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LEVOCARNITINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Carnitine is an amino acid derivative. Levocarnitine is a quaternary ammonium compound found in all mammalian tissue and is a carrier molecule in the transport of long-chain free fatty acids across the inner mitochondrial membrane. It is a trimethylated amino acid and is essential for the transformation of fatty acids into energy for muscular activity. This transformation, which occurs in the mitochondria, produces coenzyme A.
    B) Acetyl-L-Carnitine and Propionyl-L-Carnitine are related to levocarnitine.

Specific Substances

    1) 3-Carboxy-2(R)-hydroxy-N,N,N-trimethyl-1-propanaminium, inner salt
    2) B(t) factor
    3) Carnitine
    4) D-carnitine
    5) DL-carnitine
    6) L-carnitine
    7) Gamma-trimethyl-ammonium-beta-hydroxybutyrate
    8) Gamma-beta-hydroxybutyrobetaine
    9) Karnitin
    10) Levocarnitine
    11) Vitamin B(t)
    12) Vitamin BT
    13) Molecular Formula: C7-H15-NO3
    14) CAS 541-15-1

Available Forms Sources

    A) FORMS
    1) Carnitine occurs as distinct L- and D-isomers; however, naturally occurring carnitine is almost exclusively the L-isomer. L-carnitine is used in therapeutics in preference to DL-carnitine, which is the form often present in over-the-counter preparations and dietary supplements (S Sweetman , 2001).
    a) L-carnitine acts as a substrate for carnitine acetyltransferase; D-carnitine acts as a competitive inhibitor; L-carnitine-induced stimulation of palmitate oxidation is competitively inhibited by D-palmitoylcarnitine. These differences probably account for findings of benefit only with the L-isomer, or unwanted effects when D-carnitine or DL-carnitine are administered (S Sweetman , 2001).
    2) Levocarnitine is available in the United States as: 200 mg/mL and 1 g/5 mL intravenous solutions and 250 mg, 300 mg, 400 mg capsules, 100 mg/mL oral solutions, and 330 mg and 500 mg tablets (Prod Info CARNITOR(R) oral tablets, oral solution, CARNITOR(R) SF sugar-free oral solution, 2006; Prod Info CARNITOR(R) injection, 2004).
    B) SOURCES
    1) Carnitine is found endogenously in the body. Within the body, carnitine is synthesized from 2 essential amino acids, lysine and methionine. Exogenous sources of carnitine include meat, poultry, fish and dairy products. It has been suggested that approximately 50% of carnitine normally originates from the diet (Heinonen, 1996). Carnitine is generally low in foods of plant origin and higher in animal foods. Among plant foods, avocado has the highest carnitine concentration. Among animal foods, sheep skeletal muscle contains the highest concentration of carnitine, higher than beef muscle (Mitchell, 1978).
    2) The physiologically active form of carnitine is L-carnitine. D-carnitine is physiologically inactive, but appears to compete with L-carnitine, resulting in a carnitine deficiency (Heinonen, 1996). Thus, the use of D- or DL-carnitine for supplementation may be harmful.
    C) USES
    1) Levocarnitine is approved for the following conditions: primary L-carnitine deficiencies; acute and chronic treatment of patients with an inborn error of metabolism resulting in secondary carnitine deficiency; and prevention and treatment of carnitine deficiency in patients with end stage renal disease who are undergoing dialysis (Prod Info CARNITOR(R) oral tablets, oral solution, CARNITOR(R) SF sugar-free oral solution, 2006; Prod Info CARNITOR(R) injection, 2004).
    2) HEPATOTOXICITY SECONDARY TO ACUTE VALPROATE EXPOSURE
    a) Carnitine administration has been shown to lower serum ammonia levels and improve outcome in patients with valproate-induced hepatotoxicity and encephalopathy after chronic use (Ohtani et al, 1982) .
    b) INDICATIONS: Despite a lack of controlled studies, it is suggested that L-carnitine be used to treat acute valproic acid-induced toxicity under the following circumstances (Jung et al, 2008; Lheureux & Hantson, 2009; Russell, 2007):
    1) Hepatotoxicity
    2) Hyperammonemia
    3) High risk patients; especially children or those who ingested a large amount of valproic acid
    4) Valproic acid concentration greater than or equal to 450 mg/L
    c) Based on recent clinical data, the use of L-carnitine is NOT supported in patients with valproic acid-induced CNS depression without hepatotoxicity or hyperammonemia; clinical observation did not show a rapid return to consciousness (Lheureux & Hantson, 2009).
    3) COMPLEMENTARY AND ALTERNATIVE MEDICINE
    a) L-carnitine is frequently used in patients presenting with poor cardiac function and compromised circulation. It is routinely used as a supportive treatment in patients recovering from a heart attack and for chronic fatigue syndrome. L-carnitine can be effective for weight loss and metabolic dysfunction. High doses of 1 to 3 grams daily are used to promote increased energy and weight loss. Although research is not conclusive, L-carnitine continues to be used to enhance physical performance in athletes. Body builders use L-carnitine to assist in fat burning as well as to improve muscle function and exercise capacity; marathoners use it to enhance endurance; and weight lifters and sprinters use it for its touted ability to add strength and speed. L-carnitine may improve symptoms of angina. It is also used in hypertriglyceridemia (S Sweetman , 2001; Jellin et al, 2000; Brass & Hiatt, 1998).
    4) PROPIONYL-L-CARNITINE was developed in order to improve muscle metabolism in peripheral arterial disease. It is converted to carnitine and propionyl-CoA in tissues, with the potential to increase carnitine availability (Brass & Hiatt, 1998; Coto et al, 1992).
    5) ACETYL-L-CARNITINE has been used to slow progression to dementia in patients with Alzheimer's disease (Sano et al, 1992).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Levocarnitine is approved for the following conditions: primary L-carnitine deficiencies; acute and chronic treatment of patients with an inborn error of metabolism resulting in secondary carnitine deficiency; and prevention and treatment of carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. It is also used to treat hyperammonemia in patients with valproate induced hepatotoxicity and encephalopathy. Athletes use carnitine for muscle building and endurance.
    B) PHARMACOLOGY: Levocarnitine is found in all mammalian tissue and is a carrier molecule in the transport of long-chain free fatty acids across the inner mitochondrial membrane. It is a trimethylated amino acid and is essential for the transformation of fatty acids into energy for muscular activity. This transformation, which occurs in the mitochondria, produces coenzyme A.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Transient nausea, vomiting, abdominal cramps, diarrhea, body odor. Levocarnitine may cause seizures in patients with or without pre-existing seizure disorder. Headache, dizziness, and transient visual blurring have been reported in patients taking high doses of levocarnitine. A mild myasthenia has been reported following the administration of DL-carnitine to uremic patients. In clinical trials of patients on chronic hemodialysis, hypertension, tachycardia, ECG changes, anemia, and paresthesia were reported more frequently than in patients receiving placebos; however, the causal relationship to levocarnitine is not clear.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there is no acute overdose data available. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Levocarcitine is in FDA Pregnancy Category B. Positive correlations between carnitine concentrations in maternal and umbilical venous blood have been reported, suggesting placental transfer. It is not yet known whether levocarnitine is excreted in human milk.

Laboratory Monitoring

    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting or diarrhea.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Severe toxicity is not expected after overdose of levocarnitine. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed, if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary.
    2) HOSPITAL: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENTS
    1) Should not be required in these cases.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Levocarnitine is removed by hemodialysis but hemodialysis is not recommended given the low toxicity of this drug.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) Levocarnitine does not bind to plasma protein or albumin when tested at any concentration. Vd: 29 L (approximately 0.39 L/kg). Elimination half-life: 0.585 hours. Elimination occurs primarily through the kidneys.
    I) DIFFERENTIAL DIAGNOSIS
    1) Patients with a history of decreased gastrointestinal motility due to other causes. Patients with underlying cardiac dysrhythmias or electrolyte imbalance may develop more severe symptoms.
    0.4.6) PARENTERAL EXPOSURE
    A) Follow treatment recommendations in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

    A) TOXICITY: At the time of this review, a toxic dose for levocarnitine has not been established. Intravenous doses as high as 300 mg/kg have been administered with no apparent toxicity.
    B) THERAPEUTIC DOSES: ADULT: IV: 50 to 300 mg/kg depending on indication. ORAL: 1 to 3 g or 100 mg/kg depending on indication. PEDIATRIC: IV: 50 to 500 mg/kg/day (maximum 3 g/day) depending on indication. ORAL: 50 to 100 mg/kg/day, maximum 3 g/day depending on indication.

Clinical Effects

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) During intravenous dosing following dialysis sessions in patients with end stage renal disease, hypertension (magnitude undefined) was more common in patients receiving levocarnitine (18% to 21% at doses ranging between 10 to 40 mg/kg) than placebo (14%) (Prod Info CARNITOR(R) injection, 2004).
    B) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) During intravenous levocarnitine 40 mg/kg following dialysis sessions in patients with end stage renal disease, 6% of patients (n=34) were noted to have atrial fibrillation or ECG changes compared to 3% or less of patients at lower dose levels of levocarnitine and no patients on placebo. Tachycardia was noted in 9% of those at the higher levocarnitine dose of 40 mg/kg, in comparison to 5% to 6% of patients on either placebo or levocarnitine 10 to 20 mg/kg (Prod Info CARNITOR(R) injection, 2004).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) An increase in the severity and/or frequency of seizures has been reported in patients with a history of seizure activity. Seizures have also been reported in levocarnitine-treated patients without pre-existing seizure activity (Prod Info CARNITOR(R) oral tablets, oral solution, CARNITOR(R) SF sugar-free oral solution, 2006; Prod Info CARNITOR(R) injection, 2004; Prod Info levocarnitine IV injection, 2004).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During intravenous treatment following dialysis sessions in patients with end stage renal disease, headache was more common in all patients receiving levocarnitine (22%) compared to placebo (16%), with the highest prevalence in patients on 20 mg/kg (37%) (Prod Info CARNITOR(R) injection, 2004). Headache and dizziness were reported in a patient receiving 6 grams intravenously (Harper et al, 1988).
    C) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In end stage renal disease patients maintained with post-dialysis infusion treatment, levocarnitine 40 mg/kg was associated with complaints of paresthesia in 12% of 34 patients, in contrast to 3% of those on lower doses (10 to 20 mg/kg) or placebo controls (Prod Info CARNITOR(R) injection, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Adverse effects of oral L-carnitine include transient nausea and vomiting, abdominal cramps and diarrhea (Prod Info CARNITOR(R) oral tablets, oral solution, CARNITOR(R) SF sugar-free oral solution, 2006; Prod Info CARNITOR(R) injection, 2004; Prod Info levocarnitine IV injection, 2004; Rizos, 2000; De Vivo et al, 1998; Plioplys & Plioplys, 1997).
    b) With intravenous therapy in patients with end stage renal disease, high dose (40 mg/kg) treatment following dialysis sessions was associated with a higher incidence of diarrhea (35%) than 10 to 20 mg/kg dose levels (9% to 10%) or placebo (19%). Similarly, vomiting was more prevalent (21%) at the higher dose than with placebo (16%) or the lower levocarnitine doses (9% to 16%) (Prod Info CARNITOR(R) injection, 2004).
    c) INCIDENCE: In a clinical study in mitochondrial myopathy, 10% of the patients experienced gastrointestinal side effects, mainly nausea and diarrhea (Campos et al, 1993). Three out of 35 girls with Rett syndrome experienced diarrhea with L-carnitine doses of 100 mg/kg/day. Following a dose reduction to 75 mg/kg/day, symptoms resolved (Ellaway et al, 1999).
    B) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) An uncharacterized taste perversion was reported in 9% of 34 end stage renal disease patients receiving levocarnitine 40 mg/kg infusion doses at the end of dialysis sessions. An additional 2% of patients on 20 mg/kg doses complained of taste disturbances, compared to no complaints with placebo control or the lowest dose (10 mg/kg) of levocarnitine (Prod Info CARNITOR(R) injection, 2004).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL COLOR
    1) WITH POISONING/EXPOSURE
    a) Extreme and continued weakness as well as discolored urine (possible myoglobinuria; no CPK or MB statistics given) were reported in a marathon runner who had ingested 500 mg DL-carnitine nightly for 2 nights prior to a race. The author speculated that D-carnitine may inhibit the activity of L-carnitine and may have caused a levocarnitine deficiency (Keith, 1986).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) During intravenous therapy after dialysis sessions in patients with end stage renal disease, anemia (magnitude not defined) was noted in 12% of 34 patients treated with levocarnitine 40 mg/kg. In contrast, only 3% of placebo patients and 3% to 5% of lower dose (10 to 20 mg/kg) levocarnitine patients were reported with anemia (Prod Info CARNITOR(R) injection, 2004).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ABNORMAL BODY ODOR
    1) WITH THERAPEUTIC USE
    a) Patients treated with levocarnitine may develop a fishy body odor which may be eliminated by a reduction in dosage (Prod Info CARNITOR(R) oral tablets, oral solution, CARNITOR(R) SF sugar-free oral solution, 2006; De Vivo et al, 1998).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH THERAPEUTIC USE
    a) A mild myasthenia has been reported following the administration of DL-carnitine to uremic patients (Prod Info CARNITOR(R) oral tablets, oral solution, CARNITOR(R) SF sugar-free oral solution, 2006; Bazzato et al, 1979; Bazzato et al, 1981). It is thought that the symptoms may be due to the progressive accumulations of some intermediate compound of levocarnitine metabolism or of the inactive D-carnitine isomer. Three patients who had been hemodialyzed for 8 to 10 years and had received DL-carnitine 2 g intravenously at the end of each dialysis session developed severe weakness and muscle wasting, most of it in limb and jaw muscles. Symptoms improved upon hemodialysis and reappeared between dialysis sessions (Bazzato et al, 1979; Bazzato et al, 1981).
    1) Therapeutically, levocarnitine is preferred to DL-carnitine since D-carnitine has been reported to accumulate in muscles and cause a myasthenia-like syndrome (Bazzato et al, 1979).
    2) WITH POISONING/EXPOSURE
    a) Extreme and continued weakness as well as discolored urine (possible myoglobinuria) were reported in a marathon runner who had ingested 500 mg DL-carnitine nightly for 2 nights prior to a race. The author speculated that d-carnitine may inhibit the activity of L-carnitine and may have caused a levocarnitine deficiency (Keith, 1986).

Summary Of Exposure

    A) USES: Levocarnitine is approved for the following conditions: primary L-carnitine deficiencies; acute and chronic treatment of patients with an inborn error of metabolism resulting in secondary carnitine deficiency; and prevention and treatment of carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. It is also used to treat hyperammonemia in patients with valproate induced hepatotoxicity and encephalopathy. Athletes use carnitine for muscle building and endurance.
    B) PHARMACOLOGY: Levocarnitine is found in all mammalian tissue and is a carrier molecule in the transport of long-chain free fatty acids across the inner mitochondrial membrane. It is a trimethylated amino acid and is essential for the transformation of fatty acids into energy for muscular activity. This transformation, which occurs in the mitochondria, produces coenzyme A.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Transient nausea, vomiting, abdominal cramps, diarrhea, body odor. Levocarnitine may cause seizures in patients with or without pre-existing seizure disorder. Headache, dizziness, and transient visual blurring have been reported in patients taking high doses of levocarnitine. A mild myasthenia has been reported following the administration of DL-carnitine to uremic patients. In clinical trials of patients on chronic hemodialysis, hypertension, tachycardia, ECG changes, anemia, and paresthesia were reported more frequently than in patients receiving placebos; however, the causal relationship to levocarnitine is not clear.
    E) WITH POISONING/EXPOSURE
    1) At the time of this review, there is no acute overdose data available. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Transient visual blurring was reported in 2 patients who each received 6 grams of intravenous levocarnitine (Harper et al, 1988).

Reproductive

    3.20.1) SUMMARY
    A) Levocarcitine is in FDA Pregnancy Category B. Positive correlations between carnitine concentrations in maternal and umbilical venous blood have been reported, suggesting placental transfer. It is not yet known whether levocarnitine is excreted in human milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) FDA Pregnancy Category B (Prod Info Carnitor(R), levocarnitine, 2001).
    B) PLACENTAL BARRIER
    1) Positive correlations between carnitine concentrations in maternal and umbilical venous blood have been reported, suggesting placental transfer (Schmidt-Sommerfeld & Penn, 1990).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not yet known whether levocarnitine is excreted in human milk (Prod Info Carnitor(R), levocarnitine, 2001).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Carcinogenicity has NOT yet been evaluated in long-term animal studies (Prod Info Carnitor(R), levocarnitine, 2001).

Genotoxicity

    A) Following mutagenic studies in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe, no mutagenesis was seen (Prod Info Carnitor(R), levocarnitine, 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) A number of spectrophotometric, fluorometric or radioisotopic enzyme methods have been described for the measurement of L-carnitine levels. Marzo et al (1995) performed an enzyme method, which is strictly stereoselective for the natural L-enantiomer of carnitine. They used the radioenzyme method of McGarry & Foster with minor modifications and reported an assay interference with heparin when a plasma sample was used. The authors suggest avoiding the use of heparin when whole plasma is used for L-carnitine assay (Marzo et al, 1995).
    2) One study described a method to measure free levocarnitine and total levocarnitine in rat urine and serum by means of radioactivity detected by a liquid scintillation spectrometer (Morabito et al, 1994).
    3) Rebouche (1991) described a high-performance cation-exchange chromatography method, with quantitation by liquid scintillation counting of effluent fractions, for the separation and quantification of levocarnitine and its metabolites in serum, urine and feces. Metabolites were further quantitated by a high-resolution mass spectrometry technique (Rebouche, 1991). Kletzmayr et al (1999) described a similar method for determination of L-carnitine in plasma (Kletzmayr et al, 1999).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Toxicity after acute ingestion is unlikely, and is generally only expected with chronic use. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) 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.
    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).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs in symptomatic patients.
    2) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    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, 2010; 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).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Levocarnitine is removed by hemodialysis (Prod Info Carnitor(R), levocarnitine, 2001; Matsumoto et al, 2000), but hemodialysis is not recommended given the low toxicity of this drug.

Range Of Toxicity

Summary

    A) TOXICITY: At the time of this review, a toxic dose for levocarnitine has not been established. Intravenous doses as high as 300 mg/kg have been administered with no apparent toxicity.
    B) THERAPEUTIC DOSES: ADULT: IV: 50 to 300 mg/kg depending on indication. ORAL: 1 to 3 g or 100 mg/kg depending on indication. PEDIATRIC: IV: 50 to 500 mg/kg/day (maximum 3 g/day) depending on indication. ORAL: 50 to 100 mg/kg/day, maximum 3 g/day depending on indication.

Therapeutic Dose

    7.2.1) ADULT
    A) ORAL SOLUTION
    1) INITIAL: 1 g/day (equivalent to 10 mL/day) orally for a 50 kg patient, in evenly divided doses every 3 or 4 hours; may be gradually increased up to 3 g (equivalent to 30 mL/day) for a 50 kg patient; USE CAUTION at higher doses (Prod Info levocarnitine oral solution, 2009).
    B) ORAL TABLETS
    1) 990 mg (3 tablets) orally 2 or 3 times daily (Prod Info levocarnitine oral tablets, 2011)
    C) INTRAVENOUS
    1) 50 mg/kg IV administered as a slow 2 to 3 minute bolus injection or infusion; MAX: 300 mg/kg (Prod Info levocarnitine intravenous injection, 2011).
    2) SEVERE METABOLIC CRISIS: Loading dose may be given, followed by an equivalent dose over the next 24 hours; administer every 3 or 4 hours, never less than 6 hours, with subsequent daily doses around 50 mg/kg or as required (Prod Info levocarnitine intravenous injection, 2011)
    D) HEPATOTOXICITY SECONDARY TO ACUTE VALPROATE EXPOSURE
    1) Based on a review of the literature, optimal dosing of L-carnitine for acute toxicity has not been established. Suggested guidelines for the use of L-carnitine following acute valproate toxicity are as follows (Russell, 2007):
    a) Acute overdose with NO evidence of hepatotoxicity: Prophylactic dose of 100 mg/kg/day IV in divided doses every 6 hours (maximum 3 g).
    b) Acute overdose and symptomatic hepatotoxicity or hyperammonemia: Loading dose - 100 mg/kg IV over 30 minutes (maximum of 6 g); maintenance dose - 15 mg/kg every 4 hours administered over 10 to 30 minutes.
    7.2.2) PEDIATRIC
    A) ORAL SOLUTION
    1) INITIAL: 50 mg/kg orally daily, in evenly divided doses every 3 or 4 hours; may gradually increase up to 100 mg/kg/day (0.5 mL/kg/day); USE CAUTION with higher doses; MAX: 3 g (30 mL) daily (Prod Info levocarnitine oral solution, 2009)
    B) ORAL TABLETS
    1) INITIAL: 50 mg/kg orally daily, in divided doses; may gradually increase up to 100 mg/kg; MAX: 3 g daily (Prod Info levocarnitine oral tablets, 2011)
    C) INTRAVENOUS
    1) 50 mg/kg IV administered as a slow 2 to 3 minute bolus injection of infusion; MAX: 300 mg/kg (Prod Info levocarnitine intravenous injection, 2011).
    2) SEVERE METABOLIC CRISIS: Loading dose may be given, followed by an equivalent dose over the next 24 hours; administer every 3 or 4 hours, never less than 6 hours, either by infusion or IV injection, with subsequent daily doses around 50 mg/kg or as required (Prod Info levocarnitine intravenous injection, 2011).
    D) HEPATOTOXICITY SECONDARY TO ACUTE VALPROATE EXPOSURE
    1) Based on a review of the literature, optimal dosing of L-carnitine for acute toxicity has not been established. Suggested guidelines for the use of L-carnitine following acute valproate toxicity are as follows (Russell, 2007):
    a) Acute overdose with NO evidence of hepatotoxicity: Prophylactic dose of 100 mg/kg/day IV in divided doses every 6 hours (maximum 3 g).
    b) Acute overdose and symptomatic hepatotoxicity or hyperammonemia: Loading dose - 100 mg/kg IV over 30 minutes (maximum of 6 g); maintenance dose - 15 mg/kg every 4 hours administered over 10 to 30 minutes.
    2) The Pediatric Neurology Advisory Committee recommends carnitine replacement for valproate-induced hepatotoxicity and overdose. For carnitine replacement, oral doses of 100 mg/kg/day or 2 grams/day (divided into 3 or 4 doses) should be given. In cases of overdose or valproate-induced hepatotoxicity, rescue therapy with intravenous carnitine 150 to 500 mg/kg/day (up to maximum of 3 grams/day) should be administered (Lheureux & Hantson, 2009; Raskind & El-Chaar, 2000).

Maximum Tolerated Exposure

    A) ADULTS
    1) Intravenous doses as high as 300 mg/kg have been given with minimal adverse effects (Prod Info levocarnitine IV injection, 2004).
    B) CHILDREN
    1) Oral doses of 15 grams each were given to a normal child and to a 10-year-old child with carnitine deficiency for a pharmacokinetic study. No adverse effects were reported (Mitchell, 1978).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) DISEASE STATE
    a) METABOLIC DISORDERS -
    1) 35 to 60 micromoles per liter (Prod Info Carnitor(R) injection, 2001).
    2) Reported plasma carnitine levels in an 11-year-old boy following administration of 500 milligrams of DL-carnitine are as follows (Mitchell, 1978):
    TIME hrPLASMA CARNITINE micrograms/deciliter
    Fasting314
    0.5377
    1454
    2515
    3595
    8484

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 750 mg/kg (RTECS , 2001a)
    B) LD50- (ORAL)MOUSE:
    1) 19.2 g/kg (Prod Info CARNITOR(R) oral tablets, oral solution, CARNITOR(R) SF sugar-free oral solution, 2006)
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 9 g/kg (RTECS , 2001a)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Levocarnitine (3-hydroxy-4-N-trimethylaminobutyrate) is a quaternary ammonium compound found in all mammalian tissue, especially striated muscle. Levocarnitine plays an important role in lipid catabolism. It is essential for the transport of free fatty acids from the cytosol to the mitochondria where they are oxidized (Helton et al, 2000; Matsumoto et al, 2000; Goral, 1998; Ramos et al, 1984; Mitchell, 1978). Levocarnitine is synthesized in the liver from the amino acid lysine. Levocarnitine deficiency may arise from failure of hepatic synthesis or failure of transport from liver into muscle which results in lipid storage disorders with cellular accumulations of neutral fats (S Sweetman , 2001). Levocarnitine depletion is also caused by hemodialysis (Bohmer et al, 1978).
    1) When levocarnitine deficiency is limited to the muscle it is known as myopathic; when several tissues are involved, it is known as systemic levocarnitine deficiency (McGarry & Foster, 1980).
    2) Because carnitine is essential for mitochondrial energy production, it has been suggested that disturbances in mitochondrial function may contribute to or cause chronic fatigue syndrome (CFS); decreased carnitine levels are reported in CFS (Plioplys & Plioplys, 1997).
    B) In addition to increasing the rate of fatty acid metabolism (Sakurabayashi et al, 1999), L-carnitine, in conjunction with dialysis therapy, may facilitate the washing out of acyl moieties that are thought to be harmful to cellular metabolism (Sakurauchi et al, 1998).
    C) Levocarnitine stabilizes cell membranes and may be beneficial in vivo by protecting erythrocytes in which peroxidative damage of the cell structure is increased as in B-thalassemic patients (Yesilipek et al, 1998).
    D) Short-term supplementation (1 month) with levocarnitine in patients with suspected acute myocardial infarction may be protective against cardiac necrosis and complications during the first 28 days. The protective effects are accompanied by a significant decline in angina pectoris and total cardiac dysrhythmias and a reduction in class III and IV heart failure and left ventricular enlargement (Singh et al, 1996).
    E) Long-term supplementation (3 years) to patients with moderate to severe heart failure attributable to dilated cardiomyopathy was shown to improve functional status in a small group of patients (n=37). Greater electrical stability of the levocarnitine group was shown in sinus rhythm scores (Rizos, 2000).
    1) Clinical studies in heart failure patients with atrial pacing have shown L-carnitine to improve myocardial energy metabolism by increasing the use of free fatty acids and by reducing the coronary lactate outflow. It is able to increase ischemic threshold of angina and pacing tolerance through reduction of left ventricular diastolic pressure and via ST-segment and T-wave alterations. These patients also showed a moderate but significant reduction in total cholesterol and triglyceride levels (Cacciatore et al, 1991).
    F) When levocarnitine is given as a long-term supplement (greater than 6 months) to maintenance dialysis patients, it appears that an interrelation exists, with improvement of muscle and myocardial metabolism, with effects on hepatic albumin synthesis and on body compartment distribution of albumin (Trovato et al, 1998).
    G) Acetyl levocarnitine has been shown in rat studies to support axonal regeneration and synaptic remodeling, the latter by stimulation of nerve terminal sprouting at the neuromuscular junction following a crush injury (De Angelis et al, 1992).
    H) L-carnitine has been used in the treatment of valproic acid (VPA)-induced carnitine deficiency. VPA may cause carnitine deficiency through renal losses of a valproate-carnitine adduct. This carnitine deficiency may lead to hyperammonemia (which may be symptomatic or asymptomatic). It may also play a role in the pathogenesis of VPA-induced hepatotoxicity (Bohan et al, 2001; Barrueto & Hack, 2001; Raby, 1997).

Physicochemical

Physical Characteristics

    A) Levocarnitine, as a bulk drug substance, is a white powder with a melting point of 196-197 degrees C; it is readily soluble in water, hot alcohol, and insoluble in acetone (S Sweetman , 2001; Prod Info Carnitor(R), levocarnitine, 2001).

Ph

    A) pH of a 1:20 solution is between 6-8, with a pKa value of 3.8 (Prod Info Carnitor(R), levocarnitine, 2001).

Molecular Weight

    A) 161.23 (RTECS , 2001)

References

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