Levocarnitine Paediatric 30 % oral solution

Oral solution. Clear, colourless to yellowish solution with cherry odour.

4.1 Therapeutic indications Indicated for the treatment of primary and secondary carnitine deficiency in children of under 12 years, infants and newborns.4.2 Posology and method of administration **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. **Method of administration** For oral administration only. An oral syringe and a bottle adaptor are provided with the pack. The adaptor should be inserted in the bottle before use. The paediatric solution can be drunk directly or diluted further with water or fruit juices. If diluted, it should be drunk within 40 minutes of preparation.4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.4.4 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 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** *Sorbitol* The 30% oral solution contains sorbitol. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. *Sodium methyl parahydroxybenzoate (E219)* This medicinal product contains approximately 1 mg sodium methyl parahydroxybenzoate per ml. Sodium methyl parahydroxybenzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old). May cause allergic reactions (possibly delayed). *Sucrose* This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. It may be harmful to the teeth. *Sodium* This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.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 levocarnitine and coumarinic drugs (see sections 4.4 and 4.8).4.6 Fertility, pregnancy and lactation **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. Levocarnitine should only be used by nursing mothers if benefit to the mother outweighs any potential risks to the child from excess carnitine exposure. **Fertility** In three small clinical studies conducted on fertility, no safety issues were identified, however further studies are required to evaluate the effect of levocarnitine on fertility.4.7 Effects on ability to drive and use machines Levocarnitine Paediatric has no influence on the ability to drive and use machines.4.8 Undesirable effects Adverse reactions from any source are listed in the table below by MedDRA 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 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.4.9 Overdose There have been no reports of toxicity from levocarnitine overdosage. Overdosage should be treated with supportive care.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Amino acids and derivatives, ATC code: A16AA01. **Pharmacodynamic effects** 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 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.5.3 Preclinical safety data 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.

6.1 List of excipients Sorbitol solution (70%) (E420) Sodium methyl parahydroxybenzoate (E219) Sucrose Sucralose (E955) Cherry flavour (including propylene glycol) Sodium hydroxide (E524) Tartaric acid (E334) Tartaric acid 30 % w/w (E334) (for pH adjustment) Purified Water6.2 Incompatibilities None known.6.3 Shelf life 36 months 20 ml bottle: Discard after 30 days of first opening. 40 ml and 100 ml bottle: Discard after 60 days of first opening.6.4 Special precautions for storage This medicinal product does not require any special storage conditions.6.5 Nature and contents of container Amber glass (Type III) bottle or a white HDPE bottle containing either 20 ml, 40 ml or 100 ml of oral solution with a child proof cap with a tamper evident closure. A 2 ml graduated oral syringe and a bottle adaptor are provided with the 20 ml pack size. A 5 ml graduated oral syringe and a bottle adaptor are provided with the 40 ml or 100 ml pack sizes. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements.