Levocarnitine is a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. CARNITOR®( Levocarnitine) injection is a sterile aqueous solution containing 1g of levocarnitine per 5 mL ampule and 500 mg of levocarnitine per 2.5 mL ampoule. The pH is adjusted to 6.0 - 6.5 with hydrochloric acid. Chemically, levocarnitine is (R)-3-carboxy-2-hydroxy-N, N, N-trimethyl-I- propanaminium hydroxide, inner salt. It is a white powder with a melting point of 196-197° C and is readily soluble in water, hot alcohol, and insoluble in acetone. The pH of a solution (1 in 20) is between 6-8 and its pKa value is 3.8. It has empirical formula C₇H₁₅NO₃ with a molecular weight of 161.20.

For the acute and chronic treatment of patients with an inborn error of metabolism that results in secondary carnitine deficiency.

CARNITOR® Injection is administered intravenously. The recommended dose is 50mg/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 q.h. 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 level 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 level should be between 35 and 60 micromoles/liter) and overall clinical condition.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Compatibility and Stability

CARNITOR® Injection is compatible and stable when mixed in parenteral solutions of Sodium Chloride 0.9% or Lactated Ringers in concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4200 mg/500 mL (8.0 mg/mL) and stored at room temperature (25° C) for up to 24 hours in PVC plastic bags.

CARNITOR® (Levocarnitine) Injection, 200 mg per 1 mL, is available in 5 mL single dose ampules packaged 5 ampules per carton (NDC 54482-146-09) and in 2.5 mL single dose ampules packaged 5 ampules per carton (NDC 54482-146-10). Made in Italy.

Store ampules at room temperature (25° C / 77° F) in carton until their use to protect from light. Discard unused portion of an opened ampule, as they contain no preservative.

CARNITOR® (Levocarnitine) is also available in the following dosage forms for oral administration:

CARNITOR® (Levocarnitine) Tablets are supplied as 330 mg (unit dose), individually foil wrapped tablets embossed with CARNITOR-ST in boxes of 90 (NDC 54482-144-07). Made in Italy.

CARNITOR® (Levocarnitine) Oral Solution, 118 mL (4 fl. oz.), supplied as a red, cherry flavored solution in a multiple-dose plastic bottle. (NDC 54482-145-08).

Caution: Federal (U. S. A.) law prohibits dispensing without prescription.

References

1. Bohmer T, Rynding A, Solberg HE: Carnitine levels in human serum in health and disease. Clin Chim Acta 57:55-61, 1974.

2. Brooks H, Goldberg L, Holland R et al: Carnitine-induced effects on cardiac and peripheral hemodynam-ics. J Clin Pharmacol 17:561-578, 1977.

3. Christiansen R, Bremer J: Active transport of butyrobetaine and carnitine into isolated liver cells. Biochem Biophys Acta 448:562-577, 1977.

4. Lindstedt S, Lindstedt G: Distribution and excretion of carnitine 14002 in the rat. Acta Chim Scand 15:701 -702, 1961.

5. Rebouche CJ, Engel AG: Carnitine metabolism and deficiency syndromes. Mayo CIin Proc 58:533-540, 1983.

6. Rebouche CJ, Paulson DJ: Carnitine metabolism and function in humans. Ann Rev Nutr 6:41 -68, 1986.

7. Scriver CR, Beaudet AL, Sly WS, Valle D: The Metabolic Basis of Inherited Disease. McGraw-Hill, New York, 1989.

8. Schaub J, Van Hoof F, Vis HL: Inborn Errors of Metabolism. Raven Press, New York, 1991.

9. Marzo A, Arrigoni Martelli E, Mancinelli A, Cardace G, Corbelletta C, Bassani E, Solbiati M: Protein bind-ing of L-carnitine family components. Eur J Drug Met Pharmacokin, Special Issue Ill: 364-368, 1992.

10. Rebouche C: Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism:1305-1310, 1991.

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.

None.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombe indicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine.

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 CARNITOR®. 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

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

See DOSAGE AND ADMINISTRATION.

There have been no reports of toxicity from levocarnitine overdosage. The oral LD₅₀ of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.

None known.

CARNITOR® (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, therefore 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 they serve as major fuel. Primary systemic carnitine deficiency is characterized by low plasma, A.C. and/or tissue levels. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to the underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with carnitine. 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 acyl CoA esters.^1,6

Secondary levocarnitine deficiency can be a consequence of inborn errors of metabolism. CARNITOR® may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect was demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acyl CoA dehydrogenase deficiency. ^7,8 Autointoxication occurs in these patients due to the accumulations of acyl CoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acyl CoA compound to its free acid results in acidosis that can be life threatening. Levocarnitine clears the acyl CoA compound by formation of acyl carnitine which is quickly excreted. Levocarnitine deficiency is defined biochemically as abnormally low plasma levels of free carnitine, less than 20 µM/ Lat age greater than one week post term and may be associated with low tissue and or urine levels. Further, this condition may be associated with a ratio of plasma ester/ free levocarnitine levels greater than 0.4 or abnormally elevated levels of esterified levocarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma free levocarnitine levels below age related normal levels.

Bioavailability/ Pharmacokinetics

In a relative bioavailability study in 15 healthy adult male volunteers CARNITOR® Tablets were found to be bio-equivalent to CARNITOR® Oral Solution. Following the administration of 1980 mg bid., the maximum plasma concentration level (C_max) was 80 nmol/mL and the time to maximum concentration (T_max) occurred at 3.3 hours. There were no significant differences for AUC and urinary excretion observed between these two formulations.

In the same bioavailability study of 15 healthy adult males, CARNITOR® (Levocarnitine) Injection administered as a slow 3 minute bolus intravenous injection at a dose of 20 mg/Kg showed that free levocarnitine plasma profiles are best fit by a two compartment model. Approximately 76% of free levocarnitine is eliminated in the urine. Using plasma levels 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 following a single intravenous dose.

The absolute bioavailability of L-carnitine from CARNITOR® Tablets and Oral Solution was determined cornpared to the bioavailability of L-carnitine from CARNITOR® (Injection) Intravenous in 15 healthy male volunteers. After correction for circulating endogenous levels of L-carnitine in the plasma, absolute bioavailability was 15.1% ±5.3% for L-carnitine from CARNITOR® Tablets and 15.9% ±4.9% from the Oral Solution. Total body clearance of L-carnitine (Dose/AUC including endogenous baseline levels) was a mean of 4.00 L/hr. Endogenous baseline levels were not subtracted since total body clearance of L-carnitine does not distinguish between exogenous sources of L-carnitine and endogenously synthesized L-carnitine. Volume of distribution of the intravenously administered dose above baseline endogenous levels was calculated to be a mean of 29.0 L ±7.1 L (approximately 0.39 L/kg) which is an underestimate of the true volume of distribution since plasma L-carnitine is known to equilibrate slowly with, for instance, muscle L-carnitine.

L-carnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.

Metabolism and Excretion

Five normal adult male volunteers, administered a dose of [3H-methylj-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, excreted 58% to 65% of administered radioactive dose in 5 to 11 days in the urine and feces. Maximum concentration of {3H-methyl]-L-carnitine in serum occurred from 2.0 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 [3H}-y-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of carnitine was 4% to 8% of the dose. Fecal excretion of total carnitine was less than 1% of total carnitine excretion.¹⁰

After attainment of steady state following 4 days of oral administration of L-carnitine with CARNITOR® Tablets (1980 mg ql2h) or Oral Solution (2000 mg ql2h) to 15 healthy male volunteers, urinary excretion of L-carnitine was a mean of 2107 and 2339 µmoles respectively, equivalent to 8.6% and 9.4%, respectively, of the orally administered doses (uncorrected for enddgenous urinary excretion). After a single intravenous dose (20 mg/kg) prior to multiple oral doses, urinary excretion of L-carnitine was 6974 µmoles equivalent to 75.6% of the intravenously administered dose (uncorrected for endogenous urinary excretion).

See WARNINGS, CONTRAINDICATIONS, and PRECAUTIONS.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

LEVOCARNITINE - INJECTION

(lee-voh-KAR-nih-teen)

COMMON BRAND NAME(S): Carnitor

USES: This medication is used to prevent and treat low blood levels of carnitine. Carnitine is a substance made in the body from meat and dairy products. It helps the body use certain chemicals (long-chain fatty acids) for energy and to keep you in good health. Low blood levels of carnitine may occur in people whose bodies cannot properly use carnitine from their diets, people on dialysis due to serious kidney disease, and people being treated with certain drugs (e.g., valproic acid, zidovudine). Carnitine levels that are too low can cause liver, heart, and muscle problems.

The injectable form of this drug is recommended if you have serious kidney disease (e.g., ESRD/dialysis) because high doses of the form taken by mouth may increase the risk of serious side effects. Consult your doctor or pharmacist for details.

HOW TO USE: This medication is given into a vein by slow injection or through an IV, usually by a health care professional.

Follow all instructions for proper mixing with the correct IV fluids. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. If you have any questions about the use of this medication, consult your pharmacist.

The dosage is based on your weight, medical condition, and response to therapy.

Learn how to store and discard needles and medical supplies safely. Consult your pharmacist.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Upset stomach, nausea, vomiting, diarrhea, headache, muscle pain/weakness, swelling of hands/lower legs/feet, tingling skin, or body odor ("fishy" smell) may occur. If any of these effects persist or worsen, contact your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using levocarnitine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, seizures.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood chemistries, vital signs, serum carnitine levels) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the unmixed solution at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. After mixing with IV fluids, store the IV mixture at room temperature and use/discard within 24 hours. Discard any unused portion of the vial immediately. Do not freeze. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.