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CARNITOR® (Levocarnitine) is (R)-3-carboxy-2-hydroxy-N,N,N-trimethyl-1-propanaminium hydroxide, inner salt. Levocarnitine is a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. As a bulk drug substance it is a white powder with a melting point of 196-197°C and is readily soluble in water, hot alcohol, and insoluble in acetone. The pH of a solution (1 in 20) is between 6-8 and its pKa value is 3.8. Its chemical structure is:
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Each CARNITOR® (Levocarnitine) Tablet contains 330 mg of levocarnitine and the inactive ingredients magnesium stearate, microcrystalline cellulose and povidone.
Each 118 mL container of the CARNITOR® (Levocarnitine) Oral Solution 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.
CARNITOR® (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, therefore 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 they serve as major fuel. Primary systemic carnitine deficiency is characterized by low plasma, RBC, and/or tissue levels. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to the underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with carnitine. 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 acyl CoA esters. 1 - 6
Secondary levocarnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR® may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect was demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acyl CoA dehydrogenase deficiency. 7,8 Autointoxication occurs in these patients due to the accumulations of acyl CoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acyl CoA compound to its free acid results in acidosis that can be life threatening. Levocarnitine clears the acyl CoA compound by formation of acyl carnitine which is quickly excreted.
Levocarnitine deficiency is defined biochemically as abnormally low plasma levels of free carnitine (less than 20 µ mol/L at one week post term) and may be associated with low tissue and/or urine levels. Further, this condition may be associated with a ratio of plasma ester/free levocarnitine levels greater than 0.4 or abnormally elevated levels of esterified levocarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma free levocarnitine levels below age related normal levels.
In a relative bioavailability study in 15 healthy adult male volunteers CARNITOR® Tablets were found to be bio-equivalent to CARNITOR® Oral Solution. Following the administration of 1980 mg b.i.d., the maximum plasma concentration level (C max ) was 80 nmol/mL and the time to maximum concentration (T max ) occurred at 3.3 hours. There were no significant differences for AUC and urinary excretion observed between these two formulations.
In the same bioavailability study of 15 healthy adult males, CARNITOR® (Levocarnitine) Injection administered as a slow 3 minute bolus intravenous injection at a dose of 20 mg/kg showed that free levocarnitine plasma profiles are best fit by a two compartment model. Approximately 76% of free levocarnitine is eliminated in the urine. Using plasma levels 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 following a single intravenous dose.
The absolute bioavailability of L-carnitine from CARNITOR® Tablets and Oral Solution was determined compared to the bioavailability of L-carnitine from CARNITOR® Injection Intravenous in 15 healthy male volunteers. After correction for circulating endogenous levels of L-carnitine in the plasma, absolute bioavailability was 15.1% ± 5.3% for L-carnitine from CARNITOR® Tablets and 15.9% ± 4.9% from the Oral Solution.
Total body clearance of L-carnitine (Dose/AUC including endogenous baseline levels) was a mean of 4.00 L/hr. Endogenous baseline levels were not subtracted since total body clearance of L-carnitine does not distinguish between exogenous sources of L-carnitine and endogenously synthesized L-carnitine. Volume of distribution of the intravenously administered dose above baseline endogenous levels was calculated to be a mean of 29.0 L ± 7.1 L (approximately 0.39 L/kg) which is an underestimate of the true volume of distribution since plasma L-carnitine is known to equilibrate slowly with, for instance, muscle L-carnitine.
L-carnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human. 9
Five normal adult male volunteers, administered a dose of [ 3 H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, excreted 58 - 65% of administered radioactive dose in 5 to 11 days in the urine and feces. 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]-(gamma)-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of carnitine was 4% to 8% of the dose. Fecal excretion of total carnitine was less than 1% of total carnitine excretion. 10
After attainment of steady state following 4 days of oral administration of L-carnitine with CARNITOR® Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, urinary excretion of L-carnitine was a mean of 2107 and 2339 µ moles, respectively, equivalent to 8.6% and 9.4%, respectively, of the orally administered doses (uncorrected for endogenous urinary excretion). After a single intravenous dose (20 mg/kg) prior to multiple oral doses, urinary excretion of L-carnitine was 6974 µ moles equivalent to 75.6% of the intravenously administered dose (uncorrected for endogenous urinary excretion).
CARNITOR® (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 ). 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.
CARNITOR® (Levocarnitine) is also indicated for acute and chronic treatment of patients with an inborn error of metabolism that results in a secondary carnitine deficiency.
None known.
None.
CARNITOR® (Levocarnitine) Oral Solution is for oral/internal use only.
Gastrointestinal reactions may result from too rapid consumption of carnitine. CARNITOR® (Levocarnitine) Oral Solution may be consumed alone, or dissolved in drinks or other liquid foods to reduce taste fatigue. It should be consumed slowly and doses should be spaced evenly throughout the day to maximize tolerance.
Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that CARNITOR® (Levocarnitine) is not mutagenic. Long-term animal studies have not been conducted to evaluate the carcinogenicity of the compound.
Pregnancy Category 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.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
See Dosage and Administration .
Various mild gastrointestinal complaints have been reported during the long-term administration of oral L- or D,L-carnitine; these include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. Gastrointestinal adverse reactions with CARNITOR® (Levocarnitine) Oral Solution dissolved in liquids might be avoided by a slow consumption of the solution or by a greater dilution. Decreasing the dosage often diminishes or eliminates drug-related patient body odor or gastrointestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration, and after any dosage increases.
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.
There have been no reports of toxicity from carnitine overdosage. The oral LD 50 of levocarnitine in mice is 19.2 g/kg. Carnitine may cause diarrhea. Overdosage should be treated with supportive care.
CARNITOR® (Levocarnitine) Tablets.
Adults: The recommended oral dosage for adults is 990 mg two or three times a day using the 330 mg tablets, depending on clinical response.
Infants and children: The recommended oral dosage for infants and children is between 50 and 100 mg/kg/day in divided doses, with a maximum of 3 g/day. Dosage should begin at 50 mg/kg/day. The exact dosage will depend on clinical response.
Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations and overall clinical condition.
CARNITOR® (Levocarnitine) Oral Solution.
For oral use only. Not for parenteral use.
Adults: The recommended dosage of levocarnitine is 1 to 3 g/day for a 50 kg subject, which is equivalent to 10 to 30 mL/day of CARNITOR® (Levocarnitine) Oral Solution. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 1 g/day, (10 mL/day), and be increased slowly while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
Infants and children: The recommended dosage of levocarnitine is 50 to 100 mg/kg/day which is equivalent to 0.5 mL/kg/day CARNITOR® (Levocarnitine) Oral Solution. Higher doses should be administered only with caution and only where clinical and biochemical considerations make it seem likely that higher doses will be of benefit. Dosage should start at 50 mg/kg/day, and be increased slowly to a maximum of 3 g/day (30 mL/day) while assessing tolerance and therapeutic response. Monitoring should include periodic blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition.
CARNITOR® (Levocarnitine) Oral Solution may be consumed alone or dissolved in drink or other liquid food. Doses should be spaced evenly throughout the day (every three or four hours) preferably during or following meals and should be consumed slowly in order to maximize tolerance.
CARNITOR® (Levocarnitine) Tablets are supplied as 330 mg tablets embossed with "CARNITOR ST" in individual blisters, packaged in boxes of 90 (NDC 54482-144-07).
Store at controlled room temperature (25°C). See USP.
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). Store at controlled room temperature (25°C). See USP.
CARNITOR® (Levocarnitine) Oral Solution is manufactured for Sigma-tau Pharmaceuticals, Inc. by: Alpharma USPD, Inc. Baltimore, MD 21244-2654 and/or Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701.
CARNITOR® (Levocarnitine) is also available in the following dosage forms for intravenous injection:
CARNITOR® (levocarnitine) Injection is available in 1 g per 5 mL single dose vials packaged 5 vials per carton (NDC 54482-147-01). CARNITOR® (levocarnitine) Injection 5 mL vial is manufactured for Sigma-Tau Pharmaceuticals, Inc. by Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230-2591.
CARNITOR® (Levocarnitine) Injection is also available in 1 g per 5 mL single dose ampoules packaged 5 ampoules per carton (NDC 54482-146-09). Made in Italy.
Rx only.
Sigma-Tau
Pharmaceuticals, Inc.
Gaithersburg, MD 20877
PREVIOUS EDITION IS OBSOLETE
ST-N18-948-05/00 OPI-1