VEDROP 50mg / ml oral solution medication leaflet

Vedrop 50 mg/ml oral solution

Each ml contains 50 mg of d-alpha-tocopherol, in the form of tocofersolan, corresponding to 74.5 IU oftocopherol.

Each ml contains 6 mg sodium methyl parahydroxybenzoate (E219), 4 mg sodium ethylparahydroxybenzoate (E215) and 0.18 mmoles (4.1 mg) of sodium.

For the full list of excipients, see section 6.1.

Oral solution.

Slightly viscous, pale yellow solution.

Vedrop is indicated in vitamin E deficiency due to digestive malabsorption in paediatric patients withcongenital chronic cholestasis or hereditary chronic cholestasis, from birth (full term newborns) up to 18years of age.

The treatment with Vedrop should be initiated and supervised by a physician experienced in themanagement of patients suffering from congenital chronic cholestasis or hereditary chronic cholestasis.

Bioavailability of vitamin E from Vedrop differs from that of other medicinal products. The dose should beprescribed in mg of d-alpha-tocopherol in the form of tocofersolan. Plasma vitamin E level should bemonitored monthly for at least the first few months of therapy, thereafter at regular intervals and the doseadjusted accordingly if necessary.

The recommended total daily dose in paediatric patients suffering from congenital chronic cholestasis orhereditary chronic cholestasis is 0.34 ml/kg/day (17 mg/kg of d-alpha-tocopherol in the form oftocofersolan). The dose should be prescribed in ml.

The dose should be adjusted according to plasma vitamin E level.

To calculate the dose of Vedrop to be administered, divide the prescribed dose of d-alpha-tocopherol (in mg)by 50. The result is the volume of Vedrop in ml:

Dose of Vedrop (in ml) = dose of d-alpha-tocopherol (in mg)

The following table gives the volume of oral solution in function of patients’ weights.

Weight (kg) Oral solution volume (ml)3 1.04 1.45 1.76 2.07 2.48 2.79 3.110 3.415 5.1

Hepatic or renal impairment

Experience with tocofersolan therapy in patients with renal impairment or underlying liver impairment hasdemonstrated no need to adapt the dose regimen of Vedrop (see section 4.4).

Vedrop is administered orally with or without water. The 1-ml or 2-ml oral syringes included in thecontainer are designed to assist in measuring out the exact dose in accordance with the prescribed posology.

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

Vedrop must not be used in preterm newborn infants.

As large doses of vitamin E have been reported to increase bleeding tendency in vitamin-K deficient patientsor those taking oral anti-vitamins K treatment, it is therefore recommended to monitor the prothrombin timeand international normalised ratio (INR). A possible adjustment of the dose of oral anticoagulant during andafter treatment with Vedrop may be necessary.

As data on patients with renal impairment are limited, Vedrop should be administered with caution andunder close monitoring of the renal function in patients with renal impairment e.g. dehydrated patients (seesection 4.2).

Vedrop should be administered with caution in patients with underlying liver impairment and under closemonitoring of the hepatic functions in such patients (see section 4.2).

Vedrop contains sodium methyl parahydroxybenzoate (E219) and sodium ethyl parahydroxybenzoate(E215) which may cause allergic reactions (possibly delayed).

This medicinal product contains sodium. It should be taken into consideration by patients on a controlledsodium diet.

No interaction studies have been performed.

It is recommended to monitor the coagulation function when administered with anti-vitamins K treatment(see section 4.4).

Due to inhibition of P-Glycoprotein transporter, tocofersolan may also enhance intestinal absorption of otherconcomitant fat-soluble vitamins (A, D, E, K) or that of highly lipophilic medicinal products (such assteroids, antibiotics, antihistamines, cyclosporine, tacrolimus). Therefore, monitoring should be performedand, when necessary, doses should be adjusted.

For tocofersolan no clinical data on exposed pregnancies are available. Animal studies do not indicate director indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

It is unknown whether tocofersolan is excreted in human breast milk. The excretion of tocofersolan in milkhas not been studied in animals. A decision on whether to continue/discontinue breast-feeding or tocontinue/discontinue therapy with Vedrop should be made taking into account the benefit of breast-feedingto the child and the benefit of tocofersolan therapy to the woman.

No data is available

Vedrop has no or negligible influence on the ability to drive and use machines.

The most commonly reported adverse reaction during treatment is diarrhoea.

Reported adverse reactions are listed below, by system organ class and by frequency.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to< 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from theavailable data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class Adverse reactions

Gastrointestinal disorders Common: diarrhoea

Not known: abdominal pain

Skin and subcutaneous tissue disorders Uncommon: alopecia, pruritus, rash

General disorders and administration site Uncommon: asthenia, headacheconditions

Investigations Uncommon: serum sodium abnormal, serum potassiumabnormal, transaminases increase

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Large vitamin E doses may cause diarrhoea, abdominal pain, and other gastrointestinal disturbances.

In case of overdose, a symptomatic treatment should be proposed.

Pharmacotherapeutic group: Vitamins, Other plain vitamin preparations; ATC code: A11HA08

Vitamin E is the principal lipo-soluble antioxidant in the organism. It acts as a free radical chain breakingmolecule, stopping the peroxidation of polyunsaturated fatty acids and it is involved in maintaining thestability and integrity of cell membranes.

This medicinal product has been authorised under “exceptional circumstances”. This means that due to therarity of the disease it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency will review any new information which may become available every yearand this SmPC will be updated as necessary.

The active substance d-alpha-tocopherol-polyethylene glycol 1000 succinate (tocofersolan) is a pro-drug; theactive metabolite is the d-alpha-tocopherol. At low concentrations, tocofersolan forms micelles whichenhance absorption of non-polar lipids such as fat-soluble vitamins. Its critical micellar concentration is low(0.04 to 0.06 mmol/l).

The hydrolysis of tocofersolan occurs in the gut lumen. Taken up by cells, the alpha-tocopherol moietyappears in chylomicrons in the lymph in a manner identical to vitamin E absorbed from the diet. Cellularuptake does not require receptors, binding proteins or metabolic processes and does not occur bypinocytosis. Absorption of deuterated tocofersolan showed a normal pattern in lipoproteins: alpha-tocopherol peaked first in chylomicrons, then in very low- density lipoproteins (VLDL) and finally in low-density lipoproteins (LDL) and high-density lipoproteins (HDL), and the disappearance portions of thecurves paralleled those in control subjects.

A study in 12 healthy volunteers compared tocofersolan with a water-miscible reference vitamin E after asingle oral loading dose of 1200 IU. The relative bioavailability of tocofersolan tended to be higher (Frel of1.01 ± 1.74) with AUC0-t of 0.383 ± 0.203µM.h/mg, Cmax of 0.013 ± 0.006, tmax of 6.0 h (6.0 - 24.0), and t1/2of 29.7 h (16.0 - 59.5).

In a similar study tocofersolan showed a higher bioavailability than a water-miscible reference vitamin E inpaediatric patients with chronic cholestasis (n=6), absorption was significantly higher on both plasmaconcentration maximum increase (p=0.008) and AUC (p=0.0026).

Located principally on cell membranes, within mitochondria and microsomes, vitamin E is ubiquitouslydistributed (red blood cells, brain, muscle, liver, platelets) and fat tissues are its major reservoir.

Vitamin E is mainly eliminated in the bile (75%) and stools, either as free tocopherol or as oxidized forms.

Urine represents a minor elimination route of vitamin E (as glucuro-conjugate).

Non-clinical data in the literature reveal no special hazard for humans based on conventional studies ofrepeated dose toxicity, genotoxicity and toxicity to reproduction.

Potassium sorbate

Sodium methyl parahydroxybenzoate (E219)

Sodium ethyl parahydroxybenzoate (E215)

Glycerol

Disodium phosphate dodecahydrate

Concentrated hydrochloric acid

Purified water

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years.

After first opening the bottle: 1 month.

This medicinal product does not require any special storage conditions.

Type III brown glass bottle with a child-resistant screw cap of HDPE and LDPE seal. Oral syringes withhousing of LDPE and piston of polystyrol. Each bottle contains 10 ml, 20 ml or 60 ml of oral solution.

Boxes containing: one 10 ml bottle and one 1 ml oral syringe one 20 ml bottle and one 1 ml oral syringe one 60 ml and one 2 ml oral syringe

Not all pack sizes may be marketed.

Doses for administration should be extracted from the bottle using the oral syringes which are provided inthe pack.

The 1 ml oral syringe is graduated from 0.05 to 1 ml in steps of 0.05 ml. One graduation of the 1 ml oralsyringe corresponds to 2.5 mg of d-alpha-tocopherol in the form of tocofersolan.

The 2 ml oral syringe is graduated from 0.1 to 2 ml in steps of 0.1 ml. One graduation of the 2-ml oralsyringe corresponds to 5 mg of d-alpha-tocopherol in the form of tocofersolan.

Recordati Rare Diseases

Tour Hekla52 avenue du Général de Gaulle92800 Puteaux

France

EU/1/09/533/001 10ml bottle

EU/1/09/533/002 20ml bottle

EU/1/09/533/003 60ml bottle

Date of first authorisation: 24 July 2009

Date of latest renewal: 23 April 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu