Professional Drug Information > L-Carnitine

Levocarnitine (Systemic)

VA CLASSIFICATION
Primary: TN900

Commonly used brand name(s): Carnitor.

Another commonly used name is
L-Carnitine .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Carnitine deficiency therapy agent—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Carnitine deficiency (treatment)—Levocarnitine is indicated for treatment of primary systemic carnitine deficiency, a genetic impairment of normal biosynthesis or utilization of levocarnitine from dietary sources ^{33}, or for the treatment of secondary carnitine deficiency resulting from an inborn error of metabolism. ^{33}
—Deficiency of levocarnitine may lead to elevated triglyceride and free fatty acid concentrations, reduced ketogenesis, and lipid infiltration of liver and muscle. Severe, chronic deficiency may lead to hypoglycemia, life-threatening acidosis, progressive myasthenia, hypotonia, lethargy, hepatomegaly, hepatic encephalopathy, hepatic coma, cardiomegaly, congestive heart failure, cardiac arrest, muscle weakness and failure to thrive, neurologic disturbances, and impaired infant growth and development. ^{33}

Carnitine deficiency, in end-stage renal disease (ESRD) patients on hemodialysis (prevention and treatment)¹—Parenteral levocarnitine is indicated for the prevention and treatment of carnitine deficiency in patients with end-stage renal disease supported on hemodialysis. ^{31}

[Carnitine deficiency, secondary to valproic acid toxicity (prophylaxis and treatment)]¹—Levocarnitine oral solution is used for the prevention and treatment of carnitine deficiency secondary to valproic acid toxicity. ^{{22} {23} {24}}

Unaccepted
Levocarnitine has not been proven effective for treatment of abnormal plasma lipoprotein patterns or cardiac conditions unrelated to systemic carnitine deficiency. ^{29} It has also not been proven effective for improvement of athletic performance. ^{03}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    161.20 ^{06}{33}


pH
    Oral solution—5.
    Intravenous solution—6–6.5; adjusted with hydrochloric acid^{31}

Mechanism of action/Effect:

Levocarnitine is necessary for normal mammalian fat utilization and energy metabolism. It facilitates entry of long-chain fatty acids into cellular mitochondria, where they are used during oxidation and energy production. ^{{15} {16}{33}} It also exports acyl groups from subcellular organelles and from cells to urine before they accumulate to toxic concentrations. ^{{13} {25}}

Only the L isomer of carnitine (sometimes called vitamin B _T) affects lipid metabolism. The “vitamin B _T" form actually contains D,L-carnitine, which competitively inhibits levocarnitine and can cause deficiency.^{03}

Absorption:


Bioavailability:

Oral—15% (tablets or solution).^{33}


Distribution:


Vol _D:

29 L (0.39 liters per kg).^{33}


Protein binding:

Not bound to plasma protein or albumin.^{33}

Biotransformation:

Major metabolites include trimethylamine N-oxide and [³H]-γ-butyrobetaine.^{33}

Half-life:

Distribution—0.585 hours.^{33}

Elimination—17.4 hours

Time to peak concentration:


Oral:

Solution: 3.3 hours.^{33}

Tablet: 3.3 hours.


Peak serum concentration:


Oral:

80 nanomoles per mL.^{33}



Parenteral (following hemodialysis):

1140–1190 micromoles per L (20 mg per kg dose, three times weekly, after dialysis session).^{31}


Elimination:
    Total body clearance—4 L/hour.^{33}
    Fecal—<1%.^{33}
    Renal—8.6% to 9.4% (after oral dosing); 75.6% (after single IV dose).^{33} Plasma carnitine concentrations may be increased in patients with renal failure.^{33}
    In dialysis—Removable by hemodialysis; deficiency may occur.^{{02} {03} {04} {05} {08}}


Precautions to Consider

Carcinogenicity

Studies have not been done in either animals or humans. ^{33}

Mutagenicity

Studies in Salmonella typhimurium , Saccharomyces cerevisiae , and Schizosaccharomyces pombe found no evidence of mutagenicity. ^{33}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies have not been done in humans.

Studies in rats and rabbits at levocarnitine doses up to 3.8 times the usual adult dose (based on body surface area (mg/m ²)) have not demonstrated impaired fertility or fetal harm. ^{33}

FDA Pregnancy Category B. ^{33}

Breast-feeding

It is not known whether levocarnitine is distributed into breast milk. Problems in humans have not been documented. Carnitine occurs naturally in human milk. ^{33}

Studies in dairy cows indicate that levocarnitine is distributed into dairy milk.^{31}

Pediatrics

Appropriate studies on the relationship of age to the effects of levocarnitine have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medicine in children are not expected.


Geriatrics


Appropriate studies on the relationship of age to the effects of levocarnitine have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Valproic acid    (requirements for carnitine may be increased in patients receiving valproic acid ^{{03} {04} {22} {23} {24}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Seizures^{33}    (Seizures may occur in patients with or without pre-existing seizure activity; increased seizure frequency and/or severity has been reported in patients with pre-existing seizure activity)


» End stage renal disease^{34}    (Administration of high doses of the oral formulations of levocarnitine for long periods of time is not recommended in patients with severely compromised renal function or in end stage renal disease patients on dialysis due to the fact that major metabolites formed following oral administration (trimethylamine [TMA] and trimethylamine-N-oxide [TMAO]) will accumulate since they cannot be efficiently removed by the kidneys. This does not occur to the same extent following intravenous administration. Only the intravenous form of levocarnitine is indicated for use in end stage renal disease patients on hemodialysis.^{34})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Carnitine concentrations (free carnitine levels should be 35 to 60 micromoles per L)^{33} and
Free fatty acid concentrations and
Triglyceride concentrations    (plasma determinations recommended at periodic intervals to assess efficacy of levocarnitine; weekly to monthly monitoring during parenteral therapy is recommended ^{{31} {33}})


Periodic blood chemistries
Vital signs
Overall clinical condition


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parenthesis where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypertension — in dialysis patients with end-stage renal disease (ESRD)

Incidence less frequent
    
Fever — in dialysis patients with ESRD
    
tachycardia (fast heartbeat)— in dialysis patients with ESRD

Incidence rare
    
Seizures — may occur in patients with or without seizure history; increased seizure frequency and/or severity has been reported in patients with pre-existing seizure activity^{33}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal or stomach cramps ^{03}{33}
    
diarrhea ^{03}{33}
    
headache —in dialysis patients with ESRD
    
nausea or vomiting ^{03}{33}

Incidence less frequent
    
Body odor ^{03}
    
gastritis (abdominal discomfort ; loss of appetite)

Note: Gastrointestinal symptoms and levocarnitine-induced body odor are dose-related ^{33}.


Incidence less frequent—In dialysis patients with ESRD
    
Amblyopia (blurred vision ; change in vision; impaired vision)
    
anorexia (loss of appetite; weight loss)
    
asthenia (loss of strength or energy; muscle pain or weakness )
    
depression
    
dizziness ^{31}
    
hypercalcemia (abdominal pain; confusion; constipation; depression ; dry mouth; headache; incoherent speech; increased urination; loss of appetite; metallic taste; muscle weakness; nausea; thirst; unusual tiredness; vomiting; weight loss )
    
paresthesias ( burning, crawling, itching, numbness, prickling, “pins and needles,” or tingling feelings)
    
peripheral edema (bloating or swelling of face, arms, hands, lower legs, or feet; rapid weight gain; tingling of hands or feet; unusual weight gain or loss)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
There are no reports of toxicity from overdose of l-carnitine. Adverse effects Include nausea, vomiting, abdominal cramps, diarrhea, and drug-induced body odor.^{33}

To enhance elimination
Removing levocarnitine from plasma via hemodialysis.^{31}


Supportive care:
Treatment is symptomatic and supportive.^{33}



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Levocarnitine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use
Description should include caution against confusion with the D,L-carnitine form

Before using this medication
  Conditions affecting use, especially:
Other medical problems, especially history of end stage renal disease (ESRD) and seizure activity

Proper use of this medication
Taking during or immediately following meals and consuming slowly to reduce gastrointestinal upset

Taking at evenly spaced times throughout day (every 3 or 4 hours).

» Proper dosing
Not taking at all and not doubling doses

» Proper storage

Precautions while using this medication
» Not changing brands or dosage forms of levocarnitine without checking with physician


Side/adverse effects
Signs of potential side effects, especially hypertension, fever, tachycardia, and seizures


General Dosing Information
Even spacing of doses throughout the day (every 3 or 4 hours) will help increase tolerance of levocarnitine.^{33} Gastrointestinal side effects are dose-related.^{33}

Diet/Nutrition
Levocarnitine oral solution may be given alone. However, to reduce gastrointestinal side effects caused by overly rapid ingestion, it is recommended that the solution be dissolved in drinks or other liquid foods and that no more than 10 mL (1 gram) be taken at each dose.^{33}

Levocarnitine tablets should be taken with meals to minimize gastrointestinal upset. ^{33}

Bioequivalence information
There are few data showing the therapeutic equivalence of those levocarnitine products approved for drug use and those products sold as food supplements. However, Carnitor-brand tablets and oral solution are bioequivalent. ^{33}

The effects of supplemental levocarnitine on either the signs and symptoms of carnitine deficiency or clinical outcomes have not been studied in the population of end stage renal disease hemodialysis patients being maintained on parenteral levocarnitine.^{31}


Oral Dosage Forms

LEVOCARNITINE ORAL SOLUTION USP

Usual adult and adolescent dose
Carnitine deficiency
Oral/enteral, initially 1 gram once a day with food, the dosage being increased slowly as needed and tolerated. For a 50-kg patient, the usual dose is 1 gram one to three times a day with meals. ^{33}


Usual pediatric dose
Carnitine deficiency
Oral/enteral, initially 50 mg per kg of body weight a day with food, the dosage being increased slowly as needed and tolerated. The usual dose is 50 to 100 mg per kg of body weight a day with meals (maximum 3 grams a day). ^{33}


Strength(s) usually available
U.S.—


100 mg per mL (Rx) [Carnitor]

Canada—


100 mg per mL (Rx) [Carnitor]

Packaging and storage:
Store at controlled room temperature between 20 and 25° C (68 and 77° F).^{33}

Auxiliary labeling:
   • Take with meals.

Note: Not for parenteral use.^{33}



LEVOCARNITINE TABLETS USP

Note: Certain levocarnitine tablets are labeled and sold as food supplements only. These products have not been approved as drugs by the Food and Drug Administration for use in the treatment of carnitine deficiency. When used on prescription, one levocarnitine product should not be substituted for another unless otherwise directed by the patient's physician. There are no data showing the therapeutic equivalence of those products approved for drug use and those products sold as food supplements.


Usual adult and adolescent dose
Carnitine deficiency
Oral, 990 milligrams two or three times a day with meals. ^{33}


Usual pediatric dose
Carnitine deficiency
Oral, initially 50 mg per kg of body weight a day with food, the dosage being increased slowly as needed and tolerated. The usual dose is 50 to 100 mg per kg of body weight a day with meals (maximum 3 grams a day). ^{33}


Strength(s) usually available
U.S.—


330 mg (Rx) [Carnitor]

Canada—


330 mg (Rx) [Carnitor]

Packaging and storage:
Store at controlled room temperature between 20 and 25 °C (68 and 77 °F). ^{33}

Auxiliary labeling:
   • Take with meals.



Parenteral Dosage Forms

LEVOCARNITINE INJECTION

Usual adult dose
Carnitine deficiency
Intravenous, 50 mg per kg (mg/kg) of body weight a day given by infusion or as a slow (2- to 3-minute) injection. ^{33}

For severe metabolic crisis
Intravenous, loading dose of 50 mg/kg of body weight, followed by a total of 50 mg/kg every 3 or 4 hours for one day, then 50 mg/kg a day. The highest dose administered has been 300 mg/kg.^{33}

Carnitine deficiency in patients with end-stage renal disease on hemodialysis (prevention and treatment) ¹
Intravenous, initially: 10 to 20 mg per kg (mg/kg) of dry body weight a day given as a slow (2- to 3-minute) bolus injection into the venous return line after each dialysis session. Treatment should be given to those with pre-dialysis (trough) plasma levocarnitine levels below normal range (40 to 50 micromoles per L). ^{31}

Intravenous, maintenance: Downward dose titrations are guided by trough plasma levocarnitine concentrations, with the earliest dose adjustment made after 3 to 4 weeks of therapy.^{31}

Pediatric dose
See Usual adult dose .


Strength(s) usually available
U.S.—


200 mg per mL (Rx) [Carnitor^{32}]

Canada—


200 mg per mL (Rx) [Carnitor]

Packaging and storage:
Store ampules at controlled room temperature between 20 and 25 °C (68 and 77 °F). Keep ampules in original container and protect from light. Ampules contain no preservative; discard any unused, opened ampules.^{31}{33}

Stability:
Solutions ranging in concentration between 0.5 and 8 mg per mL (250 to 4200 mg per 500 mL) prepared in Sodium Chloride 0.9% or Lactated Ringers are stable and compatible stored in polyvinyl chloride (PVC) containers at room temperature (25° C) for up to 24 hours.^{31}

Developed: 09/02/1999
Revised: 08/01/2001

References

1. Not used.
   

2. Not used.
   

3. Med Lett Drugs Ther 1986 Sep 12; 28: 88-9.
   

4. Borum P: Carnitine as an essential nutrient. J Am Coll Nutr 1986; 5: 177-182.
   

5. Siami G, Clinton M & Miak R et al: Evaluation of the effects of intravenous L-carnitine therapy on function, structure and fatty acid metabolism of skeletal muscle in patients receiving chronic hemodialysis. Nephron 1991; 57(3): 306-313.
   

6. Fleeger CA, editor. USP dictionary of USAN and international drug names. 1995. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994.
   

7. Not used.
   

8. Bohmer T, Bergrem H & Eiklid K: Carnitine deficiency induced during intermittent haemodialysis for renal failure. Lancet 1978; 1: 126-128.
   

9. Rudman D, Sewell C & Andley J: Deficiency of carnitine in cachectic cirrhotic patients. J Clin Invest 1977; 60: 716-723.
   

10. Shenai J & Borum P: Tissue carnitine reserves of newborn infants. Pediatr Res 1984; 18(7): 679-681.
    

11. Allen R, Hansch D & Wu H: Hypocarnitinaemia in disorders of organic acid metabolism. Lancet 1982; 2: 500-501.
    

12. Roe C & Bohan T: L-Carnitine therapy in propionicacidaemia. Lancet 1982; 1: 1411-1412.
    

13. Reviewer comment, 1990.
    

14. Stumpf D, Parker D & Haas R: Carnitine deficiency with valproate therapy. J Pediatr 1983; 103: 175-176.
    

15. Helms R, Whitington P, Mauer E et al: Enhanced lipid utilization in infants receiving oral L-carnitine during long-term parenteral nutrition. J Pediatr 1986; 109: 984-988.
    

16. Bremer J: Carnitine-metabolism and functions. Physiol Rev 1983; 63: 1420-1480.
    

17. USAN 1989.
    

18. USP XXI, Supp. 8.
    

19. Not used.
    

20. Feller A & Rudman D: Role of carnitine in human nutrition. Am Inst of Nutr 1988; 18: 541-547.
    

21. Phone call to Kendall McGaw of Canada 4/18/90.
    

22. Orphan Drug Product Designations, USP DI Update #4, 1990.
    

23. Ohtani Y, Endo F & Matsuda I: Carnitine deficiency and hyperammonemia associated with valproic acid therapy. J Pediatr 1982; 101(5): 782-775.
    

24. Laub M, Paetzke-Brunner I & Jaeger G: Serum carnitine during valproic acid therapy. Epilepsia 1987; 27(5): 559-562.
    

25. Stumpf D, Parker D & Angelini C: Carnitine deficiency, organic acidemias, and Reye's syndrome. Neurology 1985; 35: 1041-1045.
    

26. Roe C, Hoppel C, Stacey T et al: Metabolic response to carnitine in methylmalonic aciduria. Arch Dis Child 1983; 58: 916-920.
    

27. Mayatepek E, Kurczynski T & Hoppel C: Long-term L-carnitine treatment in isovaleric acidemia. Pediatr Neurol 1991; 7(2): 137-140.
    

28. Seccomb D, James L & Booth F: L-carnitine treatment in glutaric aciduria type I. Neurology 1986; 36(2): 264-267.
    

29. Panelists" comments, 1993.
    

30. The United States pharmacopeia. The national formulary. USP 22nd revision (January 1, 1990). NF 17th ed (January 1, 1990). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1990: Ninth supplement, 1993: 3476.
    

31. Product Information: Carnitor injection, levocarnitine. Sigma-Tau Pharmaceuticals, Gaithersburg, MD, (PI revised 12/99) Reviewed 03/2000.
    

32. Olin BR, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc, June 1993: 54c.
    

33. Product Information: Carnitor, levocarnitine. Sigma-Tau Pharmaceuticals, Gaithersburg, MD, USA, Rev 10/98, Rec 2/99.
    

34. Product Information: Carnitor, levocarnitine. Sigma-Tau Pharmaceuticals, Gaithersburg, MD, USA,( PI revised 07/2001) Reviewed 07/2001.
    

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