Levocarnitine for Carbohydrate Metabolism Disorders

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.

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.

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 pre­existing seizure activity, receiving either oral or intravenous levocarnitine. In patients with pre­existing seizure activity, an increase in seizure frequency and/or severity has been reported. Hypersensitivity reactions : Anaphylaxis, laryngeal edema and bronchospasm (see WARNINGS ) 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 pre­existing seizure activity, receiving either oral or intravenous levocarnitine. In patients with pre­existing seizure activity, an increase in seizure frequency and/or severity has been reported. Hypersensitivity reactions : Anaphylaxis, laryngeal edema and bronchospasm (see WARNINGS )