ADVERSE REACTIONS SECTION.

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.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.Adverse Events with Frequency >=5% Regardless of Causality by Body SystemPlacebo (n=63)Levocarnitine 10 mg (n=34)Levocarnitine 20 mg (n=62)Levocarnitine 40 mg (n=34)Levocarnitine 10, 20 40 mg (n=130)Body as Whole Abdominal pain1721569 Accidental injury101281210 Allergic reaction562 Asthenia898129 Back pain 109868 Chest pain 146151212 Fever565127 Flu syndrome4015272925 Headache161237322 Infection1715102415 Injection site reaction5938273833 Pain4921323530Cardiovascular Arrhythmia5332 Atrial fibrillation 262 Cardiovascular disorder63565 Electrocardiogram abnormal362 Hemorrhage69234 Hypertension1418212120 Hypotension191519314 Palpitations385 Tachycardia56596 Vascular disorder2262Digestive Anorexia33565 Constipation63333 Diarrhea199103516 Dyspepsia10965 Gastrointestinal disorder2362 Melena362 Nausea1095128 Stomach atony5 Vomiting169162115Endocrine System Parathyroid disorder26264Hemic/Lymphatic Anemia335126Metabolic/Nutritional Hypercalcemia315869 Hyperkalemia66666 Hypervolemia1733125 Peripheral edema 36535 Weight decrease33835 Weight increase2362Musculo-Skeletal Leg cramps 1384 Myalgia6Nervous Anxiety521 Depression36565 Dizziness1118101513 Drug dependence262 Hypertonia531 Insomnia6364 Paresthesia333125 Vertigo62Respiratory Bronchitis533 Cough increase1610189 Dyspnea1931137 Pharyngitis3324271523 Respiratory disorder5 Rhinitis1061169 Sinusitis5232Skin And Appendages Pruritus13835 Rash3533Special Senses Amblyopia263 Eye disorder3633 Taste perversion293Urogenital Urinary tract infect 6332 Kidney failure56666. Postmarketing Experience The 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. CARNITOR (R) (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 CARNITOR (R). 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 or iatrogenic factors such as hemodialysis. CARNITOR (R) 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 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. 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.Pharmacokinetic and clinical studies with CARNITOR (R) have shown that administration of levocarnitine to ESRD patients on hemodialysis results in increased plasma levocarnitine concentrations.

DESCRIPTION SECTION.

DESCRIPTION. CARNITOR (R) (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: Empirical Formula: 7H 15NO Molecular Weight: 161.20CARNITOR (R) (levocarnitine) Injection is sterile aqueous solution containing g of levocarnitine per mL vial. The pH is adjusted to 6.0 6.5 with hydrochloric acid or sodium hydroxide. chemical structure.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. CARNITOR (R) Injection is administered intravenously. Metabolic Disorders. The recommended dose is 50 mg/kg given as slow 2-3 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 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 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.. ESRD Patients on Hemodialysis. The recommended starting dose is 10-20 mg/kg dry body weight as 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 umol/L). Dose adjustments should be guided by trough (pre-dialysis) levocarnitine concentrations, and downward dose adjustments (e.g. to 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL CARTON LABEL. CARNITOR (R) (levocarnitine) Injection 1g/5mL [200 mg/mL] FOR INTRAVENOUS USE ONLYUS Patent Nos, 6,335,369; 6,429,230; 6,696,493CARNITOR (R) (levocarnitine) Injection 1g/5mL [200 mg/mL]FOR INTRAVENOUS USE ONLYEach 5mL vial contains: 1g of Levocarnitine as an aqueous solution 1g/5mL [200mg/mL]. May contain HCl or NaOH for pH adjustment. Dosage: See package insert. Store at controlled room temperature (25C). See USP. Avoid excessive heat. Protect from freezing. Discard any unused portion as the formulation does not contain preservative. Rx only.VC(l)-5 0217Leadiant Biosciences Distributed by Leadiant Biosciences, Inc. Gaithersburg, MD 20878 Principal Display Panel Carton Label.

PHARMACOKINETICS SECTION.

PHARMACOKINETICS. In relative bioavailability study in 15 healthy adult male volunteers, CARNITOR (R) Tablets were found to be bio-equivalent to CARNITOR (R) Oral Solution. Following days of dosing with tablets of CARNITOR (R) 330 mg b.i.d. or g of CARNITOR (R) oral solution b.i.d., the maximum plasma concentration (C max) was about 80 umol/L and the time to maximum plasma concentration (T max) occurred at 3.3 hours. The plasma concentration profiles of levocarnitine after slow minute intravenous bolus dose of 20 mg/kg of CARNITOR (R) were described by two-compartment model. Following 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 (R), calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 +- 5.3% for CARNITOR (R) Tablets and 15.9 +- 4.9% for CARNITOR (R) 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. In 9-week study, 12 ESRD patients undergoing hemodialysis for at least months received CARNITOR (R) 20 mg/kg three times per week after dialysis. Prior to initiation of CARNITOR (R) therapy, mean plasma levocarnitine concentrations were approximately 20 umol/L pre-dialysis and umol/L post-dialysis. The table summarizes the pharmacokinetic data (mean +- SD umol/L) after the first dose of CARNITOR (R) and after weeks of CARNITOR (R) therapy. N=12BaselineSingle dose8 weeksC max -1139 +- 2401190 +- 270Trough (pre-dialysis, pre-dose)21.3 +- 7.768.4 +- 26.1190 +- 55After one week of CARNITOR (R) therapy (3 doses), all patients had trough concentrations between 54 and 180 umol/L (normal 40-50 umol/L) and concentrations remained relatively stable or increased over the course of the study. In similar study in ESRD patients also receiving 20 mg/kg CARNITOR (R) times per week after hemodialysis, 12- and 24-week mean pre-dialysis (trough) levocarnitine concentrations were 189 (N=25) and 243 (N=23) umol/L, respectively. In dose-ranging study in ESRD patients undergoing hemodialysis, patients received 10, 20, or 40 mg/kg CARNITOR (R) times per week following dialysis (N~30 for each dose group). Mean +- SD trough levocarnitine concentrations (umol/L) by dose after 12 and 24 weeks of therapy are summarized in the table. 12 weeks24 weeks10 mg/kg116 +- 69148 +- 5020 mg/kg210 +- 58240 +- 6040 mg/kg371 +- 111456 +- 162While the efficacy of CARNITOR (R) 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.

PRECAUTIONS SECTION.

PRECAUTIONS. General. 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.. 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 CARNITOR (R). 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.

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. PREVIOUS EDITION IS OBSOLETE Date of Issue: 04/18 VPI-15 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. Leadiant Logo.

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 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 CARNITOR (R) Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).

WARNINGS SECTION.

WARNINGS. Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm have been reported following CARNITOR (R) administration, mostly in patients with end stage renal disease who are undergoing dialysis. Some reactions occurred within minutes after intravenous administration of CARNITOR (R). If severe hypersensitivity reaction occurs, discontinue CARNITOR (R) treatment and initiate appropriate medical treatment. Consider the risks and benefits of re-administering CARNITOR (R) 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.