Levocarnitine Paediatric 30% Oral Solution

Levocarnitine 30% w/v (300mg/ml)

Excipients with known effect

Sorbitol solution (70%) (E420)

Sodium propyl hydroxybenzoate (E217)

Sodium methyl hydroxybenzoate (E219)

Sucrose

Hydrochloric acid, concentrated (for pH-adjustment)(E507)

For the full list of excipients, see section 6.1.

Oral solution.

Colourless to yellowish, clear solution

Levocarnitine Paediatric 30% Oral Solution is indicated for the treatment of primary and secondary carnitine deficiency in children of under 12 years, infants and newborns.

Posology

Children under 12 years, infants and newborns

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.

An oral dosage of up to 200mg/kg/day in divided doses (2 to 4) is recommended for chronic use in some disorders, with lower doses sufficing in other conditions. If clinical and biochemical symptoms do not improve, the dose may be increased on a short-term basis. Higher doses of up to 400mg/kg/day may be necessary in acute metabolic decompensation or the i.v. route may be required.

Haemodialysis - maintenance therapy

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

Maximum dose for children is 1g daily if used as a maintenance therapy for secondary deficiency in dialysis patients

Method of administration

For oral administration only. The Paediatric Solution can be drunk directly or diluted further in water or fruit juices

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 levocarnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine 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 levocarnitine.

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

Excipients

The 30% oral solution contains sucrose and sorbitol. This must be considered when treating diabetics or patients who are following diets to reduce calorie intake. Patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

The 30% oral solution contains Sodium propyl hydroxybenzoate (E217) and Sodium methyl hydroxybenzoate (E219). It may cause hypersensitivity (anaphylactoid) reactions (possibly delayed).

There have been very rare reports of International Normalised Ratio (INR) increased in patients treated concomitantly with levocarnitine 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 levocarnitine.

Pregnancy

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 (600mg/kg daily) as compared with control animals. The significance of these findings in man is unknown. There is no experience of use in pregnant patients with primary systemic carnitine deficiency.

Taking into account the serious consequences in 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.

Breast-feeding

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

None known

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).

* There have been very rare reports of International Normalised Ratio (INR) increased in patients treated concomitantly with levocarnitine and coumarinic drugs (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 - Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

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

Pharmacotherapeutic group: Amino acids and derivatives, ATC Code: A16AA01.

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 Lisomer 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 utilization of fatty acids and ketone bodies but also that of glucose and some amino acids.

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 depend on several metabolic processes, carnitine bio-synthesis and dietary contributions, transport into and out of tissues, degradation and excretion may all affect tissue carnitine concentrations.

It has been demonstrated that pharmacokinetic parameters increase significantly with dosage. Apparent bioavailability in healthy volunteers is about 10-16%. The data suggests a relationship between maximal plasma concentration/dosage, dosage, plasma AUC, dosage/urinary accumulation. Maximum concentration is reached about four hours after ingestion.

Levocarnitine is a naturally occurring body substance in human beings, plants and animals. Levocarnitine 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.

Sorbitol solution (70%) (E420)

Sodium propyl hydroxybenzoate (E217)

Sodium methyl hydroxybenzoate (E219)

Sucrose

Hydrochloric acid,concentrated (E507) (for pH-adjustment)

None known.

2 years.

Discard 30 days after first opening

Store below 25 ° C.

Carton box that contains an amber glass bottle with 20ml of drug product, with a plastic polypropylene and low density polyethylene child proof cap and a graduated dosage pipette, along with the patient information leaflet.

No special requirements for disposal.

Cenoté Pharma Ltd.

Griffins Court

24-32 London Road

Newbury, Berkshire

RG14 1JX

UK

PL 46052/0001

11/01/2018

18/04/2018