SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Carnitor 1 g Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Levocarnitine 1 g

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

A clear, colourless or light straw- coloured solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Indicated for the treatment of primary and secondary carnitine deficiency in adults, children, infants and neonates.

Secondary carnitine deficiency in haemodialysis patients.

Secondary carnitine deficiency should be suspected in long-term haemodialysis patients who have the following conditions:

1.    Severe and persistent muscle cramps and/or hypotensive episodes during dialysis.

2.    Lack of energy causing a significant negative effect on the quality of life.

3.    Skeletal muscle weakness and/or myopathy.

4.    Cardiomyopathy.

5.    Anaemia or uraemia unresponsive to or requiring large doses of erythropoietin.

6.    Muscle mass loss caused by malnutrition.

4.2    Posology and method of administration

For slow intravenous administration over 2-3 minutes

Adults, Children, infants and neonates:

It is advisable to monitor therapy by measuring free and acyl carnitine levels in both plasma and urine.

The management of inborn errors of metabolism:

The dosage required depends upon the specific inborn error of metabolism concerned and the severity of presentation at the time of treatment. However, the following can be considered as a general guide.

In acute decompensation, dosages of up to 100 mg/kg/day in 3-4 divided doses are recommended. Higher doses have been used although an increase in adverse events, primarily diarrhoea, may occur.

Secondary carnitine deficiency in haemodialysis patients:

It is strongly recommended that, before initiating therapy with Carnitor, plasma carnitine is measured. Secondary carnitine deficiency is suggested by a plasma ratio of acyl to free carnitine of greater than 0.4 and/or when free carnitine concentrations are lower than 20 pmol/litre.

A dose of 20mg per kg should be administered as an intravenous bolus at the end of each dialysis session (assuming three sessions per week). The duration of intravenous treatment should be at least three months, which is the time usually required to restore normal muscle levels of free carnitine. The overall response should be assessed by monitoring plasma acyl to free carnitine levels and by evaluating the patient's symptoms. When carnitine supplementation has been stopped there will be a progressive decline in carnitine levels. The need for a repeat course of therapy can be assessed by plasma carnitine assays at regular intervals and by monitoring the patient's symptoms.

Haemodialysis - maintenance therapy:

If significant clinical benefit has been gained by the first course of intravenous Carnitor then maintenance therapy can be considered using 1 g per day of Carnitor orally. On the day of the dialysis, oral Carnitor has to be administered at the end of the session.

4.3 Contra-indications

Hypersensitivity to any of the constituents of the product.

4.4 Special warnings and precautions for use

While improving glucose utilisation, the administration of levocarnitine to diabetic patients receiving either insulin or hypoglycaemic oral treatment may result in hypoglycaemia. Plasma glucose levels in these subjects must be monitored regularly in order to adjust the hypoglycaemic treatment immediately, if required.

The safety and efficacy of oral levocamitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocamitine in patients with severely compromised renal function or in end stage renal disease (ESRD) patients on dialysis may result in an accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are usually excreted in the urine. This situation has not been observed following intravenous administration of levocamitine.

There have been very rare reports of International Normalised Ratio (INR) increased in patients treated concomitantly with levocamitine and coumarinic drugs. See section 4.5 ‘Interactions’ and Section 4.8 ‘Undesirable Effects’.

4.5 Interaction with other medicinal products and other forms of interaction

There have been very rare reports of International Normalised Ratio (INR) increased in patients treated concomitantly with levocamitine and coumarinic drugs (see Section 4.4 ‘Special Warnings and Precautions’ and Section 4.8 ‘Undesirable Effects’). INR - or other appropriate test of coagulation - should be checked weekly until they become stable, and monthly thereafter, in patients taking such anticoagulants together with levocamitine.

4.6 Pregnancy and Lactation

Reproductive studies were performed in rats and rabbits. There was no evidence of a teratogenic effect in either species. In the rabbit but not in the rat, there was a statistically insignificant greater number of post-implantation losses at the highest dose tested (600 mglkg daily) as compared with control animals. The significance of these findings for man is unknown. There is no experience of use in pregnant patients with primary systemic carnitine deficiency.

Taking into account the serious consequences to a pregnant woman who has primary systemic carnitine deficiency stopping treatment, the risk to the mother of discontinuing treatment seems greater than the theoretical risk to the foetus if treatment is continued.

Levocarnitine is a normal component of human milk. Use of levocarnitine supplementation in nursing mothers has not been studied.

4.7 Effects on Ability to Drive and Use Machines

None known.

4.8 Undesirable effects

Adverse reactions from any source are listed in the table below by MedRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. In addition the corresponding frequency category for each adverse drug reaction is based on the following conventions: very common (>1/10);

common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000).

SYSTEM ORGAN CLASS	FREQUENCY	ADVERSE REACTION
Gastrointestinal disorders	Very rare	Vomiting Nausea Diarrhoea Abdominal cramp
General disorders and administration site conditions	Very rare	Body odour
Investigations	Very rare	International Normalised Ratio increased *

* There have been very rare reports of International Normalised Ratio (INR) increased in patients treated concomitantly with levocarnitine and coumarinic rugs (acenocumarol and warfarin) -see Section 4.4 ‘Special Warnings’ and Section 4.5 ‘Interactions’.

Decreasing the dosage often diminishes or eliminates drug related patient body odour or gastro-intestinal symptoms when present. Tolerance should be monitored very closely during the first week of administration and after any dosage increase.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

There have been no reports of toxicity from levocarnitine overdosage. Overdosage should be treated with supportive care.

5 PHARMACOLOGICAL PROPERTIES

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: A16AA01 (Amino acids and derivatives)

Levocarnitine is present as a natural constituent in animal tissues, micro-organisms and plants. In man the physiological metabolic requirements are met both by the consumption of food containing carnitine

and the endogenous synthesis in the liver and kidneys from lysine with methionine serving as the methyl donor. Only the L-isomer is biologically active, playing an essential role in lipid metabolism as well as in the metabolism of ketone bodies as branched chain-amino-acids. Levocarnitine as a factor is necessary in the transport of long-chain fatty acids into the mitochondria - facilitating the oxidation of fatty acids rather than their incorporation into triglycerides. By releasing CoA from its thioesters, through the action of CoA; carnitine acetyl transferase, levocarnitine also enhances the metabolic flux in the Kreb's cycle; with the same mechanism it stimulates the activity of pyruvate dehydrogenase and in skeletal muscle, the oxidation of branched chain-amino acids. Levocarnitine is thus involved, directly or indirectly in several pathways so that its availability should be an important factor controlling not only the oxidative utilisation of fatty acids and ketone bodies but also that of glucose and some amino acids.

5.2 Pharmacokinetic properties

The absorbed levocarnitine is transported to various organ systems via the blood. The presence of membrane-bound proteins in several tissues including red blood cells that bind carnitine, suggest that a transport system in the blood and a cellular system for the collective uptake is present in several tissues. Tissue and serum carnitine concentration depends on several metabolic processes, carnitine biosynthesis and dietary contributions, transport into and out of tissues, degradation and excretion may all affect tissue carnitine concentrations.

Absorption

Levocarnitine is absorbed by the mucosal cells of the small intestine and enters the blood stream relatively slowly; the absorption is probably associated with an active transluminal mechanism.

The apparent systemic availability after oral administration is limited (<10%) and variable.

Distribution

Absorbed levocarnitine is transported to various organ systems via the blood; it is thought that a transport system in the blood and a cellular system for selective uptake is involved.

Excretion

Levocarnitine is excreted mainly in the urine and is variable. The excretion is directly proportional to the blood levels.

Metabolism

Levocarnitine is metabolised to a very limited extent.

5.3 Preclinical safety data

Levocarnitine is a naturally occurring body substance in human beings, plants and animals. Carnitor products are used to bring the level of levocarnitine in the body up to those found naturally. Appropriate pre-clinical studies have been undertaken and show no signs of toxicity at normal therapeutic doses.

6.1 List of excipients

Hydrochloric acid 10% Water for injection

Incompatibilities

None known.

6.3    Shelf life

5 years.

6.4    Special precautions for storage

Store below 25^oC.

Store in the original carton in order to protect from light.

6.5    Nature and contents    of container

Ph.Eur. Type 1 clear glass ampoules of 5 ml capacity.

The ampoules are packed in cardboard outer cartons containing 5 ampoules.

6.6    Instructions for use,    handling and disposal

None.

ADMINISTRATIVE DATA

7.    MARKETING AUTHORISATION HOLDER

Sigma-Tau Industrie Farmaceutiche Riunite SpA,

Viale Shakespeare 47-00 144,

Rome, Italy.

8.    MARKETING AUTHORISATION NUMBER

PL 0838 1/0003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/02/2007 24/04/2014