Levocarnitine

LEVOCARNITINE — levocarnitine tablet
ANI Pharmaceuticals, Inc.

DESCRIPTION

Levocarnitine is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane.

The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N, N, N-trimethyl-1-propanaminium, inner salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure is:

structure
(click image for full-size original)

Empirical Formula: C7 H15 NO3

Molecular Weight: 161.20

Each Levocarnitine Tablet, USP for oral use contains 330 mg of levocarnitine and the inactive ingredients Magnesium Stearate, Microcrystalline Cellulose and Povidone.

Each 118 mL container of Levocarnitine Oral Solution, USP contains 1 g of levocarnitine/10 mL. Also contains: Artificial Cherry Flavor, D,L,-Malic Acid, Purified Water, Sucrose Syrup. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5.

Each 118 mL container of Levocarnitine Oral Solution, USP (Sugar Free) contains 1 g of levocarnitine/10 mL. Also contains: Artificial Cherry Flavor, D,L,-Malic Acid, Purified Water, Sodium Saccharin USP. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5.

FDA approved dissolution test specifications differ from USP.

CLINICAL PHARMACOLOGY

Levocarnitine is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production.

Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with Levocarnitine. The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters.1-6

Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. Levocarnitine may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in acidosis which can be life-threatening. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related normal concentrations.

PHARMACOKINETICS

In a relative bioavailability study in 15 healthy adult male volunteers, Levocarnitine Tablets were found to be bio-equivalent to Levocarnitine Oral Solution. Following 4 days of dosing with 6 tablets of Levocarnitine 330 mg b.i.d. or 2 g of Levocarnitine Oral Solution b.i.d., the maximum plasma concentration (Cmax ) was about 80 µmol/L and the time to maximum plasma concentration (Tmax ) occurred at 3.3 hours.

The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of Levocarnitine were described by a two-compartment model. Following a single i.v. administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half-life was 0.585 hours and the mean apparent terminal elimination half-life was 17.4 hours.

The absolute bioavailability of levocarnitine from the two oral formulations of Levocarnitine, calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for Levocarnitine Tablets and 15.9 ± 4.9% for Levocarnitine Oral Solution.

Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00 L/h.

Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.9

METABOLISM AND EXCRETION

In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3 H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [3 H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3 H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10

After attainment of steady state following 4 days of oral administration of Levocarnitine Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).

INDICATIONS & USAGE

Levocarnitine is indicated in the treatment of primary systemic carnitine deficiency. In the reported cases, the clinical presentation consisted of recurrent episodes of Reye-like encephalopathy, hypoketotic hypoglycemia, and/or cardiomyopathy. Associated symptoms included hypotonia, muscle weakness and failure to thrive. A diagnosis of primary carnitine deficiency requires that serum, red cell and/or tissue carnitine levels be low and that the patient does not have a primary defect in fatty acid or organic acid oxidation (see CLINICAL PHARMACOLOGY). In some patients, particularly those presenting with cardiomyopathy, carnitine supplementation rapidly alleviated signs and symptoms. Treatment should include, in addition to carnitine, supportive and other therapy as indicated by the condition of the patient.

Levocarnitine is also indicated for acute and chronic treatment of patients with an inborn error of metabolism which results in a secondary carnitine deficiency.

CONTRAINDICATIONS

None known.

WARNINGS

Hypersensitivity Reactions

Serious hypersensitivity reactions, including rash, urticaria, and facial edema have been reported with oral Levocarnitine. Other serious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm have been reported following intravenous levocarnitine administration, mostly in patients with end stage renal disease undergoing dialysis.

Discontinue use of Levocarnitine and instruct patients to seek medical attention if they experience symptoms suggestive of a hypersensitivity reaction.

PRECAUTIONS

GENERAL PRECAUTIONS

Levocarnitine Oral Solution and Levocarnitine Oral Solution (Sugar Free) are for oral/internal use only.

Not for parenteral use.

Gastrointestinal reactions may result from a too rapid consumption of carnitine. Levocarnitine Oral Solution and Levocarnitine Oral Solution (Sugar Free) may be consumed alone, or dissolved in drinks or other liquid foods to reduce taste fatigue. They should be consumed slowly and doses should be spaced evenly throughout the day to maximize tolerance.

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 severely compromised renal function 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.

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