspartame and increased incidence of brain tumors (FDA, 1996).
    a) A case control study of adults (n=56) with primary brain tumors between 1984 and 1991 in West Coast counties of the United States revealed case patients no more likely to have consumed foods containing aspartame (Gurney et al, 1997). There was NO dose-response relationship based on age at first consumption, number of years of consumption, of frequency of consumption. There was also NO increased tumor risk from maternal consumption during pregnancy or during breast-feeding.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Phenylketonurics who have ingested large amounts may need to have serum phenylalanine and glucose levels monitored.
    B) If large amounts (in excess of 10 g) have been ingested by a small child, methanol levels may be indicated.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Levels of aspartame are not clinically useful.
    2) Phenylketonurics who had ingested large amounts may need to have serum phenylalanine and glucose levels monitored.
    3) If large amounts (in excess of 10 g) have been ingested by a small child, methanol levels may be indicated.

Methods

    A) SAMPLING
    1) AIR SAMPLING - An air sampling technique using polytetrafluoroethylene (PTFE) filters as sampling media was developed to detect aspartame in the workplace environment. HPLC was used to analyze the samples, with a limit of detection of 2 micrograms per filter (Albrecht et al, 1989).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Phenylketonurics who have ingested large amounts may need to have serum phenylalanine and glucose levels monitored.
    B) If large amounts (in excess of 10 g) have been ingested by a small child, methanol levels may be indicated.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Single ingestions of less than 10 grams are unlikely to produce symptoms unless the patient is a phenylketonuric.
    2) Phenylketonuric "challenge" (done with approximately 100 to 180 mg/kg of phenylalanine) may produce symptoms of irritability, restlessness, increases in deep tendon reflexes, and rarely seizures and hypoglycemia.
    3) Amounts greater than about 150 mg/kg phenylalanine or 270 mg/kg aspartame) may produce symptoms (Personal Communication, 1983).
    B) ACTIVATED CHARCOAL
    1) For amounts in excess of 10 grams: Consider prehospital administration of activated charcoal as a gaseous slurry in patients who are awake and able to protect their airway.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) For amounts in excess of 10 grams:
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) If greater than 10 grams of aspartame has been ingested in a small child, consider a methanol level.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Range Of Toxicity

Summary

    A) ASPARTAME - Up to 100 mg/kg has been given chronically without toxic effects. There is no acute toxic dose. Small children have ingested 25 to 100 tablets without adverse effects.
    B) PHENYLALANINE - 100 doses of aspartame would only produce 1 g of phenylalanine upon metabolism. This is a potential danger only in phenylketonurics.
    C) METHANOL - 500 mg of aspartame will produce 55 mg of methanol. For a patient to receive even 1000 mg of methanol, over 9,200 mg of aspartame must be ingested.

Maximum Tolerated Exposure

    A) ACUTE
    1) INFANTS - Aspartame has been given in bolus doses of up to 100 mg/kg in infants, with no adverse effects (Filer et al, 1983; Stegink et al, 1983). Acute ingestion of 25 to 100 tablets in 9 young children did not result in adverse effects (Butchko & Strathman, 1989).
    2) ADI - The acceptable daily dose (ADI) for aspartame in Canada is 40 milligrams/kilogram, and 50 milligrams/kilogram in the United States (Sturtevant, 1985).
    B) CHRONIC
    1) INFANT - A 6-month, double-blind, placebo-controlled trial of 108 healthy volunteers given 75 milligrams/kilogram/day in three divided doses found no difference in the frequency of symptoms, such as headaches, nor any persistent laboratory abnormalities. No change in pulse or blood pressure was evident (Leon et al, 1989).
    2) Dikitopiperazine (DKP) is a decomposition product of aspartame. No toxic effect could be found in doses up to 3,000 milligrams/kilogram (Anon, 1983b).
    3) Rats fed 6 percent aspartame or 3 percent phenylalanine from conception to 90 days of life had statistically significant increases in offspring mortality (Brunner et al, 1979). Human significance is unknown.

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Peak blood methanol concentrations ranged from 1.3 to 2.6 milligrams/deciliter following abuse doses of aspartame 100 to 200 milligrams/kilogram (Stegink, 1984).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) >5 g/kg (RTECS, 2001)
    2) LD50- (ORAL)MOUSE:
    a) >10 g/kg (RTECS, 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) >5 g/kg (RTECS, 2001)
    4) LD50- (ORAL)RAT:
    a) >10 g/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Aspartame is a dipeptide sweetening agent.

Physicochemical

Physical Characteristics

    A) A nearly white crystalline powder that is practically odorless with an intensely sweet taste (S Sweetman , 2001).
    B) The product is 150-200 times sweeter than sucrose. It contains 4 cal/g (Mazure, 1976).
    C) Dikitopiperazine (DKP), a decomposition product of aspartame, is tasteless (Mazure, 1976).

Ph

    A) 4.0 to 6.5 (for a 0.8% aqueous solution) (S Sweetman , 2001)

Molecular Weight

    A) 294.3 (S Sweetman , 2001)

References

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