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Introduction

  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. While 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) causes carnitine deficiency, resulting in mitochondrial dysfunction. The resulting 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. However, published studies have failed to show that dietary supplementation of L-carnitine has any benefit in well-nourished individuals. Additionally, since the FDA does not regulate dietary supplements, the purity of L-carnitine is unknown (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 VPA.
    3. Primary or secondary carnitine deficiency.
    4. Infants and children younger than 2 years receiving VPA who are at greater risk of hepatotoxicity (more than one anticonvulsant drug, poor nutritional status, ketogenic diet).
  3. Contraindications. None known.
  4. Adverse effects
    1. Dose- and duration-related nausea, vomiting, and diarrhea, and a fishy body odor.
    2. Tachydysrhythmias, hypertension, and hypotension associated with IV administration were reported during FDA postmarketing surveillance, although they appear to be rare.
    3. Seizures were reported during FDA postmarketing surveillance in five patients, but due to underlying seizure disorders or concurrent use of other medications, no direct link could be established.
    4. Use in pregnancy. FDA Category B (Introduction). No adequate studies have been conducted in pregnant women. It is not known whether 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 is 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. Note: carnitine is removed by hemodialysis, so consider giving a repeat maintenance dose at the end of the dialysis procedure. Therapy can continue until clinical improvement occurs and/or ammonia levels decrease. Up to 4 days of carnitine therapy have been utilized in case reports.
    2. Drug-induced carnitine deficiency and asymptomatic hyperammonemia. Give 100 mg/kg/d orally in divided doses for up to 3 g/d in adults and 2 g/d in children.