ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Clinical Trials ExperienceTransient 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.Postmarketing ExperienceThe following adverse reactions have been reported:Neurologic Reactions: 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.Hypersensitivity reactions: Anaphylaxis, laryngeal edema and bronchospasm (see WARNINGS).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Levocarnitine is 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 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 accumulations 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 umol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with 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.

DESCRIPTION SECTION.

DESCRIPTION. Levocarnitine is 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 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:Levocarnitine injection, USP is sterile aqueous solution containing g of levocarnitine per mL vial, and water for Injection q.s. The pH is adjusted to to 6.5 with hydrochloric acid.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Levocarnitine Injection, USP is administered intravenously.Metabolic Disorders The recommended dose is 50 mg/kg given as slow to minute bolus injection or by infusion. Often loading dose is given in patients with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. It should be administered every hours or every hours, and never less than every hours 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 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 umol/L) and overall clinical condition.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

NURSING MOTHERS SECTION.

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.

PHARMACOKINETICS SECTION.

PHARMACOKINETICS. In relative bioavailability study in 15 healthy adult male volunteers levocarnitine tablets were found to be bio-equivalent to levocarnitine oral solution. Following days of dosing with tablets of levocarnitine 330 mg b.i.d. or g of levocarnitine oral solution twice daily, the maximum plasma concentration (Cmax) was about 80 umol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.The plasma concentration profiles of levocarnitine after slow minute intravenous bolus dose of 20 mg/kg of levocarnitine were described by two-compartment model. Following single intravenous administration, approximately 76% of the levocarnitine dose was excreted in the urine during the to 24 hour 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 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.

PRECAUTIONS SECTION.

PRECAUTIONS. Drug Interactions. Reports of INR increase with the use of warfarin have been observed. It is recommended that INR levels be monitored in patients on warfarin therapy after the initiation of treatment with levocarnitine or after dose adjustments.. 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.. Pregnancy. 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.. 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.

PREGNANCY SECTION.

Pregnancy. 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.

REFERENCES SECTION.

REFERENCES. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta 57:55-61.Brooks, H., Goldberg L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568.Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim. Biophys. Acta 448:562-577.Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand. 15:701-702.Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Proc. 58:533-540.Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr. 6:41-66.Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill.Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press.Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E., and Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue III: 364-368.Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of carnitine supplement by human adults. Metabolism 40:1305-1310.AMERICANREGENT, INC.SHIRLEY, NY 11967IN1055Rev. 10/19MG 16074. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta 57:55-61.. Brooks, H., Goldberg L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and peripheral hemodynamics. J. Clin. Pharmacol. 17:561-568.. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim. Biophys. Acta 448:562-577.. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand. 15:701-702.. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Proc. 58:533-540.. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr. 6:41-66.. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill.. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press.. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E., and Solbiati, M. 1991. Protein binding of L-carnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue III: 364-368.. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of carnitine supplement by human adults. Metabolism 40:1305-1310.

WARNINGS SECTION.

WARNINGS. Hypersensitivity ReactionsSerious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm have been reported following levocarnitine administration, mostly in patients with end stage renal disease who are undergoing dialysis. Some reactions occurred within minutes after intravenous administration of levocarnitine. If severe hypersensitivity reaction occurs, discontinue levocarnitine treatment and initiate appropriate medical treatment. Consider the risks and benefits of re-administering levocarnitine to individual patients following severe reaction. If the decision is made to re-administer the product, monitor patients for reoccurrence of signs and symptoms of severe hypersensitivity reaction.

SPL UNCLASSIFIED SECTION.

METABOLISM AND EXCRETION. In pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-L-carnitine following 15 days of high carnitine diet and additional carnitine supplement, 58% to 65% of the administered radioactive dose was recovered in the urine and feces in 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]--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 days of oral administration of levocarnitine tablets (1980 mg every 12 hours) or oral solution (2000 mg every 12 hours) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during single dosing interval (12 hours) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).