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  1. Pharmacology

    1. Levocarnitine (l-carnitine) is an endogenous carboxylic acid that facilitates transport of long-chain fatty acids into mitochondria for beta-oxidation and prevents intracellular accumulation of toxic acyl-CoA. l-Carnitine is ubiquitous in diets rich in meats and dairy products and is also synthesized in the body from the amino acids lysine and methionine. Although dietary deficiencies are rare, hypocarnitinemia can result from certain medical conditions and inborn errors of metabolism, and it may develop in patients receiving multiple anticonvulsant medications. It is hypothesized that valproic acid (VPA [See Valproic acid]) causes carnitine deficiency, resulting in mitochondrial dysfunction. The resultant impaired beta-oxidation favors production of toxic VPA metabolites via microsomal oxidation. These metabolites are implicated in hepatotoxicity and urea cycle disruption causing hyperammonemia. Supplementation with l-carnitine has been shown to be beneficial in both the prevention and the treatment of hyperammonemia associated with VPA therapy, and it may improve the outcome in cases of VPA-induced hepatotoxicity and encephalopathy.

    2. l-Carnitine is also sold as a dietary supplement with a wide range of unproven claims ranging from improved sperm motility to prevention of Alzheimer disease. It is postulated that carnitine supplementation enhances fat utilization during exercise, thereby improving endurance and promoting weight loss. However, published studies have failed to show that supraphysiologic doses of l-carnitine have any benefit in well-nourished individuals. Because the FDA does not regulate dietary supplements, the safety of l-carnitine supplements cannot be guaranteed (see “Herbal and Alternative Products,”).

  2. Indications

    1. Hyperammonemia, encephalopathy, and hepatotoxicity related to VPA therapy or overdose

    2. Low plasma free carnitine concentrations (reference range, 19–60 mcmol/L) or total carnitine (reference range, 30–73 mcmol/L) in patients taking valproic acid.

    3. Primary or secondary carnitine deficiency.

    4. Infants and children younger than 2 years of age receiving VPA as part of a regimen of multiple anticonvulsant drugs.

  3. Contraindications. None known.

  4. Adverse effects

    1. Dose- and duration-related nausea, vomiting, and diarrhea, and a fishy body odor.

    2. Tachyarrhythmias, hypertension, and hypotension have been associated with IV administration.

    3. Seizures have been reported in patients receiving l-carnitine, even in the absence of a known underlying seizure disorder.

    4. Use in pregnancy. FDA Category B (See Introduction in Section III). No adequate studies have been conducted in pregnant women. It is not known if this drug is secreted in human breast milk.

  5. Drug or laboratory interactions. None known.

  6. Dosage and method of administration

    1. Severe valproate-induced hepatotoxicity, hyperammonemia, encephalopathy, or acute valproic acid overdose. Early intervention with IV carnitine has been associated with better outcomes. Intravenous administration is preferred because of poor oral bioavailability (5–15%). Optimal dosing is unknown, but a common approach is a loading dose of 100 mg/kg (by IV infusion over 15–30 minutes or slow bolus injection over 2–3 minutes), followed by a maintenance dose of 50 mg/kg (up to a maximum of 3 g per dose) every 8 hours. Therapy can continue until clinical improvement occurs and/or ammonia levels decrease. Up to 4 days of carnitine therapy has been required in case reports.

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