Levocarnitine (injection)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
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Overview
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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.
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)
There is limited information regarding Levocarnitine (injection) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
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.
Postmarketing Experience
There is limited information regarding Levocarnitine (injection) Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Levocarnitine (injection) Drug Interactions in the drug label.
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 CARNITOR®. 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 should 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
There is limited information regarding Levocarnitine (injection) Administration in the drug label.
Monitoring
There is limited information regarding Levocarnitine (injection) Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Levocarnitine (injection) and IV administrations.
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
There is limited information regarding Levocarnitine (injection) Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Levocarnitine (injection) Mechanism of Action in the drug label.
Structure
There is limited information regarding Levocarnitine (injection) Structure in the drug label.
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, CARNITOR® Tablets were found to be bio-equivalent to CARNITOR® Oral Solution. Following 4 days of dosing with 6 tablets of CARNITOR® 330 mg b.i.d. or 2 g of CARNITOR® 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 CARNITOR® 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 CARNITOR®, calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for CARNITOR® Tablets and 15.9 ± 4.9% for CARNITOR® 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 CARNITOR® 20 mg/kg three times per week after dialysis. Prior to initiation of CARNITOR® 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 CARNITOR® and after 8 weeks of CARNITOR® therapy.
After one week of CARNITOR® 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 CARNITOR® 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 CARNITOR® 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.
While the efficacy of CARNITOR® 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.
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 Levocarnitine (injection) Clinical Studies in the drug label.
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
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Levocarnitine (injection) Patient Counseling Information in the drug label.
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
There is limited information regarding Levocarnitine (injection) Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Levocarnitine (injection) Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.