Levocarnitine (injection)

Levocarnitine (injection)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Turky Alkathery, M.D. [2]

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Overview

Levocarnitine (injection) is a amino acid supplement that is FDA approved for the treatment of patients with an inborn error of metabolism which results in secondary carnitine deficiency. Common adverse reactions include diarrhea, nausea, stomach cramps and vomiting.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• For the acute and chronic treatment of patients with an inborn error of metabolism which results in secondary carnitine deficiency.

• For the prevention and treatment of carnitine deficiency in patients with end stage renal disease who are undergoing dialysis.

Dosage

Metabolic Disorders

• The recommended dose is 50 mg/kg given as a slow 2-3 minute bolus injection or by infusion. Often a loading dose is given in patients with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. It should be administered q3h or q4h, and never less than q6h either by infusion or by intravenous injection. All subsequent daily doses are recommended to be in the range of 50 mg/kg or as therapy may require. The highest dose administered has been 300 mg/kg.

• It is recommended that a plasma carnitine concentration be obtained prior to beginning this parenteral therapy. Weekly and monthly monitoring is recommended as well. This monitoring should include blood chemistries, vital signs, plasma carnitine concentrations (the plasma free carnitine concentration should be between 35 and 60 µmol/L) and overall clinical condition.

ESRD Patients on Hemodialysis

• The recommended starting dose is 10-20 mg/kg dry body weight as a slow 2-3 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 (40-50 µmol/L). Dose adjustments 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.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

• There is limited information regarding Off-Label Guideline-Supported Use of Levocarnitine (injection) in adult patients.

Non–Guideline-Supported Use

• There is limited information regarding Off-Label Non–Guideline-Supported Use of Levocarnitine (injection) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Indications

• For the acute and chronic treatment of patients with an inborn error of metabolism which results in secondary carnitine deficiency.

• For the prevention and treatment of carnitine deficiency in patients with end stage renal disease who are undergoing dialysis.

Dosage

Metabolic Disorders

• The recommended dose is 50 mg/kg given as a slow 2-3 minute bolus injection or by infusion. Often a loading dose is given in patients with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. It should be administered q3h or q4h, and never less than q6h either by infusion or by intravenous injection. All subsequent daily doses are recommended to be in the range of 50 mg/kg or as therapy may require. The highest dose administered has been 300 mg/kg.

• It is recommended that a plasma carnitine concentration be obtained prior to beginning this parenteral therapy. Weekly and monthly monitoring is recommended as well. This monitoring should include blood chemistries, vital signs, plasma carnitine concentrations (the plasma free carnitine concentration should be between 35 and 60 µmol/L) and overall clinical condition.

ESRD Patients on Hemodialysis

• The recommended starting dose is 10-20 mg/kg dry body weight as a slow 2-3 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 (40-50 µmol/L). Dose adjustments 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.

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

• There is limited information regarding Off-Label Guideline-Supported Use of Levocarnitine (injection) in pediatric patients.

Non–Guideline-Supported Use

• There is limited information regarding Off-Label Non–Guideline-Supported Use of Levocarnitine (injection) in pediatric patients.

Contraindications

• None known.

Warnings

• None.

Precautions

• 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.

Adverse Reactions

Clinical Trials Experience

• Transient nausea and vomiting have been observed. Less frequent adverse reactions are body odor, nausea, and gastritis. An incidence for these reactions is difficult to estimate due to the confounding effects of the underlying pathology.

• Seizures have been reported to occur in patients, with or without pre-existing seizure activity, receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported.

• The table below lists the adverse events that have been reported in two double-blind, placebo-controlled trials in patients on chronic hemodialysis. Events occurring at ≥5% are reported without regard to causality.

This image is provided by the National Library of Medicine.

Postmarketing Experience

• There is limited information regarding postmarketing experience.

Drug Interactions

• There is limited information regarding Drug Interactions.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): B

• Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to levocarnitine (injection). There are, however, no adequate and well controlled studies in pregnant women.

• Because animal reproduction studies are not always predictive of human response, this drug s*hould be used during pregnancy only if clearly needed.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Levocarnitine (injection) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Levocarnitine (injection) during labor and delivery.

Nursing Mothers

• Levocarnitine supplementation in nursing mothers has not been specifically studied.

• Studies in dairy cows 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.

Pediatric Use

• See Dosage and Administration.

Geriatic Use

There is no FDA guidance on the use of Levocarnitine (injection) in geriatric settings.

Gender

There is no FDA guidance on the use of Levocarnitine (injection) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Levocarnitine (injection) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Levocarnitine (injection) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Levocarnitine (injection) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Levocarnitine (injection) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Levocarnitine (injection) in patients who are immunocompromised.

Administration and Monitoring

Administration

• Intravenous.

Monitoring

• Weekly and monthly monitoring is recommended as well. This monitoring should include blood chemistries, vital signs, plasma carnitine concentrations and overall clinical condition.

IV Compatibility

• There is limited information regarding IV Compatibility.

Overdosage

• There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.

Pharmacology

Mechanism of Action

• levocarnitine (injection) 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 (injection). 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 or iatrogenic factors such as hemodialysis. Levocarnitine (injection) 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.

• End Stage Renal Disease (ESRD) patients on maintenance hemodialysis may have low plasma carnitine concentrations and an increased ratio of acylcarnitine/carnitine because of reduced intake of meat and dairy products, reduced renal synthesis and dialytic losses. Certain clinical conditions common in hemodialysis patients such as malaise, muscle weakness, cardiomyopathy and cardiac arrhythmias may be related to abnormal carnitine metabolism.

Structure

• Levocarnitine (injection) 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:

This image is provided by the National Library of Medicine.

Empirical Formula: C7H15NO3

Molecular Weight: 161.20

• Levocarnitine (injection) is a sterile aqueous solution containing 1 g of levocarnitine per 5 mL vial. The pH is adjusted to 6.0 - 6.5 with hydrochloric acid or sodium hydroxide.

Pharmacodynamics

There is limited information regarding Levocarnitine (injection) Pharmacodynamics in the drug label.

Pharmacokinetics

• In a relative bioavailability study in 15 healthy adult male volunteers, Levocarnitine Tablets were found to be bio-equivalent to 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 (injection) 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

• In a 9-week study, 12 ESRD patients undergoing hemodialysis for at least 6 months received Levocarnitine (injection) 20 mg/kg three times per week after dialysis. Prior to initiation of Levocarnitine (injection) therapy, mean plasma levocarnitine concentrations were approximately 20 µmol/L pre-dialysis and 6 µmol/L post-dialysis. The table summarizes the pharmacokinetic data (mean ± SD µmol/L) after the first dose of Llevocarnitine (injection) and after 8 weeks of levocarnitine (injection) therapy.

This image is provided by the National Library of Medicine.

• After one week of levocarnitine (injection) therapy (3 doses), all patients had trough concentrations between 54 and 180 µmol/L (normal 40-50 µmol/L) and concentrations remained relatively stable or increased over the course of the study.

• In a similar study in ESRD patients also receiving 20 mg/kg levocarnitine (injection) 3 times per week after hemodialysis, 12- and 24-week mean pre-dialysis (trough) levocarnitine concentrations were 189 (N=25) and 243 (N=23) µmol/L, respectively.

• In a dose-ranging study in ESRD patients undergoing hemodialysis, patients received 10, 20, or 40 mg/kg levocarnitine (injection) 3 times per week following dialysis (N~30 for each dose group). Mean ± SD trough levocarnitine concentrations (µmol/L) by dose after 12 and 24 weeks of therapy are summarized in the table.

This image is provided by the National Library of Medicine.

• While the efficacy of levocarnitine (injection) to increase carnitine concentrations in patients with ESRD undergoing dialysis has been demonstrated, the effects of supplemental carnitine on the signs and symptoms of carnitine deficiency and on clinical outcomes in this population have not been determined.

• Metabolism and Excretion

• In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-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 [3H-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 [3H]-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).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine.

Clinical Studies

• There is limited information regarding Clinical Studies.

How Supplied

• CARNITOR® (levocarnitine) is also available in the following dosage forms:

• CARNITOR® (levocarnitine) Tablets are supplied as 330 mg tablets embossed with “CARNITOR ST” in blister packages, in boxes of 90 tablets (NDC 54482-144-07). Made in Italy.

• CARNITOR® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC 54482-145-08). CARNITOR® (levocarnitine) Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by Hi-Tech Pharmacal Co., Inc., Amityville, NY 11701.

• CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic containers. The multiple-unit containers are packaged 24 per case (NDC 54482-148-01). CARNITOR® SF (levocarnitine) Sugar-Free Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by Hi-Tech Pharmacal Co., Inc., Amityville, NY 11701.

Storage

• Store vials at controlled room temperature (25°C). See USP. Discard unused portion of an opened vial, as the formulation does not contain a preservative.

Images

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Patient Counseling Information

• There is limited information regarding Patient Counseling Information.

Precautions with Alcohol

• Alcohol-Levocarnitine (injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• CARNITOR®

Look-Alike Drug Names

• There is limited information regarding Look-Alike Drug Names.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.