LEVOCARNITINE INJECTION USP 1G/5ML TAJ PHARMA
  1. DESCRIPTION

Levocarnitine is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane.

The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N, N, N-trimethyl-1-propanaminium, inner salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone. The specific rotation of levocarnitine is between –29° and –32°. Its chemical structure is:

 

 

Levocarnitine injection, USP is a sterile aqueous solution containing 1 g of levocarnitine per 5 mL vial, and water for Injection q.s. The pH is adjusted to 6 to 6.5 with hydrochloric acid.

2.      CLINICAL PHARMACOLOGY

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 levocarnitine. 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.1-6

Secondary carnitine deficiency can be a consequence of inborn errors of metabolism. Levocarnitine 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.7,8 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 20 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.

3.      PHARMACOKINETICS

In a relative bioavailability study in 15 healthy adult male volunteers levocarnitine  tablets  were found to be bio-equivalent to levocarnitine oral solution. Following 4 days of dosing with 6 tablets of

levocarnitine 330 mg b.i.d. or 2 g of levocarnitine oral solution twice daily, the maximum plasma concentration (Cmax) was about 80 μmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.

The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of levocarnitine were described by a two-compartment model. Following a

single intravenous administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0 to 24 hour 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.

The absolute bioavailability of levocarnitine from the two oral formulations of levocarnitine, calculated after correction for circulating endogenous plasma concentrations  of levocarnitine, was  15.1%  ± 5.3% for levocarnitine tablets and 15.9% ± 4.9% for levocarnitine oral solution.

Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean 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.9

METABOLISM AND EXCRETION

In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H- methyl]-L-carnitine following 15 days of a high carnitine  diet and additional carnitine  supplement, 58% to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days.

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]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4% to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10

After attainment of steady state  following  4  days  of oral administration of levocarnitine  tablets  (1980 mg every 12 hours) or oral solution (2000 mg every 12 hours) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12 hours) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

None known.

WARNINGS

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, laryngeal edema,  and  bronchospasm have been reported following levocarnitine administration, mostly in patients with end stage renal  disease who are undergoing dialysis. Some reactions occurred within minutes  after intravenous  administration of levocarnitine.

If a severe hypersensitivity reaction occurs, discontinue levocarnitine treatment and initiate appropriate medical treatment. Consider the risks and benefits of re-administering levocarnitine 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.

PRECAUTIONS

Drug Interactions

Reports of INR increase with the use of warfarin have  been observed. It is  recommended that INR levels be monitored in patients on warfarin therapy after the initiation of treatment with levocarnitine or after dose adjustments.

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

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

See DOSAGE AND ADMINISTRATION.

  1. 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.

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).

OVERDOSAGE

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.

5.      DOSAGE AND ADMINISTRATION

Levocarnitine Injection, USP 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 every 3 hours or every 4  hours, and never  less than every 6 hours 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.

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

6.      COMPATIBILITY AND STABILITY

Levocarnitine Injection, USP 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.

  1. MANUFACTURED IN INDIA BY:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

PACKAGE LEAFLET: INFORMATION FOR THE USER

LEVOCARNITINE INJECTION USP
1G/5ML
TAJ PHARMA
Read all of this leaflet carefully before you start taking this medicine.
·         Keep this leaflet. You may need to read it again
·         If you have any further questions, ask your doctor or pharmacist
·         This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours
·         If any of the side effects get serious, or you notice any side effects not listed in this leaflet please tell your doctor or pharmacist.
·         In this leaflet Levocarnitine Injection USP 1g/5ml Taj Pharma Injection will be called Levocarnitine Injection USP 1g/5ml Taj Pharma injection.
IN THIS LEAFLET:
  1. What Levocarnitine Injection USP 1g/5ml Taj Pharma injection is and what it is used for
  2. Before you are given Levocarnitine Injection USP 1g/5ml Taj Pharma injection
  3. How you will be given Levocarnitine Injection USP 1g/5ml Taj Pharma injection
  4. Possible side effects
  5. How to store Levocarnitine Injection USP 1g/5ml Taj Pharma injection
  6. Further information

1.   WHAT LEVOCARNITINE INJECTION USP 1G/5ML TAJ PHARMA INJECTION IS AND WHAT IT IS USED FOR

Levocarnitine Injection USP 1g/5ml Taj Pharma injection contains levocarnitine which is a type of protein. It is used to treat primary and secondary carnitine deficiency in adults, children, infants and newborn children. It can also be used to treat secondary carnitine deficiency in haemodialysis patients.

Carnitine deficiency occurs when the body has a shortage of levocarnitine. Levocarnitine Injection USP 1g/5ml Taj Pharma injection makes up for your bodies lack of levocarnitine and helps give your body more energy.

2.   BEFORE YOU ARE GIVEN LEVOCARNITINE INJECTION USP 1G/5ML TAJ PHARMA INJECTION
Do not take Levocarnitine Injection USP 1g/5ml Taj Pharma injection:

-if you are allergic to levocarnitine or any other ingredients in Levocarnitine Injection USP 1g/5ml Taj Pharma injection. These ingredients are listed in section 6 of this leaflet. If this applies to you, do not take Levocarnitine Injection USP 1g/5ml Taj Pharma injection.

Tell your doctor before you are given Levocarnitine Injection USP 1g/5ml Taj Pharma injection if:
  • you have severe kidney problems or kidney disease and are having dialysis
  • you are diabetic and taking insulin, or any other drug to treat your diabetes
  • you are taking anticoagulant medicine, such as warfarin, or any other drug to reduce blood clotting.

If any of the above applies to you, talk to your doctor or pharmacist.

Taking other medicines

Tell your doctor if you are taking anticoagulant medicine, such as warfarin, or any other drug to reduce blood clotting. Your doctor may need to change how often you are tested to see how fast your blood clots.

Tell your doctor if you are taking or have recently taken any other medicines, including those obtained without a prescription.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, think you may be pregnant or if you become pregnant while having Levocarnitine Injection USP 1g/5ml Taj Pharma injection. Your doctor will decide whether or not you should continue to have your medicine. If you wish to breastfeed, ask your doctor for advice.

Driving and using machines

You can drive or use machines whilst taking Levocarnitine Injection USP 1g/5ml Taj Pharma injection.

3.     HOW YOU WILL BE GIVEN LEVOCARNITINE INJECTION USP 1G/5ML TAJ PHARMA

How much Levocarnitine Injection USP 1g/5ml Taj Pharma injection will you be given
Your doctor will carefully calculate the amount of Levocarnitine Injection USP 1g/5ml Taj Pharma injection that you should be given and may vary it depending on your response to the treatment. The doctor may take blood and urine samples to check the amount of the drug in your body.
Method of administration

Your doctor will give the injection slowly into your vein (intravenous injection) over a period of 2-3 minutes.

Primary carnitine deficiency

The usual recommended dose is 100 mg per kg of your body weight per day. This will be given in 3-4 doses.

Secondary carnitine deficiency in haemodialysis patients (dialysis of the blood)

A dose of 20 mg per kg of your body weight should be given in the same way as above at the end of each dialysis session (assuming three sessions per week). The treatment should last at least three months, which is the time required to restore normal muscle levels of free carnitine. If significant benefit is seen following this first course of treatment ongoing therapy using 1 g per day of Levocarnitine Injection USP 1g/5ml Taj Pharma Oral Solution may be used.  On the day of dialysis Levocarnitine Injection USP 1g/5ml Taj Pharma Oral Solution should be taken at the end of the dialysis session.

If you are given more Levocarnitine Injection USP 1g/5ml Taj Pharma injection than you should
If you think you have been given too much Levocarnitine Injection USP 1g/5ml Taj Pharma injection tell your doctor.

If you have any further questions about taking this medicine, please ask your doctor or pharmacist.

4.           POSSIBLE SIDE EFFECTS

Like all medicines Levocarnitine Injection USP 1g/5ml Taj Pharma injection can cause side effects, although not everybody gets them.

 

Side effects are:

-Drug-related body odour. Your doctor may reduce your dose to help lessen or stop the odour.

-For people also taking anticoagulant medicine, such as warfarin, tests may show your blood is taking longer than usual to clot.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any side effects not listed in this leaflet. By reporting side affects you can help provide more information on the safety of this medicine.

5.           HOW TO STORE LEVOCARNITINE INJECTION USP 1G/5ML TAJ PHARMA INJECTION

Keep out of the reach and sight of children.

Do not use Levocarnitine Injection USP 1g/5ml Taj Pharma injection after the expiry date stated on the sealed glass ampoule. The expiry date refers to the last day of that month.

Store below 25°C and protect from light.

Medicines should not be disposed of via wastewater or in household waste. Return any medicine you no longer need to the pharmacist.

6.     FURTHER INFORMATION

What Levocarnitine Injection USP 1g/5ml Taj Pharma injection contains

-The active substance is levocarnitine inner salt. Each Levocarnitine Injection USP 1g/5ml Taj Pharma injection contains 1 g levocarnitine in each 5 ml sealed glass container (ampoule).

-The other ingredients are hydrochloric acid 10% and water for injection.

What Levocarnitine Injection USP 1g/5ml Taj Pharma injection looks like and contents of the pack

Levocarnitine Injection USP 1g/5ml Taj Pharma injection is a clear, colourless or light straw-coloured liquid. It comes in 5 ml clear sealed glass containers (ampoules). There are 5 ampoules in each pack of Levocarnitine Injection USP 1g/5ml Taj Pharma injection.

  1. MANUFACTURED IN INDIA BY:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com