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DESCRIPTION Levocarnitine is a 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 a 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: C 7 H 15 NO 3 Molecular Weight: 161.20 Levocarnitine Injection, USP is a sterile aqueous solution containing 1 g of levocarnitine per 5 mL vial. The pH is adjusted to 6.0 - 6.5 with hydrochloric acid or sodium hydroxide. chemical structure

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, 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 a consequence of inborn errors of metabolism or iatrogenic factors such as hemodialysis. 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 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 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a 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 Levocarnitine have shown that administration of levocarnitine to ESRD patients on hemodialysis results in increased plasma levocarnitine concentrations.

PHARMACOKINETICS In a relative bioavailability study in 15 healthy adult male volunteers, Levocarnitine Tablets were found to be bio-equivalent to Levocarnitine Oral Solution. Following 4 days of dosing with 6 tablets of Levocarnitine 330 mg b.i.d. or 2 g of Levocarnitine 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 Levocarnitine 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 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 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 Levocarnitine 20 mg/kg three times per week after dialysis. Prior to initiation of Levocarnitine 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 Levocarnitine and after 8 weeks of Levocarnitine therapy. N=12 Baseline Single dose 8 weeks C max - 1139 ± 240 1190 ± 270 Trough (pre-dialysis, pre-dose) 21.3 ± 7.7 68.4 ± 26.1 190 ± 55 After one week of Levocarnitine 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 Levocarnitine 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 Levocarnitine 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. 12 weeks 24 weeks 10 mg/kg 116 ± 69 148 ± 50 20 mg/kg 210 ± 58 240 ± 60 40 mg/kg 371 ± 111 456 ± 162 While the efficacy of Levocarnitine 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.

<table width="100%"><colgroup><col width="33%"/><col width="22%"/><col width="22%"/><col width="22%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="middle"><paragraph>N=12</paragraph></td><td styleCode="Botrule Rrule Toprule" valign="middle"><paragraph>Baseline</paragraph></td><td styleCode="Botrule Rrule Toprule" valign="middle"><paragraph>Single dose</paragraph></td><td styleCode="Botrule Rrule Toprule" valign="middle"><paragraph>8 weeks</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="middle"><paragraph>C _max</paragraph></td><td styleCode="Botrule Rrule" valign="middle"><paragraph>-</paragraph></td><td styleCode="Botrule Rrule" valign="middle"><paragraph>1139 &#xB1; 240</paragraph></td><td styleCode="Botrule Rrule" valign="middle"><paragraph>1190 &#xB1; 270</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="middle"><paragraph>Trough (pre-dialysis, pre-dose)</paragraph></td><td styleCode="Botrule Rrule" valign="middle"><paragraph>21.3 &#xB1; 7.7</paragraph></td><td styleCode="Botrule Rrule" valign="middle"><paragraph>68.4 &#xB1; 26.1</paragraph></td><td styleCode="Botrule Rrule" valign="middle"><paragraph>190 &#xB1; 55</paragraph></td></tr></tbody></table> <table width="100%"><colgroup><col width="33%"/><col width="33%"/><col width="33%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph>12 weeks</paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top"><paragraph>24 weeks</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>10 mg/kg</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph>116 &#xB1; 69</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph>148 &#xB1; 50</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>20 mg/kg</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph>210 &#xB1; 58</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph>240 &#xB1; 60</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>40 mg/kg</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph>371 &#xB1; 111</paragraph></td><td styleCode="Botrule Rrule" valign="top"><paragraph>456 &#xB1; 162</paragraph></td></tr></tbody></table>

METABOLISM AND EXCRETION In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [ 3 H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. 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]-γ-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 4 days of oral administration of Levocarnitine Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion). COMPATIBILITY AND STABILITY Levocarnitine Injection is compatible and stable when mixed in parenteral solutions of Sodium Chloride 0.9% or Lactated Ringer's in concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4200 mg/500 mL (8.0 mg/mL) and stored at room temperature (25°C) for up to 24 hours in PVC plastic bags.

INDICATIONS AND USAGE For the acute and chronic treatment of patients with an inborn error of metabolism which results in secondary carnitine deficiency. For the prevention and treatment of carnitine deficiency in patients with end stage renal disease who are undergoing dialysis.

WARNINGS Hypersensitivity Reactions Serious 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 a 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 a severe reaction. If the decision is made to re-administer the product, monitor patients for a reoccurrence of signs and symptoms of a severe hypersensitivity reaction.

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 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 .

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 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.

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 a Frequency ≥5% Regardless of Causality by Body System Placebo (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 pain 17 21 5 6 9 Accidental injury 10 12 8 12 10 Allergic reaction 5 6 2 Asthenia 8 9 8 12 9 Back pain 10 9 8 6 8 Chest pain 14 6 15 12 12 Fever 5 6 5 12 7 Flu syndrome 40 15 27 29 25 Headache 16 12 37 3 22 Infection 17 15 10 24 15 Injection site reaction 59 38 27 38 33 Pain 49 21 32 35 30 Cardiovascular Arrhythmia 5 3 3 2 Atrial fibrillation 2 6 2 Cardiovascular disorder 6 3 5 6 5 Electrocardiogram abnormal 3 6 2 Hemorrhage 6 9 2 3 4 Hypertension 14 18 21 21 20 Hypotension 19 15 19 3 14 Palpitations 3 8 5 Tachycardia 5 6 5 9 6 Vascular disorder 2 2 6 2 Digestive Anorexia 3 3 5 6 5 Constipation 6 3 3 3 3 Diarrhea 19 9 10 35 16 Dyspepsia 10 9 6 5 Gastrointestinal disorder 2 3 6 2 Melena 3 6 2 Nausea 10 9 5 12 8 Stomach atony 5 Vomiting 16 9 16 21 15 Endocrine System Parathyroid disorder 2 6 2 6 4 Hemic/Lymphatic Anemia 3 3 5 12 6 Metabolic/Nutritional Hypercalcemia 3 15 8 6 9 Hyperkalemia 6 6 6 6 6 Hypervolemia 17 3 3 12 5 Peripheral edema 3 6 5 3 5 Weight decrease 3 3 8 3 5 Weight increase 2 3 6 2 Musculo-Skeletal Leg cramps 13 8 4 Myalgia 6 Nervous Anxiety 5 2 1 Depression 3 6 5 6 5 Dizziness 11 18 10 15 13 Drug dependence 2 6 2 Hypertonia 5 3 1 Insomnia 6 3 6 4 Paresthesia 3 3 3 12 5 Vertigo 6 2 Respiratory Bronchitis 5 3 3 Cough increase 16 10 18 9 Dyspnea 19 3 11 3 7 Pharyngitis 33 24 27 15 23 Respiratory disorder 5 Rhinitis 10 6 11 6 9 Sinusitis 5 2 3 2 Skin And Appendages Pruritus 13 8 3 5 Rash 3 5 3 3 Special Senses Amblyopia 2 6 3 Eye disorder 3 6 3 3 Taste perversion 2 9 3 Urogenital Urinary tract infect 6 3 3 2 Kidney failure 5 6 6 6 6 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 ).

<table width="100%" cellpadding="3.6pt"><caption>Adverse Events with a Frequency &#x2265;5% Regardless of Causality by Body System</caption><colgroup><col width="23%"/><col width="10%"/><col width="16%"/><col width="16%"/><col width="16%"/><col width="18%"/></colgroup><tbody><tr><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Lrule Rrule" align="center" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Placebo (n=63)</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Levocarnitine 10 mg (n=34)</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Levocarnitine 20 mg (n=62)</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule" align="center" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Levocarnitine 40 mg (n=34)</content></content></paragraph></td><td styleCode="Botrule Lrule" align="center" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Levocarnitine 10, 20 &amp; 40 mg (n=130)</content></content></paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Body as Whole</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Abdominal pain</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>17</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>21</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Accidental injury</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Allergic reaction</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><pa

gn="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><pa ragraph> Asthenia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Back pain</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Chest pain</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>14</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Fever</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Flu syndrome</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>40</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>27</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>29</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>25</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Headache</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>16</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>37</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>22</paragraph></td></tr><t

aragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>37</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>22</paragraph></td></tr><t r><td styleCode="Botrule Rrule" valign="top"><paragraph> Infection</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>17</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>24</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Injection site reaction</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>59</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>38</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>27</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>38</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>33</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Pain</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>49</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>21</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>32</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>35</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>30</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Cardiovascular </content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Arrhythmia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Atrial fibrillation</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Cardiovascular disorder</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></

raph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Cardiovascular disorder</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></ td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Electrocardiogram abnormal</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Hemorrhage</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Hypertension</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>14</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>18</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>21</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>21</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>20</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Hypotension</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>19</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>19</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>14</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Palpitations</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Tachycardia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></

<paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Tachycardia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></ td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Vascular disorder</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Digestive</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Anorexia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Constipation</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Diarrhea</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>19</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>35</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>16</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Dyspepsia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rru

otrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rru le Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Gastrointestinal disorder</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Melena</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Nausea</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Stomach atony</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Vomiting</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>16</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>16</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>21</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Endocrine System</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Parathyroid disorder</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center"

"top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Parathyroid disorder</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Hemic/Lymphatic</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Anemia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Metabolic/Nutritional</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Hypercalcemia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Hyperkalemia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Hypervolemia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>17</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><para

lign="top"><paragraph>17</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><para graph>12</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Peripheral edema</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Weight decrease</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Weight increase</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Musculo-Skeletal </content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Leg cramps</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>13</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Myalgia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Nervous</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprul

"top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Nervous</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprul e" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Anxiety</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Depression</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Dizziness</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>11</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>18</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>13</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Drug dependence</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Hypertonia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Insomnia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Paresthe

yleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Paresthe sia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>12</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Vertigo</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Respiratory</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Bronchitis</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Cough increase</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>16</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>18</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Dyspnea</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>19</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>11</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Pharyngitis</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>33</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>24</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>27</paragraph></td><td styleCode="Botrule Lrul

="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>33</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>24</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>27</paragraph></td><td styleCode="Botrule Lrul e Rrule Toprule" align="center" valign="top"><paragraph>15</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>23</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Respiratory disorder</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Rhinitis</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>10</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>11</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Sinusitis</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Skin And Appendages</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Pruritus</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>13</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>8</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Rash</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Special Senses</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign=

</td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Special Senses</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign= "top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Amblyopia</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Eye disorder</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Taste perversion</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>9</paragraph></td><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph><content styleCode="bold"><content styleCode="italics">Urogenital</content></content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" valign="top"/></tr><tr><td styleCode="Botrule Rrule" valign="top"><paragraph> Urinary tract infect</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><paragraph>3</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Lrule Toprule" align="center" valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Toprule" valign="top"><paragraph> Kidney failure</paragraph></td><td styleCode="Lrule Rrule Toprule" align="center" valign="top"><paragraph>5</paragraph></td><td styleCode="Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Lrule Rrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td><td styleCode="Lrule Toprule" align="center" valign="top"><paragraph>6</paragraph></td></tr></tbody></table>

OVERDOSAGE There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD 50 of levocarnitine in rats is 5.4 g/kg and the oral LD 50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.

DOSAGE AND ADMINISTRATION Levocarnitine Injection, USP is administered intravenously. 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.

HOW SUPPLIED Levocarnitine Injection, USP is available in 1 g per 5 mL single dose vials packaged 5 vials per carton (NDC 73043-034-05). Levocarnitine Injection, USP 5 mL vial is distributed by Devatis Inc. 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. Rx only.

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 a carnitine supplement by human adults. Metabolism 40:1305-1310. Made in Turkey Distributed by: Devatis, Inc. San Clemente, CA 92672Rev. 06/2025

DESCRIPTION Levocarnitine is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane. The chemical name of levocarnitine is (R)-3-carboxy-2-hydroxy-N,N,N-trimethy-1-propanaminium hydroxide, inner salt. Levocarnitine is a white, crystalline powder or colourless crystals. It is freely soluble in water, soluble in warm alcohol, practically insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure is: Empirical Formula: C 7 H 15 NO 3 Molecular Weight: 161.20 Each levocarnitine tablet, USP intended for oral administration contains 330 mg of levocarnitine. In addition, it also contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. levocarnitine-struc

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, 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 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 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 μmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a 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. PHARMACOKINETICS In a relative bioavailability study in 15 healthy adult male volunteers, levocarnitine tablets were found to be bio-equivalent to levocarnitine oral solution. Following 4 days of dosing with 6 tablets of levocarnitine 330 mg b.i.d. or 2 g of levocarnitine oral solution b.i.d., the maximum plasma concentration (C max ) was about 80 μmol/L and the time to maximum plasma concentration (T max ) occurred at 3.3 hours. The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of levocarnitine 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 one oral formulation of levocarnitine, calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for levocarnitine tablets.

ife was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours. The absolute bioavailability of levocarnitine from the one oral formulation of levocarnitine, calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for levocarnitine tablets. 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 METABOLISM AND EXCRETION In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [ 3 H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. 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]-γ-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 4 days of oral administration of levocarnitine tablets (1980 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).

INDICATIONS AND USAGE Levocarnitine tablets are 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 CLINICAL 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 tablets are also indicated for acute and chronic treatment of patients with an inborn error of metabolism which results in a secondary carnitine deficiency.

WARNINGS Hypersensitivity Reactions Serious hypersensitivity reactions, including rash, urticaria, and facial edema have been reported with oral levocarnitine. Other serious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm have been reported following intravenous levocarnitine administration, mostly in patients with end stage renal disease undergoing dialysis. Discontinue use of levocarnitine tablets and instruct patients to seek medical attention if they experience symptoms suggestive of a hypersensitivity reaction.

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 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 .

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.

ADVERSE REACTIONS The following adverse reactions associated with the use of oral formulations of levocarnitine were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency, reliability, or to establish a causal relationship to drug exposure. Gastrointestinal Reactions: 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. 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. Musculoskeletal Reactions: Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. 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: Rash, urticaria, and facial edema have been reported with oral levocarnitine (see WARNINGS ). To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION 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.

HOW SUPPLIED Levocarnitine tablets, USP are supplied as white, round compressed tablets debossed “ Cor ” over “ 160 ” on one side and other side is plain. They are supplied as follows: Blister pack of 10 tablets, packaged in boxes of 90 tablets (NDC 16571-762-09) Store in original packaging: content hygroscopic. Store at 20º to 25º C (68º to 77º F) [see USP Controlled Room Temperature]. KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN.

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 a carnitine supplement by human adults. Metabolism 40:1305-1310. Manufactured for: Rising Pharma Holdings, Inc. East Brunswick, NJ 08816 Manufactured by: Graviti Pharmaceuticals Private Limited. Telangana-502307, INDIA. Mfg. Lic. No.: 12/SRD/TS/2017/F/G. Revised: 08/2024 PIR76209-02

For oral use only. Not for parenteral use. METABOLISM AND EXCRETION In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [ 3 H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. 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]-γ-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 4 days of oral administration of CARNITOR ® Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).

DESCRIPTION CARNITOR ® (levocarnitine) is a 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 a 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: C 7 H 15 NO 3 Molecular Weight: 161.20 Each CARNITOR ® (levocarnitine) Tablet contains 330 mg of levocarnitine and the inactive ingredients magnesium stearate, microcrystalline cellulose and povidone. Each 118 mL container of CARNITOR ® (levocarnitine) Oral Solution contains 1 g of levocarnitine/10 mL. Also contains: Artificial Cherry Flavor, D,L,-Malic Acid, Purified Water, Sucrose. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5. Each 118 mL container of CARNITOR ® SF (levocarnitine) Sugar-Free Oral Solution contains 1 g of levocarnitine/10 mL. Also contains: Natural Cherry Flavor, D,L,-Malic Acid, Purified Water, Sodium Saccharin USP. Methylparaben NF and Propylparaben NF are added as preservatives. The pH is approximately 5. chemical-structure

CLINICAL PHARMACOLOGY 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, 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 ® . 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 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 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 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a 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.

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 (C max ) was about 80 µmol/L and the time to maximum plasma concentration (T max ) 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

INDICATIONS AND USAGE 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 CLINICAL 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. CARNITOR ® (levocarnitine) is also indicated for acute and chronic treatment of patients with an inborn error of metabolism which results in a secondary carnitine deficiency.

WARNINGS Hypersensitivity Reactions Serious hypersensitivity reactions, including rash, urticaria, and facial edema have been reported with oral CARNITOR ® . Other serious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm have been reported following intravenous levocarnitine administration, mostly in patients with end stage renal disease undergoing dialysis. Discontinue use of CARNITOR ® and instruct patients to seek medical attention if they experience symptoms suggestive of a hypersensitivity reaction.

PRECAUTIONS General CARNITOR ® (levocarnitine) Oral Solution and CARNITOR ® SF (levocarnitine) Sugar-Free Oral Solution are for oral/internal use only. Not for parenteral use. Gastrointestinal reactions may result from a too rapid consumption of carnitine. CARNITOR ® (levocarnitine) Oral Solution and CARNITOR ® SF (levocarnitine) Sugar-Free Oral Solution may be consumed alone, or dissolved in drinks or other liquid foods to reduce taste fatigue. They should be consumed slowly and doses should be spaced evenly throughout the day to maximize tolerance. 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 ® . 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 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.

ADVERSE REACTIONS The following adverse reactions associated with the use of oral formulations of levocarnitine were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency, reliability, or to establish a causal relationship to drug exposure. Gastrointestinal Reactions : 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. Gastrointestinal adverse reactions with CARNITOR ® (levocarnitine) Oral Solution or CARNITOR ® SF (levocarnitine) Sugar-Free 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. Musculoskeletal Reactions : Mild myasthenia has been described only in uremic patients receiving D,L-carnitine. 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 : Rash, urticaria, and facial edema have been reported with oral CARNITOR ® (see WARNINGS ).

DOSAGE AND ADMINISTRATION 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 and CARNITOR ® SF (levocarnitine) Sugar-Free 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 or CARNITOR ® SF (levocarnitine) Sugar-Free 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 or CARNITOR ® SF (levocarnitine) Sugar-Free 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 or CARNITOR ® SF (levocarnitine) Sugar-Free 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.

HOW SUPPLIED 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 in original packaging: content hygroscopic. Store at 20°C to 25°C (68°F to 77°F). See USP Controlled Room Temperature. CARNITOR ® (levocarnitine) Tablets are distributed by Leadiant Biosciences, Inc. CARNITOR ® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) plastic containers (NDC 54482-145-08 and NDC 54482-145-09). Store at 20°C to 25°C (68°F to 77°F). See USP Controlled Room Temperature. Avoid excessive heat and protect from freezing. CARNITOR ® (levocarnitine) Oral Solution is distributed by Leadiant Biosciences, Inc. CARNITOR ® SF (levocarnitine) Sugar-Free Oral Solution is supplied in 118 mL (4 FL. OZ.) plastic containers (NDC 54482-148-01 and NDC 54482-148-02). Store at 20°C to 25°C (68°F to 77°F). See USP Controlled Room Temperature. Avoid excessive heat and protect from freezing. CARNITOR ® SF (levocarnitine) Sugar-Free Oral Solution is distributed by Leadiant Biosciences, Inc. Rx only.

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 a carnitine supplement by human adults. Metabolism 40:1305-1310. PREVIOUS EDITION IS OBSOLETE Date of Issue: 07/23 OPI-16 Leadiant Logo