【Description】

 

Levfort is colorless and transparent liquid and the chemical name is (R)-3-Carboxy-2-hydroxy-N,N,N-trimethyl-1-propanaminium, inner salt.

 

Chemical structure:

 

 

Molecular formula: C₇H₁₅NO₃  Molecular Weight: 161.20

 

【Indications】

 

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.

 

【Usage and Dosage】

 

Levfort Injection 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 (predialysis) 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.

 

【Strength】

 

5 ml: 1 g (based on levocarnitine)

 

【Adverse reaction】

 

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.

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.

Below lists the adverse events that have been reported in two double-blind, placebo-controlled trials in patients on chronic hemodialysis.

1.    Body as Whole: chest pain, common cold symptom, headache, reaction of injection position, aches;

2.    Cardiovascular system: cardiovascular abnormality, hypertension, hypotension, and tachycardia.

3.    Digestive system: diarrhea, dyspepsia, nausea and vomitting.

4.    Endocrine system: thyroid dysfunction.

5.    Hemic/Lymphatic: anemia;

6.    Metabolism system: hypercalcemia, hyperkalemia, hypervolemia;

7.    Nervous: dizziness, insomnia, depression;

8.    Respiratory: cough, pharyngitis and rhinitis;

9.    Skin And appendages: pruritus, rash;

10.   Urogenital: renal insufficiency.

 

【Contraindications】　

 

Those who are allergic to the ingredients in this product are forbidden to use.

 

【Precautions】

 

Before parenteral therapy, recommend to determine levocarnitine level in plasma, and monitor it every week and every month, including blood biochemistry, vital signs, plasma levocarnitine concentration (free levocarnitine is 35-60mmol/L) and whole body situations.

Observe carefully the product if it is normal or colour changes before use.

The pharmacokinetics and clinical study indicate that when using levocarnitine to treat ESRD patients who are haemodialysis that could increase levocarnitine concentration in plasma.

 

【Pregnancy】

 

Pregnancy Category B.

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

Please see dosage and administration

Geriatric use

No relevant study is done between the age and levocarnitine, it is estimated that no limit exists when levocarnitine is used in older people.

 

【Drug interactions】

 

According to the potential clinical study, the patients administered with valproic acid should increase the dose of levocarnitine.

 

【Overdose】

　

There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.

 

【Pharmacology】

 

Levfort (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 Levfort. 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.

Secondary carnitine deficiency can be a consequence of inborn errors of metabolism or iatrogenic factors such as hemodialysis. Levfort 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. Autointoxication occurs in these patients due to the accumulations 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 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 Levfort have shown that administration of levocarnitine to ESRD patients on hemodialysis results in increased plasma levocarnitine concentrations.

 

【Pharmacokinetics】

 

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.

Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was amean 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.

 

【Storage】

 

Protect from light, store in a well-closed container

 

【Package】

 

Ampoule, 5 ml/ampoule, 2 ampoules/box.

 

【Shelf life】

 

24 months

 

 

Features

 

1. In 1999, FDA and DOQI guideline approved that levocarnitine is used for the treatment of end-stage renal disease (ESRD).

2. Levocarnitine can protect ischemic myocardium and improve myocardial metabolism.^1,2

3. In 1993, FDA recognized levocarnitine as a GARS substance.

 

 

Advantages

 

1. High quantity standard. Levocarnitine is the characteristic product of Northeast Pharm, USP standard is implemented to ensure high product quality.

2. Supply-chain advantage. As the leading manufacturer of raw material of levocarnitine, Northeast Pharm can guarantee stable supply and sales flexibility.

3. An all-around support service provided by our professional marketing team.

4. Complete CTD dossiers available.

 

 

Reference

1.  Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J, 2000, 139 (2 Pt 3):S120-123.

2. Colonna P, Iliceto S.  Myocardial infarction and left ventricular remodeling: results of the CEDIM trial. Carnitine Ecocardiografia Digitalizzata Infarto Miocardico. Am Heart J. 2000, 139 (2 Pt 3): 124-130.

 

 

 

1. Levocarnitine and Myocardial Metabolism

 

 

1. Levocarnitine is the only carrier for long chain fatty acids involving the β-oxidation into the mitochondria, and provide energy to myocardial. 
2. Levocarnitine adjusts the balance of acyl-COA/COA in the mitochondrial. 
3. Levocarnitine decreases cell damage caused by fatty acyl-COA accumulation 
4. Levocarnitine stabilizes cell membrane

 

2. Levocarnitine and Cardiac Function

 

 

1. 60%-80% of energy required by myocardial comes from fat metabolism¹. 
2. Fatty acid oxidation metabolism disorders cause myocardial cellular energy imbalance. 
3. Free carnitine are consumed in large quantities, and acyl carnitine are accumulated in myocardial cells. 
4. Acyl has toxic effect of on cell metabolism.

 

3. Levocarnitine is Used for the Treatment of Angina

 

 

 

Levocarnitine can reduce the usages of anti-angina drugs and other heart drugs (Digitalis, nitroglycerin).

 

Levocarnitine can improve exercise tolerance and reduce ST segment shift level³.

 

4. Levocarnitine is Used for the Treatment of Acute Myocardial Infarction

 

Multi-regional Clinical Trial, 472 cases,

 

4.1 Levocarnitine alleviate left ventricular dilatation caused by acute myocardial infarction⁴

 

 

Percent change in end-diastolic volume (EDV) and end-systolic volume (ESV) from baseline (hospital admission) to hospital discharge (3, 6 and 12 months) in the two treatment groups (mean value ± 95% confidence interval)

 

4.2 Levocarnitine reduced the total incidence of deaths and congestive heart failure⁴

 

 

1. Left ventricular dilatation was greatly reduced, and the end-systolic and diastolic volume were greatly decrease.⁴ The necrosis region can be reduced, and ECG performance can be improved by urgent administration.⁵ 
2. Early, long-term administration can increase survival rate ⁴, and the mortality of acute myocardial infarction can be reduced from 80% to 50% ⁵.

 

4.3 Levocarnitine reduced mortality with myocardial infarction significantly ⁵

 

 

The Cause of Death	Levocarnitine group (n=81)	Control group (n=79)
Myocardial Infarction	-	3
Sudden Death	-	2
Heart Failure	-	2
Thromboembolism	1	1
Non cardiac causes	-	1
Total	1 (1.2%)	10 (12.5%)

 

 

5. Levocarnitine is Used for the Treatment of Heart toxicity caused by Anthracycline Antibiotics

 

5.1 The Comparison of myocardial enzyme levels before and after treatment with Levocarnitine (U/L)

 

 

5.2 ECG changes

 

 

The total effective rate is 91% and 60% for Levocarnitine group and the control group, respectively.

The ECG improvement in Levocarnitine group is better than in control group.

 

 

Reference

 

1. Reigtz V, Fleck E. Role of carnitine in heart failure. L-carnitine and its role in medicine: from function to therapy. (Eds. Ferrari R, DiMauro S, Sherwood G) Academic press limited. London 1992: 295-322.

 

2. Wang YM, Yin RF. The clinical study of levocarnitine in the treatment of angina. International Journal of Cardiovascular Disease, 2001, 3(1): 30-32.

 

3. Kamikawa T, et al. Effects of L-carnitine on exercise tolerance in patients with stable angina pectoris. Japanese heart journal, 1984, 25: 587-597.

 

4. Lliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The L-carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial. J Am Coll Cardiol, 1995, 26(3):380-387.

 

5. Davini P, et al. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res, 1992, 18(8): 355-365.

 

6. Fan YM, Chen C, Zhen YF, et al. The clinical study of levocarnitine in the treatment of heart toxicity caused by anthracycline antibiotics. New Medicine.2007, 38(4): 229-231.