Levocarnitine (L-3-hydroxy-4-N-trimethylaminobutyrate) is synthesized in the liver from the amino acids methionine and lysine. This naturally occurring substance is found in all mammalian tissues, especially striated muscle, and is required in energy metabolism, such as the oxidation of fatty acids, facilitating the aerobic metabolism of carbohydrates, and enhancing the excretion of certain organic acids. Only the L isomer of carnitine is naturally present in the biologic system. Commercially, carnitine is available as both prescription and non-prescription products. The prescription version is levocarnitine, while most dietary supplements contain D, L-carnitine which is commonly sold as a nutritional supplement. Levocarnitine has been used in the treatment of primary and secondary carnitine deficiency in adults and pediatric patients, including neonates. Other uses have included valproic acid-induced hepatotoxicity in pediatric patients; it has been designated an orphan drug for this condition. Some athletes use carnitine supplements to increase exercise performance, however, the concept of carnitine loading does not appear to be very effective. The promotion of the use of dietary supplements of levocarnitine for other dietary supplemental purposes (e.g., promotion for heart health, lipid health, or memory support) is plagued by a lack of definitive supporting clinical evidence.
NOTE: In the U.S., dietary supplements of levocarnitine are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA). Consequently, scientific data supporting claimed benefit(s) are not always available for dietary supplements as they are for traditional pharmaceuticals since supplements are not regulated as drugs. Consumers should also note that rigid quality control standards are not required for these products and substantial variability can occur in both the potency and the purity of these products.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations:
-Tablets: Levocarnitine tablets should be administered 2 or 3 times daily, depending on clinical response.
Oral Liquid Formulations:
-Oral Solution: Levocarnitine doses should be spaced evenly throughout the day (every 3 or 4 hours) preferably during or following meals. Levocarnitine oral solution may be consumed alone or dissolved in a drink or other liquid food. Levocarnitine solution should be consumed slowly (over a period of several minutes) in order to maximize tolerance.
Injectable Administration
Intravenous Administration:
-Levocarnitine injection is administered intravenously.
Intravenous (IV) Injection:
-Levocarnitine should be given as a slow 2-3 minute bolus injection or by continuous infusion. Parenteral admixtures of levocarnitine in sodium chloride 0.9% or Lactated Ringers solution, with concentrations ranging from 0.5-8 mg/ml, are stable for 24 hours at room temperature in PVC plastic bags.
Gastrointestinal (GI) adverse reactions are possible with oral and intravenous (IV) levocarnitine therapy. These GI symptoms include abdominal pain, dyspepsia, diarrhea, gastritis, nausea, and vomiting. These adverse reactions with oral therapy may be reduced by slowing the rate of consumption and administering as divided doses throughout the day. During clinical trials of IV levocarnitine in patients on chronic hemodialysis, GI adverse reactions were reported at the following incidence compared to placebo: abdominal pain (5% to 21% vs. 17%), anorexia (3% to 6% vs. 3%), constipation (3% vs. 6%), diarrhea (9% to 35% vs. 19%), dyspepsia (5% to 9% vs. 10%), gastrointestinal disorder (2% to 6% vs. 2%), melena (2% to 6% vs. 3%), nausea (5% to 12% vs. 10%), vomiting (9% to 21% vs. 16%), weight gain (2% to 3% vs. 2%), and weight loss (3% to 8% vs. 3%).
Drug-induced body odor (described as "fishy" odor), headache, paresthesias, and weakness have been associated with intravenous as well as oral administration of levocarnitine. During clinical trials of IV levocarnitine in patients on chronic hemodialysis, nervous system adverse reactions were reported at the following incidence compared to placebo: headache (3% to 37% vs. 16%), anxiety (1% to 2% vs. 5%), asthenia (8% to 12% vs. 8%), depression (5% to 6% vs. 3%), dizziness (10% to 18% vs. 11%), drug dependence (2% to 6% vs. 2%), hypertonia (1% to 3% vs. 5%), insomnia (3% to 6% vs. 6%), paresthesias (3% to 12% vs. 3%), and vertigo (2% to 6% vs. 0%).
Levocarnitine therapy has been associated with seizures in patients with and without a history of seizures and an increase in seizure activity (frequency and/or severity). It should be administered with caution to patients with a history of seizures.
During clinical trials of IV levocarnitine in patients on chronic hemodialysis, respiratory and infectious adverse reactions were reported at the following incidence compared to placebo: infection (10% to 24% vs. 17%), fever (5% to 12% vs. 5%), bronchitis (3% to 5% vs. 0%), cough (9% to 18% vs. 16%), dyspnea (3% to 11% vs. 19%), pharyngitis (15% to 27% vs. 33%), rhinitis (6% to 11% vs. 10%), and sinusitis (2% to 3% vs. 5%).
During clinical trials of IV levocarnitine in patients on chronic hemodialysis, general adverse reactions were reported at the following incidence compared to placebo: anemia (3% to 12% vs. 3%), injection site reaction (27% to 38% vs. 59%), rash (3% to 5% vs. 3%), pruritus (3% to 8% vs. 13%), dysgeusia (2% to 9% vs. 0%), amblyopia (3% to 6% vs. 2%), eye disorder (3% to 6% vs. 3%), back pain (6% to 9% vs. 10%), parathyroid disorder (2% to 6% vs. 2%), hypervolemia (3% to 12% vs. 17%), hyperkalemia (6% vs. 6%), and hypercalcemia (6% to 15% vs. 3%).
Serious hypersensitivity reactions, including rash, urticaria, and facial edema have been reported with oral levocarnitine. Other serious reactions including anaphylaxis/anaphylactoid reactions, laryngeal edema, and bronchospasm have been reported after intravenous levocarnitine administration, usually in patients with end stage renal disease undergoing dialysis. Discontinue levocarnitine and initiate appropriate medical treatment if signs and symptoms of hypersensitivity occur. Consider the risks and benefits of re-administering levocarnitine after a serious reaction. If re-administration is necessary, monitor patients closely.
During clinical trials of IV levocarnitine in patients on chronic hemodialysis, cardiovascular adverse reactions were reported at the following incidence compared to placebo: arrhythmia (2% to 3% vs. 5%), atrial fibrillation (2% to 6% vs. 0%), cardiovascular disorder (3% to 6% vs. 6%), abnormal electrocardiogram (3% to 6% vs. 0%), bleeding (2% to 9% vs. 6%), chest pain (unspecified) (6% to 15% vs. 14%), hypertension (18% to 21% vs. 14%), hypotension (3% to 19% vs. 19%), palpitations (3% to 8% vs. 0%), peripheral edema (3% to 6% vs. 3%), sinus tachycardia (5% to 9% vs. 5%), and vascular disorder (2% to 6% vs. 2%).
Serious hypersensitivity reactions have been reported with both oral and intravenous levocarnitine. Discontinue levocarnitine and initiate appropriate medical treatment if signs and symptoms of hypersensitivity occur. Consider the risks and benefits of re-administering levocarnitine after a serious reaction. If re-administration is necessary, monitor patients closely.
Levocarnitine may cause gastrointestinal symptoms and should be used conservatively in patients with diarrhea.
Levocarnitine should be used during pregnancy only if clearly needed. No adequate, well controlled studies exist in pregnant women. Reproductive studies performed in rats and rabbits at doses up to 3.8 times the human dose have reported no evidence of impaired fertility or harm to the fetus.
Levocarnitine therapy has been associated with an increased seizure activity. It should be administered with caution to patients with a history of a seizure disorder.
Although levocarnitine is used in the treatment of some types of cardiomyopathy, it should be administered with caution to patients with a history of cardiac disease or cardiac dysfunction. Various cardiovascular adverse effects have been reported with the administration of intravenous levocarnitine in dialysis patients, including hypertension, peripheral edema, and ventricular arrhythmias.
Peripheral neuropathy may be potentiated by levocarnitine administration.
The safety and efficacy of oral levocarnitine has not been evaluated in the setting of renal impairment. Do not use oral formulations of levocarnitine to treat patients with severe renal impairment or renal failure, including patients on dialysis. The major metabolites formed following chronic oral administration, trimethylamine [TMA] and trimethylamine-N-oxide [TMAO] will accumulate in patients with renal failure since they can not be efficiently removed by the kidneys (manufacturer information). The accumulation of these potentially toxic metabolites is not desirable since it increases the amount of nitrogenous waste to be removed in the dialysis procedure. In addition, increased levels of TMA in dialysis patients have been reported to be associated with possible neurophysiologic effects. The inefficient removal of these metabolites may result in the development of a "fishy" body odor. Only the intravenous form of levocarnitine is indicated for use in ESRD patients on hemodialysis; accumulation of metabolites does not occur to the same extent following intravenous administration of levocarnitine.
Use levocarnitine with caution in hepatic disease since no specific information is available.
Supplementation with levocarnitine in women who are breast-feeding has not been specifically studied; however, levocarnitine is a normal component of human milk which is required for fat metabolism. Consumption of levocarnitine within the normal range of dietary intake leads to excretion into the breast-milk, which is relatively constant. Women with carnitine deficiency and preterm infants may require prescription levocarnitine supplementation under the supervision of a healthcare professional. It is unlikely that maternal levocarnitine supplements during nursing would be harmful to the infant, but it is probably best to avoid over-the-counter supplementation until more data is available. Levocarnitine has been studied in dairy cows; data indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.
For the treatment of primary or secondary carnitine deficiency:
NOTE: Levocarnitine is designated an orphan drug by the FDA for this indication.
Oral dosage (tablets):
Adults: Initially, 990 mg PO 2 to 3 times per day with food, depending on clinical response.
Children and Adolescents: Initially, 50 mg/kg/day PO in 2 to 3 divided doses. May increase to 100 mg/kg/day PO based on clinical response. Max: 3 g/day.
Oral dosage (solution):
Adults: Initially, 1 g PO once daily with food. May increase slowly as tolerated to a maximum of 1 g PO 3 times per day with food.
Infants, Children, and Adolescents: Initially, 50 mg/kg/day PO in divided doses (every 3 to 4 hours, preferably during or after meals). May increase slowly as tolerated to a maximum of 100 mg/kg/day PO based on clinical response. Max: 3 g/day.
Neonates: Initially, 50 mg/kg/day PO in divided doses (every 3 to 4 hours, preferably during or after feedings). May increase slowly as tolerated to a maximum of 100 mg/kg/day PO based on clinical response.
Intravenous dosage:
Adults: Initially, 50 mg/kg/dose IV given as a slow 2 to 3 minute bolus injection or by infusion. Often a loading dose is given to those with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. Per the FDA-approved labeling, it should be administered every 3 to 4 hours, and never less than every 6 hours. All subsequent daily doses are recommended to be in the range of 50 mg/kg/day IV or as therapy may require. The highest dose administered has been 300 mg/kg. Monitoring should include blood chemistries, plasma carnitine (the plasma free carnitine concentration should be between 35 to 60 micromol/L), and overall clinical condition.
Infants, Children, and Adolescents: Initially, 50 mg/kg/dose IV given as a slow 2 to 3 minute bolus injection or by infusion. Often a loading dose is given to those with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. Per the FDA-approved labeling, it should be administered every 3 to 4 hours, and never less than every 6 hours. All subsequent daily doses are recommended to be in the range of 50 mg/kg/day IV or as therapy may require. The highest dose administered has been 300 mg/kg. Monitoring should include blood chemistries, plasma carnitine (the plasma free carnitine concentration should be between 35 to 60 micromol/L), and overall clinical condition.
Neonates: Initially, 50 mg/kg/dose IV given as a slow 2 to 3 minute bolus injection or by infusion. Often a loading dose is given to those with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. Per the FDA-approved labeling, it should be administered every 3 to 4 hours, and never less than every 6 hours. All subsequent daily doses are recommended to be in the range of 50 mg/kg/day IV or as therapy may require. The highest dose administered has been 300 mg/kg. Monitoring should include blood chemistries, plasma carnitine (the plasma free carnitine concentration should be between 35 to 60 micromol/L), and overall clinical condition.
For the prevention and treatment of carnitine deficiency in patients with end stage renal impairment who are undergoing dialysis:
NOTE: Levocarnitine is designated an orphan drug by the FDA for this indication.
Intravenous dosage:
Adults: The recommended starting dose is 10 to 20 mg/kg dry body weight IV as a slow 2 to 3 minute bolus injection into the venous return line after each dialysis session. Initiation of therapy may be prompted by trough (pre-dialysis) plasma levocarnitine concentrations that are below normal (40 to 50 micromol/L). Dose adjustment should be guided by trough (pre-dialysis) levocarnitine concentrations, and downward dose adjustments (e.g., to 5 mg/kg after dialysis) may be made as early as the third or fourth week of therapy. Do NOT use oral formulations for this indication.
Infants, Children, and Adolescents: The recommended starting dose is 10 to 20 mg/kg dry body weight IV as a slow 2 to 3 minute bolus injection into the venous return line after each dialysis session. Initiation of therapy may be prompted by trough (pre-dialysis) plasma levocarnitine concentrations that are below normal (40 to 50 micromol/L). Dose adjustment should be guided by trough (pre-dialysis) levocarnitine concentrations, and downward dose adjustments (e.g., to 5 mg/kg after dialysis) may be made as early as the third or fourth week of therapy. Do NOT use oral formulations for this indication.
For the treatment of male infertility* due to poor sperm quality:
Oral dosage (Proxeed Plus Men's supplement, powder for oral solution):
Adult males: 3 grams/day PO, administered in 2 divided doses morning and evening, for 4 to 6 months was found to significantly increase the total number of ejaculated spermatozoa in healthy men. Sperm motility was also enhanced by the administration of levocarnitine. Marketed products are not FDA-approved to prevent, treat or diagnose any condition; the supplements contain other ingredients such as vitamin C, zinc, folic acid, selenium, etc.
For the treatment and prevention of valproate-induced hepatotoxicity* due to secondary carnitine deficiency in children:
NOTE: Levocarnitine is designated an an orphan drug by the FDA for this indication.
Oral dosage:
Children: Valproic acid induced hepatoxicity is related directly or indirectly to carnitine deficiency; hence, a 1996 consensus conference of pediatric neurologists recommended levocarnitine treatment for valproic acid induced hepatotoxicity. The panel's recommended dose was 150 to 500 mg/kg/day PO.
For nutritional supplementation* of carnitine in neonates receiving parenteral nutrition (PN):
Intravenous dosage:
Neonates: 2 to 5 mg/kg/day IV is recommended by guidelines for all neonates receiving PN. Higher doses (10 to 20 mg/kg/day IV) have also been used.
Maximum Dosage Limits:
-Adults
3 grams/day PO is FDA-approved maximum; 50 mg/kg/day IV is the usual maximum dosage; doses up to 300 mg/kg/day IV have been used.
-Geriatric
3 grams/day PO is FDA-approved maximum; 50 mg/kg/day IV is the usual maximum dosage; doses up to 300 mg/kg/day IV have been used.
-Adolescents
3 grams/day PO; 50 mg/kg/day IV is usual maximum dosage; however, doses up to 300 mg/kg/day IV have been used.
-Children
100 mg/kg/day PO (Max: 3 grams/day); 50 mg/kg/day IV is usual maximum dosage; however, doses up to 300 mg/kg/day IV have been used.
-Infants
100 mg/kg/day PO; 50 mg/kg/day IV is usual maximum dosage.
-Neonates
100 mg/kg/day PO; 50 mg/kg/day IV is usual maximum dosage.
Patients with Hepatic Impairment Dosing
Specific dosage information is not available.
Patients with Renal Impairment Dosing
The IV formulation of this drug is acceptable for use in patients with end-stage renal disease (ESRD) on dialysis; no dosage adjustments are needed.
Do not use oral levocarnitine to treat patients with severe renal impairment or ESRD. Major metabolites formed during oral administration following chronic high oral dosage may accumulate.
*non-FDA-approved indication
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with levocarnitine is necessary. Concomitant use has resulted in increased INR levels in case reports. The mechanism of this interaction has not been identified.
Levocarnitine facilitates long-chain fatty acid transport from the cytosol to the mitochondria, providing substrates for oxidation and subsequent cellular energy production. Levocarnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies that bioaccumulate acyl CoA esters. Levocarnitine clears the acyl CoA esters by formation of acylcarnitine which is rapidly excreted.
Carnitine acetyltransferases (CATs) catalyze the interconversion of fatty acid esters of coenzyme A and carnitine, which are located in the cytosol and mitochondrial membranes. Translocases, which exist in mitochondrial membranes, rapidly transport both free carnitine and its esters in and out of cells. Fatty acid esters of CoA, formed in the cytosol, inhibit enzymes of the Krebs cycle, and are involved in oxidative phosphorylation. Hence, the oxidation of fatty acids requires the formation of acylcarnitines and their translocation into mitochondria where the CoA esters are reformed and metabolized. If oxygen tension is limited, carnitine serves to maintain a ratio of free to esterified CoA within mitochondria that is optimal for oxidative phosphorylation and for the consumption of acetyl CoA.
Levocarnitine can be administered orally or intravenously. Levocarnitine is not bound to plasma proteins including albumin.
If plasma carnitine concentrations exceed the renal reabsorption maximum (roughly 60-100 umol/L), excess carnitine is eliminated in the urine. Carnitine supplementation appears to have little, if any, affect on muscle carnitine content in humans. Carnitine in the central compartment does distribute into tissue, however, muscle is particularly refractory to acute supplementation because of its slower net turnover. After administration of large doses of carnitine, most of the dose is rapidly recovered in the urine. Levocarnitine is hepatically metabolized, with the major metabolite, trimethylamine N-oxide, excreted primarily in the urine (8-49%). Urinary excretion of carnitine is 4-8% of the total administered dose. Fecal excretion of total carnitine is < 1% of total carnitine excretion.
-Route-Specific Pharmacokinetics
Oral Route
Bioavailability of oral levocarnitine (tablet or solution) is approximately 15-16%, with a time to peak concentration of 3.3 hours. Levocarnitine tablets and oral solution are considered bioequivalent. There are no differences in the AUC and urinary excretion between levocarnitine tablets and oral solution.
-Special Populations
Renal Impairment
Pharmacokinetic and clinical studies have shown that administration of levocarnitine to patients with end-stage renal disease (ESRD) on hemodialysis results in increased plasma levocarnitine concentrations. The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine in patients with severe renal impairment or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine. The accumulation of these metabolites does not occur to the same extent following intravenous administration (manufacturer information).