LEVOCARNIL 1 g/5 ml

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.

DOSAGE AND ADMINISTRATION Levocarnitine injection is administered intravenously. Metabolic Disorders The recommended dose is 50 mg/kg given as a slow 2 to 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 mg/kg to 20 mg/kg dry body weight as a slow 2 to 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 µmol/L to 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. 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 mg/mL) and stored at room temperature (25°C) for up to 24 hours in PVC plastic bags.

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

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 ). To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-877-725-2747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.