Carnitor (Levocarnitine)

CARNITOR®

Sigma-Tau

Levocarnitine

Carnitine Replenisher

Action And 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, 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.

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 was demonstrated are: glutaric aciduria II, methylmalonic aciduria, propionic acidemia, and medium chain fatty acyl CoA dehydrogenase deficiency. 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 mol/L at age greater than 1 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.

Indications And Clinical Uses: 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 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 treatments of patients with an inborn error of metabolism that results in a secondary carnitine deficiency.

Contra-Indications: None known.

Manufacturers’ Warnings In Clinical States: None.

Precautions: General: Oral Solution: For oral/internal use only. Gastrointestinal reactions may result from too rapid consumption of carnitine. The 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.

The injection is for i.v. use only.

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 levocarnitine. 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.

Lactation: 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.

Adverse Reactions: Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving either oral or i.v. levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency has been reported.

Injection: 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.

Oral Solution and Tablets: 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 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.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of toxicity from carnitine overdosage. The oral LD50 of levocarnitine in mice is 19.2 g/kg. Carnitine may cause diarrhea. Overdosage should be treated with supportive care.

Dosage And Administration: Injection: Children and Adults: Administered i.v. The recommended dose is 50 mg/kg given as a slow 2 to 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 i.v. 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 level 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 level should be between 35 and 60 mol/L at baseline) and overall clinical condition.

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

Compatibility and Stability: Injection is compatible and stable when mixed in parenteral solutions of sodium chloride 0.9% or lactated Ringers’ in concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4 200 mg/500 mL (8 mg/mL) and stored at room temperature (25°C) for up to 24 hours in PVC plastic bags.

Oral Solution: For oral use only. Not for parenteral use.

Adults: 1 to 3 g/day for a 50 kg subject which is equivalent to 10 to 30 mL/day 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: 50 to 100 mg/kg/day which is equivalent to 0.5 mL/kg/day 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.

Oral solution may be consumed alone or dissolved in drinks or other liquid food. Doses should be spaced evenly throughout the day (every 3 or 4 hours) preferably during or following meals and should be consumed slowly in order to maximize tolerance.

Tablets: For oral administration only.

Adults: The recommended oral dosage is 990 mg 2 or 3 times a day using the 330 mg tablets, depending on clinical response.

Infants and Children: The recommended oral dosage 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.

Availability And Storage: Injection: Each mL of sterile, aqueous solution, for i.v. use only, contains: levocarnitine 200 mg. pH adjusted to 6.0 to 6.5 with hydrochloric acid. Preservative-free (levocarnitine will support microbial growth). Single dose ampuls of 2.5 and 5 mL, cartons of 5. Store at room temperature in the carton until use to protect from light. Avoid excessive heat. Protect from freezing. Discard unused portion after opening.

Oral Solution: Each 10 mL of clear, cherry flavored solution, for oral use only, contains: levocarnitine 1 g. Nonmedicinal ingredients: artificial cherry flavor, D,L-malic acid, methyl- and propylparaben (as preservatives), purified water and sucrose syrup. pH is approximately 5. Multiple-unit plastic containers of 118 mL, cases of 24. Store at room temperature. Avoid excessive heat. Protect from freezing. Store upright.

Tablets: Each white, biconvex tablet, embossed with “CARNITOR ST”, for oral use only, contains: levocarnitine 330 mg. Nonmedicinal ingredients: magnesium stearate, microcrystalline cellulose and povidone. Single unit blisters of laminated aluminum foil in cards of 10, cartons of 90 (9 cards/carton). Store at room temperature. Avoid excessive heat. Protect from freezing. Do not store after removal from foil packaging: contents hygroscopic.

CARNITOR® Sigma-Tau Levocarnitine Carnitine Replenisher

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