Carnitine (L) Injection

Carnitine (L) Injection (30 mL Vial). 500 MG/ML

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. While only the L isomer is present in the biologic system, commercial synthesis of carnitine produces a D,L racemic mixture, from which the L-isomer is obtained. The D-isomer has pharmacologic effects but does not participate in lipid metabolism. Commercially, carnitine is available as both a prescription and non-prescription product. The prescription version is levocarnitine, while most dietary supplements contain D,L-carnitine which is commonly sold in health food stores.

Levocarnitine has been used in the treatment of primary and secondary carnitine deficiency in adults and neonates, Alzheimer’s disease, dilated cardiomyopathy in adults and children, valproic acid-induced hepatotoxicity in children, and hyperlipoproteinemia. It has been designated an orphan drug for a variety of conditions. Its use in alcohol induced fatty liver, Down’s syndrome, and chronic fatigue syndrome has shown varying results. Some athletes use carnitine supplements to increase exercise performance, however, the concept of carnitine loading does not appear to be very effective.^[1] Further, D,L-carnitine competitively inhibits levocarnitine. This inhibition may lead to a deficiency. Prescription forms of levocarnitine were approved by the FDA in 1985 (tablets), 1986 (oral solution), and 1992 (injection).

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.

Growth Hormone Deficiency Diagnosis: Arginine stimulates pituitary release of growth hormone in patients with normal pituitary function. Patients with impaired pituitary function who receive arginine will have lower or no increase in plasma concentrations of growth hormone after administration of arginine.

Urea Cycle Disorders (UCDs): The urea cycle is normally responsible for maintaining low blood concentrations of ammonia and glutamine from protein breakdown. The normal urea cycle requires numerous enzyme-catalyzed steps to form nitrogenous waste such as urea. Hyperammonemia may occur when there is a deficiency in one or more urea cycle enzymes or a cofactor: N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), or argininosuccinate lyase (ASL). Arginine becomes an essential amino acid when any of these enzymes is deficient. If essential amino acids are not available, protein catabolism occurs, which increases ammonia concentrations. Exogenous arginine is administered in patients with UCDs to restore serum levels and prevent the breakdown of endogenous protein. Additionally, arginine administration lowers the blood ammonia level and increases the amount of nitrogen excreted in the urine by stimulating an alternative pathway for waste nitrogen excretion.

Metabolic Alkalosis: Arginine is a precursor to hydrochloric acid and has a high chloride content and is, therefore, an alternative treatment for severe metabolic alkalosis.[6]

Cardiovascular disease: Arginine is a precursor of nitric oxide, which is a potent vasodilator with antiplatelet activity. Nitric oxide has been shown to induce vasodilation in patients with atherosclerosis.

Levocarnitine may cause gastrointestinal symptoms and should be used conservatively in patients with diarrhea.

Levocarnitine is classified as pregnancy category B. Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose and have reported no evidence of impaired fertility or harm to the fetus. No adequate, well controlled studies exist in pregnant women. This drug should be used during pregnancy only if clearly needed.^[2][3]

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.^[2][3]

Acetaminophen; Aspirin, ASA; Caffeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aluminum Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.

Aluminum Hydroxide; Magnesium Carbonate: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.

Aluminum Hydroxide; Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.

Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.

Aluminum Hydroxide; Magnesium Trisilicate: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.

Antacids: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.

Aspirin, ASA: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Butalbital; Caffeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Butalbital; Caffeine; Codeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Caffeine; Dihydrocodeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Carisoprodol: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Carisoprodol; Codeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Dipyridamole: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Omeprazole: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Oxycodone: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Aspirin, ASA; Pravastatin: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Bismuth Subsalicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Bismuth Subsalicylate; Metronidazole; Tetracycline: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Calcium Carbonate; Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.

Choline Salicylate; Magnesium Salicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Colchicine: Colchicine is an alkaloid that is inhibited by acidifying agents. The colchicine dose may need adjustment.

Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.

Magnesium Salicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Methadone: As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.

Salsalate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.

Gastrointestinal (GI) adverse effects are possible with oral and intravenous (IV) levocarnitine therapy. These GI symptoms include abdominal pain, dyspepsia, diarrhea, gastritis, nausea, and vomiting. These adverse effects 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—21% vs 17%), anorexia (3—6% vs 3%), constipation (3% vs 6%), diarrhea (9—35% vs 19%), dyspepsia (5—9% vs 10%), gastrointestinal disorder (2—6% vs 2%), melena (2—6% vs 3%), nausea (5—12% vs 10%), vomiting (9—21% vs 16%), weight gain (2—3% vs 2%), and weight loss (3—8% vs 3%).^[2][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—37% vs 16%), anxiety (1—2% vs 5%), asthenia (8—12% vs 8%), depression (5—6% vs 3%), dizziness (10—18% vs 11%), drug dependence (2—6% vs 2%), hypertonia (1—3% vs 5%), insomnia (3—6% vs 6%), paresthesias (3—12% vs 3%), and vertigo (2—6% vs 0%).^[2][3]

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.^[2][3]

During clinical trials of IV levocarnatine in patients on chronic hemodialysis, cardiovascular adverse reactions were reported at the following incidence compared to placebo: arrhythmia (2—3% vs 5%), atrial fibrillation (2—6% vs 0%), cardiovascular disorder (3—6% vs 6%), abnormal electrocardiogram (3—6% vs 0%), bleeding (2—9% vs 6%), chest pain (unspecified) (6—15% vs 14%), hypertension (18—21% vs 14%), hypotension (3—19% vs 19%), palpitations (3—8% vs 0%), peripheral edema (3—6% vs 3%), sinus tachycardia (5—9% vs 5%), and vascular disorder (2—6% vs 2%).^[2]

During clinical trials of IV levocarnatine in patients on chronic hemodialysis, respiratory and infectious adverse reactions were reported at the following incidence compared to placebo: infection (10—24% vs 17%), fever (5—12% vs 5%), bronchitis (3—5% vs 0%), cough (9—18% vs 16%), dyspnea (3—11% vs 19%), pharyngitis (15—27% vs 33%), rhinitis (6—11% vs 10%), and sinusitis (2—3% vs 5%).^[2]

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—12% vs 3%), injection site reaction (27—38% vs 59%), rash (unspecified) (3—5% vs 3%), pruritus (3—8% vs 13%), dysgeusia (2—9% vs 0%), amblyopia (3—6% vs 2%), eye disorder (3—6% vs 3%), back pain (6—9% vs 10%), parathyroid disorder (2—6% vs 2%), hypervolemia (3—12% vs 17%), hyperkalemia (6% vs 6%), and hypercalcemia (6—15% vs 3%).^[2]

Levocarnitine is classified as pregnancy category B. Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose and have reported no evidence of impaired fertility or harm to the fetus. No adequate, well controlled studies exist in pregnant women. This drug should be used during pregnancy only if clearly needed.^[2][3]

Supplementation with levocarnitine in women who are breastfeeding 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.^[2][3]

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1. Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr 2000;72(suppl):618S-623S.
2. Carnitor (levocarnitine) injection package insert. Gaithersburg, MD: Sigma Tau Pharmaceuticals; 2015 Apr.
3. Carnitor (levocarnitine) tablets, oral solution, and sugar-free oral solution package insert. Gaithersburg, MD: Sigma Tau Pharmaceuticals; 2015 Apr.