Generic Name: levocarnitine

Brand Names: L-Carnitine, Levocarnitine Novaplus, Carnitor

Uses

Primary Systemic Carnitine Deficiency

Orally for treatment of primary systemic carnitine deficiency, in addition to supportive and other therapy as indicated by the patient’s condition; designated an orphan drug by FDA for this use.

Secondary Carnitine Deficiency Resulting from an Inborn Error of Metabolism

Orally and parenterally for acute or chronic treatment in patients with secondary carnitine deficiency resulting from an inborn error of metabolism; designated an orphan drug by FDA for this use.

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Dialysis

Parenterally for prevention and treatment of carnitine deficiency in patients with end-stage renal disease undergoing dialysis (dialysis-related carnitine disorder); designated an orphan drug by FDA for this use.

Effects of supplemental carnitine on manifestations of carnitine deficiency and on clinical outcomes in patients with end-stage renal disease undergoing dialysis not determined.

Dosage and Administration

General

• Secondary Carnitine Deficiency Associated with an Inborn Error of Metabolism.
• Obtain plasma carnitine concentrations prior to initiation of parenteral therapy.
• Perform weekly and monthly monitoring of blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition of patient.
• Plasma free carnitine concentrations should be 35–60 mcmol/L.
• End-stage Renal Disease Patients undergoing Hemodialysis
• Obtain blood levocarnitine concentrations prior to therapy to establish levocarnitine deficiency.
• Some experts recommend evaluating clinical response at 3-month intervals following initiation of drug, considering dosage adjustment to lowest effective dosage once desired outcome for specific manifestation has been attained, and discontinuing drug if clinical improvement has not occurred within 9–12 months.

Administration

Administer orally (as a solution or tablets), by direct IV injection, or by IV infusion.

Oral Administration

Solutions may be administered alone or dissolved in beverages or other liquid foods to reduce taste fatigue. Slowly administer solution in evenly spaced doses throughout the day (i.e., at least 3 or 4 hours apart), preferably during or following meals, to maximize tolerance; adverse GI reactions may result from rapid administration of solution.

Periodically monitor blood chemistries, vital signs, plasma carnitine concentrations, and overall clinical condition of patient.

Closely monitor tolerance to drug during first week of administration and following any dosage increases.

IV Administration

For solution compatibility information, see Compatibility under Stability.

Vials are for single use only.

Rate of Administration

Secondary carnitine deficiency associated with an inborn error of metabolism, direct IV injection: Slowly over 2–3 minutes.

Carnitine deficiency in patients with end-stage renal disease undergoing dialysis, direct IV injection: Slowly over 2–3 minutes into the venous return line after each dialysis session.

Dosage

Decreasing the dosage of oral levocarnitine may diminish or eliminate drug-related patient body odor or GI symptoms if present.

Pediatric Patients

Primary Systemic Carnitine Deficiency

Oral

Pediatric patients (≤18 years of age): Initially, 50 mg/kg daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart); slowly increase dosage while assessing tolerance and therapeutic response. (See General and also Administration, under Dosage and Administration.)

Usual recommended dosage range is 50–100 mg/kg daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart), up to a maximum total daily dosage of 3 g.

Exact dosage based on clinical response. Administer increased dosages with caution and only when clinical and biochemical considerations make it seem likely that increased dosages will be of benefit.

Secondary Carnitine Deficiency Associated with an Inborn Error of Metabolism

Oral

Pediatric patients (≤18 years of age): Initially, 50 mg/kg daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart); slowly increase dosage while assessing tolerance and therapeutic response. (See General and also Administration, under Dosage and Administration.)

Usual recommended dosage range is 50–100 mg/kg daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart), up to a maximum total daily dosage of 3 g.

Exact dosage depends on clinical response. Administer increased dosages with caution and only when clinical and biochemical considerations make it seem likely that increased dosages will be of benefit.

IV

Pediatric patients (≤18 years of age): 50 mg/kg every 3 or 4 hours administered by slow, direct IV injection over 2–3 minutes or by IV infusion; do not administer less frequently than every 6 hours. Subsequent total daily dosage of approximately 50 mg/kg, adjusted as required and given in divided doses (i.e., every 3 or 4 hours), is recommended.

In pediatric patients (≤18 years of age) with severe metabolic crisis, a loading dose has often been administered, followed by an equivalent dose over the following 24 hours. These patients underwent close supervision and monitoring of plasma levocarnitine concentrations, with subsequent dosage adjusted accordingly. In individual case reports, highest total daily dosage administered has been 300 mg/kg.

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Dialysis

IV

Pediatric patients (≤18 years of age): Initially, 10–20 mg/kg (preferably 10 mg/kg) of dry body weight administered by slow, direct IV injection over 2–3 minutes into the venous return line after each dialysis session.

Initiation of therapy may be prompted by trough (i.e., predialysis) plasma levocarnitine concentrations that are below normal (40–50 mcmol/L).

Adjust dosage based on trough (i.e., predialysis) plasma levocarnitine concentrations; dosage reductions (e.g., to 5 mg/kg after dialysis) may be initiated as early as the third or fourth week of therapy.

Adults

Primary Systemic Carnitine Deficiency

Therapy with Levocarnitine Tablets

Oral

990 mg 2 or 3 times daily, depending on clinical response.

Therapy with Levocarnitine Oral Solution

Oral

Initially, 1 g daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart); slowly increase dosage while assessing tolerance and therapeutic response. (See General and also Administration, under Dosage and Administration.)

Usual recommended dosage range for a 50-kg patient is 1–3 g daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart).

Administer increased dosages with caution and only when clinical and biochemical considerations make it seem likely that increased dosages will be of benefit.

Secondary Carnitine Deficiency Resulting from an Inborn Error of Metabolism

Therapy with Levocarnitine Tablets

Oral

990 mg 2 or 3 times daily, depending on clinical response.

Therapy with Levocarnitine Oral Solution

Oral

Initially, 1 g daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart); slowly increase dosage while assessing tolerance and therapeutic response. (See General and also Administration, under Dosage and Administration.)

Usual recommended dosage range for a 50-kg patient is 1–3 g daily, given in 2 or 3 divided doses (administer each dose at least 3 or 4 hours apart).

Administer increased dosages with caution and only when clinical and biochemical considerations make it seem likely that increased dosages will be of benefit.

IV

50 mg/kg every 3 or 4 hours administered by slow, direct IV injection over 2–3 minutes or by IV infusion; do not administer less frequently than every 6 hours. Subsequent total daily dosage of approximately 50 mg/kg, adjusted as required and given in divided doses (i.e., every 3 or 4 hours), is recommended.

In patients with severe metabolic crisis, a loading dose often has been administered, followed by an equivalent dose during the following 24 hours. These patients underwent close supervision and monitoring of plasma levocarnitine concentrations, with subsequent dosage adjusted accordingly. In individual case reports, highest total daily dosage administered has been 300 mg/kg.

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Diaysis

IV

Initially, 10–20 mg/kg of dry body weight administered by slow, direct IV injection over 2–3 minutes into the venous return line after each dialysis session.

Initiation of therapy may be prompted by trough (i.e., predialysis) plasma levocarnitine concentrations that are below normal (40–50 mcmol/L).

Adjust dosage based on trough (i.e., predialysis) plasma levocarnitine concentrations; dosage reductions (e.g., to 5 mg/kg after dialysis) may be initiated as early as the third or fourth week of therapy.

Prescribing Limits

Pediatric Patients

Primary Carnitine Deficiency

Oral

Pediatric patients (≤18 years of age): In individual case reports, maximum 3 g daily.

Secondary Carnitine Deficiency Associated with an Inborn Error of Metabolism

Oral

Pediatric patients (≤18 years of age): In individual case reports, maximum 3 g daily.

IV

Pediatric patients (≤18 years of age): In individual case reports, total daily dosage of up to 300 mg/kg has been administered.

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Dialysis

IV

Doses >20 mg/kg have not been shown to provide additional benefit.

Adults

Secondary Carnitine Deficiency Associated with an Inborn Error of Metabolism

IV

In individual case reports, total daily dosage of up to 300 mg/kg has been administered.

Carnitine Deficiency in Patients with End-stage Renal Disease Undergoing Dialysis

IV

Doses >20 mg/kg have not been shown to provide additional benefit.

Special Populations

No special population dosage recommendations at this time. (See Renal Impairment under Cautions.)

Cautions

Contraindications

Manufacturer states none known.

Warnings/Precautions

Specific Populations

Pregnancy

Category B.

Lactation

Distributed into milk in cows; not known whether levocarnitine distributes into human milk. Consider discontinuance of nursing or the drug.

Pediatric Use

Dosage of levocarnitine in pediatric patients ≤18 years of age was based on specific patient case record observations rather than on studies that specifically defined age by protocol.

Renal Impairment

Safety and efficacy of oral levocarnitine not established in patients with renal impairment.

Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in patients with end-stage renal disease undergoing dialysis may result in accumulation of potentially toxic metabolites, trimethylamine (TMA) and trimethyloxamine (trimethylamine-N-oxide [TMAO]), since these metabolites are normally excreted in urine.

Safety of IV levocarnitine has been established in patients with end-stage renal disease.

Common Adverse Effects

Oral therapy: Transient nausea and vomiting, abdominal cramps, diarrhea, body odor.

Parenteral therapy: Transient nausea and vomiting, body odor, gastritis. Patients on chronic hemodialysis may experience injection site reactions, headache, pain, diarrhea, flu syndrome, pharyngitis, infection, hypertension, vomiting, abdominal pain, hypotension, dizziness, increased cough, chest pain, hypercalcemia, accidental injury, asthenia, nausea, fever, anemia, hypervolemia, paresthesia, rhinitis, or dyspnea.

Seizures reported in patients, with or without preexisting seizure activity, receiving either oral or IV levocarnitine. Increased seizure frequency and/or severity also reported in patients with preexisting seizure activity.

Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is about 15–16% following oral administration and correction for endogenous plasma levocarnitine concentrations.

Peak plasma concentrations attained 3.3–3.4 hours following oral administration.

Distribution

Extent

Rate and extent of distribution from plasma into erythrocytes appear to be minor or negligible.

Plasma Protein Binding

Does not appear to bind to plasma proteins or albumin.

Elimination

Metabolism

Metabolized principally to TMAO and γ-butyrobetaine in GI tract by bacteria.

Elimination Route

In healthy adults, approximately 9% of dose excreted in urine as levocarnitine (uncorrected for endogenous urinary excretion) following oral administration.

Approximately 58–65% of a dose excreted (as levocarnitine and metabolites) in urine and feces in 5–11 days following oral administration of radiolabeled drug to patients receiving a high carnitine diet and additional carnitine supplements for 15 days. About 4–8 and <1% of administered radiolabeled dose excreted in urine as levocarnitine and in feces as total carnitine, respectively. TMAO principally excreted in urine (8–49% of administered radiolabeled dose) and γ-butyrobetaine principally excreted in feces (0.44–45% of administered radiolabeled dose).

Approximately 76% of dose excreted in urine within 24 hours following direct IV injection.

Half-life

Mean distribution and apparent terminal half-lives are approximately 0.6 and 17.4 hours, respectively, using plasma concentrations uncorrected for endogenous levocarnitine following direct IV injection.

Special Populations

Potentially toxic metabolites, TMA and TMAO, may accumulate in patients with severely compromised renal function or in patients with end-stage renal disease undergoing dialysis. (See Renal Impairment under Cautions.)

Stability

Storage

Oral

Tablets

25°C.

Solution

25°C.

Parenteral

Injection

25°C. Discard unused portions.

IV solutions containing levocarnitine 0.5– 8 mg/mL prepared in 0.9% sodium chloride injection or lactated Ringer’s injection appear to be stable at 25°C for up to 24 hours in PVC plastic bags.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Actions

• Carrier molecule; facilitates long-chain fatty acid entry into cellular mitochondria, and delivers substrate for oxidation and subsequent energy production.
• May promote excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acid metabolic disorders that result in accumulation of acyl-coenzyme A (acyl-CoA) esters.
• In patients with secondary carnitine deficiency, eliminates acyl-CoA compounds by promoting formation of acylcarnitine, which is quickly excreted.
• Increases plasma levocarnitine concentrations in patients with end-stage renal disease undergoing hemodialysis.
• Not demonstrated to be a vitamin; no recommended dietary allowance (RDA) established.

Advice to Patients

• Advise patients to drink levocarnitine oral solution alone or dissolved in beverages or other liquid foods to reduce taste fatigue.
• Advise patients to drink levocarnitine oral solution slowly in evenly spaced doses throughout the day (at least 3 or 4 hours apart).
• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions August 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.