levocarnitine 330 MG Oral Tablet

INDICATIONS AND USAGE Levocarnitine Oral Solution USP 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. Levocarnitine Oral Solution USP is also indicated for acute and chronic treatment of patients with an inborn error of metabolism which results in a secondary carnitine deficiency. CONTRAINDICATIONS None known.

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.

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. 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.

Contraindications Levocarnitine Injection is contraindicated in: Patients with known hypersensitivity to Levocarnitine, benzyl alcohol, or any component of the formulation. Neonates, premature infants, or low birth weight infants due to the risk of benzyl alcohol toxicity (“gasping syndrome”). Patients with a history of serious hypersensitivity reactions associated with Levocarnitine administration. Patients in whom administration of hypertonic intravenous solutions may result in clinically significant complications unless closely monitored by a healthcare professional.

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 (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 urine during the 0 to 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 to 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. 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 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]-y-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).